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Hydrops-ectopic calcification-moth-eaten skeletal dysplasia	Hydrops-ectopic calcification-moth-eaten skeletal dysplasia is a defect in cholesterol biosynthesis. Greenberg characterized the condition in 1988.It has been associated with the lamin B receptor. Signs and Symptoms Hydrops-ectopic calcification-moth-eaten skeletal dysplasia causes the bones in a fetus to develop abnormally. This leads to a characteristic "moth eaten" appearance of the bones when viewed under an X-ray. Micromelia, polydactyly and ectopic calcification, or the built up of calcium in the soft tissues of the body, may all occur. Eighty to ninety nine percent of effected individuals will have abnormally ossified vertebrae, abnormal pelvis bone ossification, anterior rib punctate calcifications and brachydactyly.The second defining feature of hydrops-ectopic calcification-moth-eaten skeletal dysplasia is hydrops fetalis. A condition wherein an abnormal buildup of fluids occurs in the tissues of a fetus. See also Ectopic calcification Hydrops References == External links ==
Flail chest	Flail chest is a life-threatening medical condition that occurs when a segment of the rib cage breaks due to trauma and becomes detached from the rest of the chest wall. Two of the symptoms of flail chest are chest pain and shortness of breath.It occurs when multiple adjacent ribs are broken in multiple places, separating a segment, so a part of the chest wall moves independently. The number of ribs that must be broken varies by differing definitions: some sources say at least two adjacent ribs are broken in at least two places, some require three or more ribs in two or more places. The flail segment moves in the opposite direction to the rest of the chest wall: because of the ambient pressure in comparison to the pressure inside the lungs, it goes in while the rest of the chest is moving out, and vice versa. This so-called "paradoxical breathing" is painful and increases the work involved in breathing. Flail chest is usually accompanied by a pulmonary contusion, a bruise of the lung tissue that can interfere with blood oxygenation. Often, it is the contusion, not the flail segment, that is the main cause of respiratory problems in people with both injuries.Surgery to fix the fractures appears to result in better outcomes. Signs and symptoms Two of the symptoms of flail chest are chest pain and shortness of breath.The characteristic paradoxical motion of the flail segment occurs due to pressure changes associated with respiration that the rib cage normally resists: During normal inspiration, the diaphragm contracts and intercostal muscles pull the rib cage out. Pressure in the thorax decreases below atmospheric pressure, and air rushes in through the trachea. The flail segment will be pulled in with the decrease in pressure while the rest of the rib cage expands. During normal expiration, the diaphragm and intercostal muscles relax increasing internal pressure, allowing the abdominal organs to push air upwards and out of the thorax. However, a flail segment will also be pushed out while the rest of the rib cage contracts.Paradoxical motion is a late sign of flail segment; therefore, an absence of paradoxical motion does not mean the patient does not have a flail segment. The constant motion of the ribs in the flail segment at the site of the fracture is extremely painful, and, untreated, the sharp broken edges of the ribs are likely to eventually puncture the pleural sac and lung, possibly causing a pneumothorax. The concern about "mediastinal flutter" (the shift of the mediastinum with paradoxical diaphragm movement) does not appear to be merited. Pulmonary contusions are commonly associated with flail chest and that can lead to respiratory failure. This is due to the paradoxical motions of the chest wall from the fragments interrupting normal breathing and chest movement. Typical paradoxical motion is associated with stiff lungs, which requires extra work for normal breathing, and increased lung resistance, which makes air flow difficult. The respiratory failure from the flail chest requires mechanical ventilation and a longer stay in an intensive care unit. It is the damage to the lungs from the flail segment that is life-threatening. Causes The most common causes of flail chest injuries are vehicle collisions, which account for 76% of flail chest injuries. Another main cause of flail chest injuries is falling. This mainly occurs in the elderly, who are more impacted by the falls as a result of their weak and frail bones, unlike their younger counterparts who can fall without being impacted as severely. Falls account for 14% of flail chest injuries.Flail chest typically occurs when three or more adjacent ribs are fractured in two or more places, allowing that segment of the thoracic wall to displace and move independently of the rest of the chest wall. Flail chest can also occur when ribs are fractured proximally in conjunction with disarticulation of costal cartilages distally. For the condition to occur, generally there must be a significant force applied over a large surface of the thorax to create the multiple anterior and posterior rib fractures. Rollover and crushing injuries most commonly break ribs at only one point, whereas for flail chest to occur a significant impact is required, breaking the ribs in two or more places. This can be caused by forceful accidents such as the aforementioned vehicle collisions or significant falls. In the elderly, it can be caused by deterioration of bone, although rare. In children, the majority of flail chest injuries result from common blunt force traumas or metabolic bone diseases, including a group of genetic disorders known as osteogenesis imperfecta. Diagnosis Diagnosis is by physical examination performed by a physician. The diagnosis may be assisted or confirmed by use of medical imaging with either plain X ray or CT scan. Treatment Treatment of the flail chest initially follows the principles of advanced trauma life support. Further treatment includes: Good pain management includes early regional anesthesia (e.g. intercostal blocks or erector spinae plane blocks) and avoiding opioid pain medication as much as possible. This allows much better ventilation, with improved tidal volume, and increased blood oxygenation. Positive pressure ventilation, meticulously adjusting the ventilator settings to avoid pulmonary barotrauma. Chest tubes as required. Adjustment of position to make the person most comfortable and provide relief of pain. Aggressive pulmonary toiletA person may be intubated with a double lumen tracheal tube. In a double lumen endotracheal tube, each lumen may be connected to a different ventilator. Usually one side of the chest is affected more than the other, so each lung may require drastically different pressures and flows to adequately ventilate. Surgical fixation can help in significantly reducing the duration of ventilatory support and in conserving the pulmonary function. Surgical intervention has also been shown to reduce the need for tracheostomy, reduces the time spent in the intensive care unit following a traumatic flail chest injury and could reduce the risk of acquiring pneumonia after such an event. Physiotherapy In order to begin a rehabilitation program for a flail chest it is important to treat the persons pain so they are able to perform the proper exercises. Due to the underlying conditions that the flail segment has caused onto the respiratory system, chest physiotherapy is important to reduce further complications. Proper positioning of the body is key, including postural alignment for proper drainage of mucous secretions. The therapy will consist of a variety of postural positioning and changes in order to increase normal breathing. Along with postural repositioning, a variety of breathing exercises are also very important in order to allow the chest wall to reposition itself back to normal conditions. Breathing exercises will also include coughing procedures. Furthermore, range of motion exercises are given to reduce the atrophy of the musculature. With progression, resistance exercises are added to the regimen to the shoulder and arm of the side containing the injury. Moreover, trunk exercises will be introduced while sitting and will progress to during standing. Hip flexion exercises can be done to expand the thorax. This is done by lying supine on a flat surface, flexing the knees and hips and bringing them in toward the chest. The knees should come in toward the chest while the person inhales, and exhale when the knees are lowered. This exercise can be done in 3 sets of 6–8 repetitions with a pause in between sets. The person should always make sure to maintain controlled breaths.Eventually, the person will be progressed to walking and posture correction while walking. Before the person is discharged from the hospital, the person should be able to perform mobility exercises to the core and should have attained good posture. Prognosis The death rate of people with flail chest depends on the severity of their condition, ranging from 10 to 25%. A systematic review comparing the safety and effectiveness of surgical fixation versus non-surgical methods for the treatment of flail chest, reported that there was no statistically significant difference in the reported deaths between patients treated surgically and those treated non-surgically i.e. with conservative management methods. The results of the systematic review suggested that surgical intervention reduces the need for tracheostomy, reduces the time spent in the intensive care unit following a traumatic flail chest injury and could reduce the risk of acquiring pneumonia after such an event. Epidemiology Approximately 1 out of 13 people admitted to the hospital with fractured ribs are found to have flail chest. References External links Rib Fractures & Flail Chest at Trauma.org – info, images, and video of paradoxical flail-segment motion
Obesity	Obesity is a medical condition, sometimes considered a disease, in which abnormal or excess body fat has accumulated to such an extent that it may have a negative effect on health. People are classified as obese when their body mass index (BMI)—a measurement obtained by dividing a persons weight by the square of the persons height (despite known allometric inaccuracies)—is over 30 kg/m2; the range 25–30 kg/m2 is defined as overweight. Some East Asian countries use lower values to calculate obesity.Obesity is a major cause of disability and is correlated with various diseases and conditions, particularly cardiovascular diseases, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis. High BMI is a marker of risk for, but not a direct cause of, diseases caused by diet and physical activity. A reciprocal link has been found between obesity and depression, with obesity increasing the risk of clinical depression, and also depression leading to a higher chance of developing obesity.Obesity has individual, socioeconomic, and environmental causes. Some of the known causes are diet, physical activity, automation, urbanization, genetic susceptibility, medications, mental disorders, economic policies, endocrine disorders, and exposure to endocrine-disrupting chemicals. Epidemiologic studies of overweight and obesity in children and adults covering 195 countries have shown that the prevalence of obesity has steadily increased in most countries, doubling in 73 countries between the years 1980 and 2015. As of 2015, the United States and China had the largest numbers of obese adults, and China and India had the largest numbers of obese children. By 2018, 42% of Americans were obese.While a majority of obese individuals at any given time are attempting to lose weight and are often successful, research shows that maintaining that weight loss over the long term proves to be rare. The reasons for weight cycling are not fully understood but may include decreased energy expenditure combined with an increased biological urge to eat during and after caloric restriction. More studies are needed to determine if weight cycling and yo-yo dieting contribute to inflammation and disease risk in obese individuals.Although there is no effective, well-defined, evidence-based intervention for preventing obesity, obesity prevention will require a complex approach, including interventions at community, family, and individual levels. Changes to diet and exercising are the main treatments recommended by health professionals. Diet quality can be improved by reducing the consumption of energy-dense foods, such as those high in fat or sugars, and by increasing the intake of dietary fiber. However, large-scale analyses have found an inverse relationship between energy density and energy cost of foods in developed nations. Medications can be used, along with a suitable diet, to reduce appetite or decrease fat absorption. If diet, exercise, and medication are not effective, a gastric balloon or surgery may be performed to reduce stomach volume or length of the intestines, leading to feeling full earlier, or a reduced ability to absorb nutrients from food.Obesity is a leading preventable cause of death worldwide, with increasing rates in adults and children. In 2015, 600 million adults (12%) and 100 million children were obese in 195 countries. Obesity is more common in women than in men. Public health officials view it as one of the most serious public health problems of the 21st century. Today, obesity is stigmatized in most of the world. Conversely, some cultures, past and present, have a favorable view of obesity, seeing it as a symbol of wealth and fertility. Nevertheless, in 2013, several medical societies, including the American Medical Association and the American Heart Association, classified obesity as a disease. Classification Obesity is typically defined as a substantial accumulation of body fat that could impact health. Medical organizations tend to classify people as obese based on body mass index (BMI) – a ratio of a persons weight in kilograms to the square of their height in meters. For adults, the World Health Organization (WHO) defines overweight as a BMI 25 or higher, and obese as a BMI 30 or higher. For children, obesity measures take age into consideration along with height and weight. For children aged 5–19, the WHO defines obesity as a BMI two standard deviations above the median for their age (a BMI around 18 for a five-year old; around 30 for a 19-year old). For children under five, the WHO defines obesity as a weight three standard deviations above the median for their height. The U.S. Centers for Disease Control and Prevention (CDC) further subdivides obesity based on BMI, with a BMI 30 to 35 called class 1 obesity; 35 to 40, class 2 obesity; and 40+, class 3 obesity.It further evaluated in terms of fat distribution via the waist–hip ratio and total cardiovascular risk factors. BMI is closely related to both percentage body fat and total body fat.In children, a healthy weight varies with age and sex. Obesity in children and adolescents is defined not as an absolute number but in relation to a historical normal group, such that obesity is a BMI greater than the 95th percentile. The reference data on which these percentiles were based date from 1963 to 1994, and thus have not been affected by the recent increases in weight.Some modifications to the WHO definitions have been made by particular organizations. The surgical literature breaks down class II and III or only class III obesity into further categories whose exact values are still disputed. Any BMI ≥ 35 or 40 kg/m2 is severe obesity. A BMI of ≥ 35 kg/m2 and experiencing obesity-related health conditions or ≥ 40 or 45 kg/m2 is morbid obesity. A BMI of ≥ 45 or 50 kg/m2 is super obesity.As Asian populations develop negative health consequences at a lower BMI than Caucasians, some nations have redefined obesity; Japan has defined obesity as any BMI greater than 25 kg/m2 while China uses a BMI of greater than 28 kg/m2. Effects on health Excessive body weight has a strong link to many diseases and conditions, particularly cardiovascular diseases, diabetes mellitus type 2, obstructive sleep apnea, certain types of cancer, osteoarthritis, and asthma. As a result, obesity has been found to reduce life expectancy. Mortality Obesity is one of the leading preventable causes of death worldwide. A number of reviews have found that mortality risk is lowest at a BMI of 20–25 kg/m2 in non-smokers and at 24–27 kg/m2 in current smokers, with risk increasing along with changes in either direction. This appears to apply in at least four continents. Other evidence suggests that the association of BMI and waist circumference with mortality is U- or J-shaped, while the association between waist-to-hip ratio and waist-to-height ratio with mortality is more positive. In Asians the risk of negative health effects begins to increase between 22 and 25 kg/m2. In 2021, the World Health Organization estimated that obesity caused at least 2.8 million deaths annually. On average, obesity reduces life expectancy by six to seven years, a BMI of 30–35 kg/m2 reduces life expectancy by two to four years, while severe obesity (BMI ≥ 40 kg/m2) reduces life expectancy by ten years. Morbidity Obesity increases the risk of many physical and mental conditions. These comorbidities are most commonly shown in metabolic syndrome, a combination of medical disorders which includes: diabetes mellitus type 2, high blood pressure, high blood cholesterol, and high triglyceride levels. A study from the RAK Hospital found that obese people are at a greater risk of developing long COVID. The CDC has found that obesity is the single strongest risk factor for severe COVID-19 illness.Complications are either directly caused by obesity or indirectly related through mechanisms sharing a common cause such as a poor diet or a sedentary lifestyle. The strength of the link between obesity and specific conditions varies. One of the strongest is the link with type 2 diabetes. Excess body fat underlies 64% of cases of diabetes in men and 77% of cases in women.Health consequences fall into two broad categories: those attributable to the effects of increased fat mass (such as osteoarthritis, obstructive sleep apnea, social stigmatization) and those due to the increased number of fat cells (diabetes, cancer, cardiovascular disease, non-alcoholic fatty liver disease). Increases in body fat alter the bodys response to insulin, potentially leading to insulin resistance. Increased fat also creates a proinflammatory state, and a prothrombotic state. Metrics of health Newer research has focused on methods of identifying healthier obese people by clinicians, and not treating obese people as a monolithic group. Obese people who do not experience medical complications from their obesity are sometimes called (metabolically) healthy obese, but the extent to which this group exists (especially among older people) is in dispute. The number of people considered metabolically healthy depends on the definition used, and there is no universally accepted definition. There are numerous obese people who have relatively few metabolic abnormalities, and a minority of obese people have no medical complications. The guidelines of the American Association of Clinical Endocrinologists call for physicians to use risk stratification with obese patients when considering how to assess their risk of developing type 2 diabetes.: 59–60 In 2014, the BioSHaRE–EU Healthy Obese Project (sponsored by Maelstrom Research, a team under the Research Institute of the McGill University Health Centre) came up with two definitions for healthy obesity, one more strict and one less so: To come up with these criteria, BioSHaRE controlled for age and tobacco use, researching how both may effect the metabolic syndrome associated with obesity, but not found to exist in the metabolically healthy obese. Other definitions of metabolically healthy obesity exist, including ones based on waist circumference rather than BMI, which is unreliable in certain individuals.Another identification metric for health in obese people is calf strength, which is positively correlated with physical fitness in obese people. Body composition in general is hypothesized to help explain the existence of metabolically healthy obesity—the metabolically healthy obese are often found to have low amounts of ectopic fat (fat stored in tissues other than adipose tissue) despite having overall fat mass equivalent in weight to obese people with metabolic syndrome.: 1282 Survival paradox Although the negative health consequences of obesity in the general population are well supported by the available evidence, health outcomes in certain subgroups seem to be improved at an increased BMI, a phenomenon known as the obesity survival paradox. The paradox was first described in 1999 in overweight and obese people undergoing hemodialysis, and has subsequently been found in those with heart failure and peripheral artery disease (PAD).In people with heart failure, those with a BMI between 30.0 and 34.9 had lower mortality than those with a normal weight. This has been attributed to the fact that people often lose weight as they become progressively more ill. Similar findings have been made in other types of heart disease. People with class I obesity and heart disease do not have greater rates of further heart problems than people of normal weight who also have heart disease. In people with greater degrees of obesity, however, the risk of further cardiovascular events is increased. Even after cardiac bypass surgery, no increase in mortality is seen in the overweight and obese. One study found that the improved survival could be explained by the more aggressive treatment obese people receive after a cardiac event. Another study found that if one takes into account chronic obstructive pulmonary disease (COPD) in those with PAD, the benefit of obesity no longer exists. Causes The "a calorie is a calorie" model of obesity posits a combination of excessive food energy intake and a lack of physical activity as the cause of most cases of obesity. A limited number of cases are due primarily to genetics, medical reasons, or psychiatric illness. In contrast, increasing rates of obesity at a societal level are felt to be due to an easily accessible and palatable diet, increased reliance on cars, and mechanized manufacturing.A 2006 review identified ten other possible contributors to the recent increase of obesity: (1) insufficient sleep, (2) endocrine disruptors (environmental pollutants that interfere with lipid metabolism), (3) decreased variability in ambient temperature, (4) decreased rates of smoking, because smoking suppresses appetite, (5) increased use of medications that can cause weight gain (e.g., atypical antipsychotics), (6) proportional increases in ethnic and age groups that tend to be heavier, (7) pregnancy at a later age (which may cause susceptibility to obesity in children), (8) epigenetic risk factors passed on generationally, (9) natural selection for higher BMI, and (10) assortative mating leading to increased concentration of obesity risk factors (this would increase the number of obese people by increasing population variance in weight). According to the Endocrine Society, there is "growing evidence suggesting that obesity is a disorder of the energy homeostasis system, rather than simply arising from the passive accumulation of excess weight". Diet A 2016 review supported excess appetite for palatable, high-calorie food (especially fat, sugar, and certain animal proteins) as the primary factor driving obesity worldwide, likely because of imbalances in neurotransmitters affecting the drive to eat. Dietary energy supply per capita varies markedly between different regions and countries. It has also changed significantly over time. From the early 1970s to the late 1990s the average food energy available per person per day (the amount of food bought) increased in all parts of the world except Eastern Europe. The United States had the highest availability with 3,654 calories (15,290 kJ) per person in 1996. This increased further in 2003 to 3,754 calories (15,710 kJ). During the late 1990s, Europeans had 3,394 calories (14,200 kJ) per person, in the developing areas of Asia there were 2,648 calories (11,080 kJ) per person, and in sub-Saharan Africa people had 2,176 calories (9,100 kJ) per person. Total food energy consumption has been found to be related to obesity.The widespread availability of dietary guidelines has done little to address the problems of overeating and poor dietary choice. From 1971 to 2000, obesity rates in the United States increased from 14.5% to 30.9%. During the same period, an increase occurred in the average amount of food energy consumed. For women, the average increase was 335 calories (1,400 kJ) per day (1,542 calories (6,450 kJ) in 1971 and 1,877 calories (7,850 kJ) in 2004), while for men the average increase was 168 calories (700 kJ) per day (2,450 calories (10,300 kJ) in 1971 and 2,618 calories (10,950 kJ) in 2004). Most of this extra food energy came from an increase in carbohydrate consumption rather than fat consumption. The primary sources of these extra carbohydrates are sweetened beverages, which now account for almost 25 percent of daily food energy in young adults in America, and potato chips. Consumption of sweetened beverages such as soft drinks, fruit drinks, and iced tea is believed to be contributing to the rising rates of obesity and to an increased risk of metabolic syndrome and type 2 diabetes. Vitamin D deficiency is related to diseases associated with obesity.As societies become increasingly reliant on energy-dense, big-portions, and fast-food meals, the association between fast-food consumption and obesity becomes more concerning. In the United States, consumption of fast-food meals tripled and food energy intake from these meals quadrupled between 1977 and 1995.Agricultural policy and techniques in the United States and Europe have led to lower food prices. In the United States, subsidization of corn, soy, wheat, and rice through the U.S. farm bill has made the main sources of processed food cheap compared to fruits and vegetables. Calorie count laws and nutrition facts labels attempt to steer people toward making healthier food choices, including awareness of how much food energy is being consumed. Obese people consistently under-report their food consumption as compared to people of normal weight. This is supported both by tests of people carried out in a calorimeter room and by direct observation. Sedentary lifestyle A sedentary lifestyle plays a significant role in obesity. Worldwide there has been a large shift towards less physically demanding work, and currently at least 30% of the worlds population gets insufficient exercise. This is primarily due to increasing use of mechanized transportation and a greater prevalence of labor-saving technology in the home. In children, there appear to be declines in levels of physical activity (with particularly strong declines in the amount of walking and physical education), likely due to safety concerns, changes in social interaction (such as fewer relationships with neighborhood children), and inadequate urban design (such as too few public spaces for safe physical activity). World trends in active leisure time physical activity are less clear. The World Health Organization indicates people worldwide are taking up less active recreational pursuits, while a study from Finland found an increase and a study from the United States found leisure-time physical activity has not changed significantly. A 2011 review of physical activity in children found that it may not be a significant contributor.In both children and adults, there is an association between television viewing time and the risk of obesity. A review found 63 of 73 studies (86%) showed an increased rate of childhood obesity with increased media exposure, with rates increasing proportionally to time spent watching television. Genetics Like many other medical conditions, obesity is the result of an interplay between genetic and environmental factors. Polymorphisms in various genes controlling appetite and metabolism predispose to obesity when sufficient food energy is present. As of 2006, more than 41 of these sites on the human genome have been linked to the development of obesity when a favorable environment is present. People with two copies of the FTO gene (fat mass and obesity associated gene) have been found on average to weigh 3–4 kg more and have a 1.67-fold greater risk of obesity compared with those without the risk allele. The differences in BMI between people that are due to genetics varies depending on the population examined from 6% to 85%.Obesity is a major feature in several syndromes, such as Prader–Willi syndrome, Bardet–Biedl syndrome, Cohen syndrome, and MOMO syndrome. (The term "non-syndromic obesity" is sometimes used to exclude these conditions.) In people with early-onset severe obesity (defined by an onset before 10 years of age and body mass index over three standard deviations above normal), 7% harbor a single point DNA mutation.Studies that have focused on inheritance patterns rather than on specific genes have found that 80% of the offspring of two obese parents were also obese, in contrast to less than 10% of the offspring of two parents who were of normal weight. Different people exposed to the same environment have different risks of obesity due to their underlying genetics.The thrifty gene hypothesis postulates that, due to dietary scarcity during human evolution, people are prone to obesity. Their ability to take advantage of rare periods of abundance by storing energy as fat would be advantageous during times of varying food availability, and individuals with greater adipose reserves would be more likely to survive famine. This tendency to store fat, however, would be maladaptive in societies with stable food supplies. This theory has received various criticisms, and other evolutionarily-based theories such as the drifty gene hypothesis and the thrifty phenotype hypothesis have also been proposed. Other illnesses Certain physical and mental illnesses and the pharmaceutical substances used to treat them can increase risk of obesity. Medical illnesses that increase obesity risk include several rare genetic syndromes (listed above) as well as some congenital or acquired conditions: hypothyroidism, Cushings syndrome, growth hormone deficiency, and some eating disorders such as binge eating disorder and night eating syndrome. However, obesity is not regarded as a psychiatric disorder, and therefore is not listed in the DSM-IVR as a psychiatric illness. The risk of overweight and obesity is higher in patients with psychiatric disorders than in persons without psychiatric disorders.Certain medications may cause weight gain or changes in body composition; these include insulin, sulfonylureas, thiazolidinediones, atypical antipsychotics, antidepressants, steroids, certain anticonvulsants (phenytoin and valproate), pizotifen, and some forms of hormonal contraception. Social determinants While genetic influences are important to understanding obesity, they cannot explain the current dramatic increase seen within specific countries or globally. Though it is accepted that energy consumption in excess of energy expenditure leads to increases in body weight on an individual basis, the cause of the shifts in these two factors on the societal scale is much debated. There are a number of theories as to the cause but most believe it is a combination of various factors. The correlation between social class and BMI varies globally. A review in 1989 found that in developed countries women of a high social class were less likely to be obese. No significant differences were seen among men of different social classes. In the developing world, women, men, and children from high social classes had greater rates of obesity. An update of this review carried out in 2007 found the same relationships, but they were weaker. The decrease in strength of correlation was felt to be due to the effects of globalization. Among developed countries, levels of adult obesity, and percentage of teenage children who are overweight, are correlated with income inequality. A similar relationship is seen among US states: more adults, even in higher social classes, are obese in more unequal states.Many explanations have been put forth for associations between BMI and social class. It is thought that in developed countries, the wealthy are able to afford more nutritious food, they are under greater social pressure to remain slim, and have more opportunities along with greater expectations for physical fitness. In undeveloped countries the ability to afford food, high energy expenditure with physical labor, and cultural values favoring a larger body size are believed to contribute to the observed patterns. Attitudes toward body weight held by people in ones life may also play a role in obesity. A correlation in BMI changes over time has been found among friends, siblings, and spouses. Stress and perceived low social status appear to increase risk of obesity.Smoking has a significant effect on an individuals weight. Those who quit smoking gain an average of 4.4 kilograms (9.7 lb) for men and 5.0 kilograms (11.0 lb) for women over ten years. However, changing rates of smoking have had little effect on the overall rates of obesity.In the United States, the number of children a person has is related to their risk of obesity. A womans risk increases by 7% per child, while a mans risk increases by 4% per child. This could be partly explained by the fact that having dependent children decreases physical activity in Western parents.In the developing world urbanization is playing a role in increasing rate of obesity. In China overall rates of obesity are below 5%; however, in some cities rates of obesity are greater than 20%. In part, this may be because of urban design issues (such as inadequate public spaces for physical activity). Time spent in motor vehicles, as opposed to active transportation options such as cycling or walking, is correlated with increased risk of obesity.Malnutrition in early life is believed to play a role in the rising rates of obesity in the developing world. Endocrine changes that occur during periods of malnutrition may promote the storage of fat once more food energy becomes available. Gut bacteria The study of the effect of infectious agents on metabolism is still in its early stages. Gut flora has been shown to differ between lean and obese people. There is an indication that gut flora can affect the metabolic potential. This apparent alteration is believed to confer a greater capacity to harvest energy contributing to obesity. Whether these differences are the direct cause or the result of obesity has yet to be determined unequivocally. The use of antibiotics among children has also been associated with obesity later in life.An association between viruses and obesity has been found in humans and several different animal species. The amount that these associations may have contributed to the rising rate of obesity is yet to be determined. Other factors A number of reviews have found an association between short duration of sleep and obesity. Whether one causes the other is unclear. Even if short sleep does increase weight gain it is unclear if this is to a meaningful degree or if increasing sleep would be of benefit.Certain aspects of personality are associated with being obese. Loneliness, neuroticism, impulsivity, and sensitivity to reward are more common in people who are obese while conscientiousness and self-control are less common in people who are obese. Because most of the studies on this topic are questionnaire-based, it is possible that these findings overestimate the relationships between personality and obesity: people who are obese might be aware of the social stigma of obesity and their questionnaire responses might be biased accordingly. Similarly, the personalities of people who are obese as children might be influenced by obesity stigma, rather than these personality factors acting as risk factors for obesity. Pathophysiology Two distinct but related processes are considered to be involved in the development of obesity: sustained positive energy balance (energy intake exceeding energy expenditure) and the resetting of the body weight "set point" at an increased value. The second process explains why finding effective obesity treatments has been difficult. While the underlying biology of this process still remains uncertain, research is beginning to clarify the mechanisms.At a biological level, there are many possible pathophysiological mechanisms involved in the development and maintenance of obesity. This field of research had been almost unapproached until the leptin gene was discovered in 1994 by J. M. Friedmans laboratory. While leptin and ghrelin are produced peripherally, they control appetite through their actions on the central nervous system. In particular, they and other appetite-related hormones act on the hypothalamus, a region of the brain central to the regulation of food intake and energy expenditure. There are several circuits within the hypothalamus that contribute to its role in integrating appetite, the melanocortin pathway being the most well understood. The circuit begins with an area of the hypothalamus, the arcuate nucleus, that has outputs to the lateral hypothalamus (LH) and ventromedial hypothalamus (VMH), the brains feeding and satiety centers, respectively.The arcuate nucleus contains two distinct groups of neurons. The first group coexpresses neuropeptide Y (NPY) and agouti-related peptide (AgRP) and has stimulatory inputs to the LH and inhibitory inputs to the VMH. The second group coexpresses pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) and has stimulatory inputs to the VMH and inhibitory inputs to the LH. Consequently, NPY/AgRP neurons stimulate feeding and inhibit satiety, while POMC/CART neurons stimulate satiety and inhibit feeding. Both groups of arcuate nucleus neurons are regulated in part by leptin. Leptin inhibits the NPY/AgRP group while stimulating the POMC/CART group. Thus a deficiency in leptin signaling, either via leptin deficiency or leptin resistance, leads to overfeeding and may account for some genetic and acquired forms of obesity. Public health The World Health Organization (WHO) predicts that overweight and obesity may soon replace more traditional public health concerns such as undernutrition and infectious diseases as the most significant cause of poor health. Obesity is a public health and policy problem because of its prevalence, costs, and health effects. The United States Preventive Services Task Force recommends screening for all adults followed by behavioral interventions in those who are obese. Public health efforts seek to understand and correct the environmental factors responsible for the increasing prevalence of obesity in the population. Solutions look at changing the factors that cause excess food energy consumption and inhibit physical activity. Efforts include federally reimbursed meal programs in schools, limiting direct junk food marketing to children, and decreasing access to sugar-sweetened beverages in schools. The World Health Organization recommends the taxing of sugary drinks. When constructing urban environments, efforts have been made to increase access to parks and to develop pedestrian routes. There is low quality evidence that nutritional labelling with energy information on menus can help to reduce energy intake while dining in restaurants. Reports Many organizations have published reports pertaining to obesity. In 1998, the first US Federal guidelines were published, titled "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report". In 2006, the Canadian Obesity Network, now known as Obesity Canada published the "Canadian Clinical Practice Guidelines (CPG) on the Management and
Obesity	Prevention of Obesity in Adults and Children". This is a comprehensive evidence-based guideline to address the management and prevention of overweight and obesity in adults and children.In 2004, the United Kingdom Royal College of Physicians, the Faculty of Public Health and the Royal College of Paediatrics and Child Health released the report "Storing up Problems", which highlighted the growing problem of obesity in the UK. The same year, the House of Commons Health Select Committee published its "most comprehensive inquiry [...] ever undertaken" into the impact of obesity on health and society in the UK and possible approaches to the problem. In 2006, the National Institute for Health and Clinical Excellence (NICE) issued a guideline on the diagnosis and management of obesity, as well as policy implications for non-healthcare organizations such as local councils. A 2007 report produced by Derek Wanless for the Kings Fund warned that unless further action was taken, obesity had the capacity to debilitate the National Health Service financially. In 2022 the National Institute for Health and Care Research (NIHR) published a comprehensive review of research on what local authorities can do to reduce obesity.The Obesity Policy Action (OPA) framework divides measure into upstream policies, midstream policies, and downstream policies. Upstream policies have to do with changing society, while midstream policies try to alter behaviors believed to contribute to obesity at the individual level, while downstream policies treat currently obese people. Management The main treatment for obesity consists of weight loss via lifestyle interventions, including prescribed diets and physical exercise. Although it is unclear what diets might support long-term weight loss, and although the effectiveness of low-calorie diets is debated, lifestyle changes that reduce calorie consumption or increase physical exercise over the long term also tend to produce some sustained weight loss, despite slow weight regain over time. Although 87% of participants in the National Weight Control Registry were able to maintain 10% body weight loss for 10 years, the most appropriate dietary approach for long term weight loss maintenance is still unknown. In the US, intensive behavioral interventions combining both dietary changes and exercise are recommended. Intermittent fasting has no additional benefit of weight loss compared to continuous energy restriction. Adherence is a more important factor in weight loss success than whatever kind of diet an individual undertakes.Several hypo-caloric diets are effective. In the short-term low carbohydrate diets appear better than low fat diets for weight loss. In the long term, however, all types of low-carbohydrate and low-fat diets appear equally beneficial. A 2014 review found that the heart disease and diabetes risks associated with different diets appear to be similar. Promotion of the Mediterranean diets among the obese may lower the risk of heart disease. Decreased intake of sweet drinks is also related to weight-loss. Success rates of long-term weight loss maintenance with lifestyle changes are low, ranging from 2–20%. Dietary and lifestyle changes are effective in limiting excessive weight gain in pregnancy and improve outcomes for both the mother and the child. Intensive behavioral counseling is recommended in those who are both obese and have other risk factors for heart disease. Medical interventions Five medications have evidence for long-term use orlistat, lorcaserin, liraglutide, phentermine–topiramate, and naltrexone–bupropion. They result in weight loss after one year ranged from 3.0 to 6.7 kg (6.6-14.8 lbs) over placebo. Orlistat, liraglutide, and naltrexone–bupropion are available in both the United States and Europe, phentermine–topiramate is available only in the United States. European regulatory authorities rejected lorcaserin and phentermine-topiramate, in part because of associations of heart valve problems with lorcaserin and more general heart and blood vessel problems with phentermine–topiramate. Lorcaserin was available in the United States and then removed from the market in 2020 due to its association with cancer. Orlistat use is associated with high rates of gastrointestinal side effects and concerns have been raised about negative effects on the kidneys. There is no information on how these drugs affect longer-term complications of obesity such as cardiovascular disease or death, however, liraglutide, when used for type 2 diabetes, does reduce cardiovascular events.The most effective treatment for obesity is bariatric surgery. The types of procedures include laparoscopic adjustable gastric banding, Roux-en-Y gastric bypass, vertical-sleeve gastrectomy, and biliopancreatic diversion. Surgery for severe obesity is associated with long-term weight loss, improvement in obesity-related conditions, and decreased overall mortality, however, improved metabolic health results from the weight loss, not the surgery. One study found a weight loss of between 14% and 25% (depending on the type of procedure performed) at 10 years, and a 29% reduction in all cause mortality when compared to standard weight loss measures. Complications occur in about 17% of cases and reoperation is needed in 7% of cases. Epidemiology See or edit source data. In earlier historical periods obesity was rare, and achievable only by a small elite, although already recognised as a problem for health. But as prosperity increased in the Early Modern period, it affected increasingly larger groups of the population. Prior to the 1970s, obesity was a relatively rare condition even in the wealthiest of nations, and when it did exist it tended to occur among the wealthy. Then, a confluence of events started to change the human condition. The average BMI of populations in first-world countries started to increase and, consequently, there was a rapid increase in the proportion of people overweight and obese.In 1997, the WHO formally recognized obesity as a global epidemic. As of 2008, the WHO estimates that at least 500 million adults (greater than 10%) are obese, with higher rates among women than men. The global prevalence of obesity more than doubled between 1980 and 2014. In 2014, more than 600 million adults were obese, equal to about 13 percent of the worlds adult population. The percentage of adults affected in the United States as of 2015–2016 is about 39.6% overall (37.9% of males and 41.1% of females).The rate of obesity also increases with age at least up to 50 or 60 years old and severe obesity in the United States, Australia, and Canada is increasing faster than the overall rate of obesity. The OECD has projected an increase in obesity rates until at least 2030, especially in the United States, Mexico and England with rates reaching 47%, 39% and 35%, respectively.Once considered a problem only of high-income countries, obesity rates are rising worldwide and affecting both the developed and developing world. These increases have been felt most dramatically in urban settings. The only remaining region of the world where obesity is not common is sub-Saharan Africa. History Etymology Obesity is from the Latin obesitas, which means "stout, fat, or plump". Ēsus is the past participle of edere (to eat), with ob (over) added to it. The Oxford English Dictionary documents its first usage in 1611 by Randle Cotgrave. Historical attitudes Ancient Greek medicine recognizes obesity as a medical disorder, and records that the Ancient Egyptians saw it in the same way. Hippocrates wrote that "Corpulence is not only a disease itself, but the harbinger of others". The Indian surgeon Sushruta (6th century BCE) related obesity to diabetes and heart disorders. He recommended physical work to help cure it and its side effects. For most of human history mankind struggled with food scarcity. Obesity has thus historically been viewed as a sign of wealth and prosperity. It was common among high officials in Europe in the Middle Ages and the Renaissance as well as in Ancient East Asian civilizations. In the 17th century, English medical author Tobias Venner is credited with being one of the first to refer to the term as a societal disease in a published English language book.With the onset of the Industrial Revolution it was realized that the military and economic might of nations were dependent on both the body size and strength of their soldiers and workers. Increasing the average body mass index from what is now considered underweight to what is now the normal range played a significant role in the development of industrialized societies. Height and weight thus both increased through the 19th century in the developed world. During the 20th century, as populations reached their genetic potential for height, weight began increasing much more than height, resulting in obesity. In the 1950s increasing wealth in the developed world decreased child mortality, but as body weight increased heart and kidney disease became more common. During this time period, insurance companies realized the connection between weight and life expectancy and increased premiums for the obese.Many cultures throughout history have viewed obesity as the result of a character flaw. The obesus or fat character in Ancient Greek comedy was a glutton and figure of mockery. During Christian times the food was viewed as a gateway to the sins of sloth and lust. In modern Western culture, excess weight is often regarded as unattractive, and obesity is commonly associated with various negative stereotypes. People of all ages can face social stigmatization, and may be targeted by bullies or shunned by their peers.Public perceptions in Western society regarding healthy body weight differ from those regarding the weight that is considered ideal – and both have changed since the beginning of the 20th century. The weight that is viewed as an ideal has become lower since the 1920s. This is illustrated by the fact that the average height of Miss America pageant winners increased by 2% from 1922 to 1999, while their average weight decreased by 12%. On the other hand, peoples views concerning healthy weight have changed in the opposite direction. In Britain, the weight at which people considered themselves to be overweight was significantly higher in 2007 than in 1999. These changes are believed to be due to increasing rates of adiposity leading to increased acceptance of extra body fat as being normal.Obesity is still seen as a sign of wealth and well-being in many parts of Africa. This has become particularly common since the HIV epidemic began. The arts The first sculptural representations of the human body 20,000–35,000 years ago depict obese females. Some attribute the Venus figurines to the tendency to emphasize fertility while others feel they represent "fatness" in the people of the time. Corpulence is, however, absent in both Greek and Roman art, probably in keeping with their ideals regarding moderation. This continued through much of Christian European history, with only those of low socioeconomic status being depicted as obese.During the Renaissance some of the upper class began flaunting their large size, as can be seen in portraits of Henry VIII of England and Alessandro dal Borro. Rubens (1577–1640) regularly depicted heavyset women in his pictures, from which derives the term Rubenesque. These women, however, still maintained the "hourglass" shape with its relationship to fertility. During the 19th century, views on obesity changed in the Western world. After centuries of obesity being synonymous with wealth and social status, slimness began to be seen as the desirable standard. In his 1819 print, The Belle Alliance, or the Female Reformers of Blackburn!!!, artist George Cruikshank criticised the work of female reformers in Blackburn and used fatness as a means to portray them as unfeminine. Society and culture Economic impact In addition to its health impacts, obesity leads to many problems including disadvantages in employment and increased business costs. These effects are felt by all levels of society from individuals, to corporations, to governments. In 2005, the medical costs attributable to obesity in the US were an estimated $190.2 billion or 20.6% of all medical expenditures, while the cost of obesity in Canada was estimated at CA$2 billion in 1997 (2.4% of total health costs). The total annual direct cost of overweight and obesity in Australia in 2005 was A$21 billion. Overweight and obese Australians also received A$35.6 billion in government subsidies. The estimate range for annual expenditures on diet products is $40 billion to $100 billion in the US alone.The Lancet Commission on Obesity in 2019 called for a global treaty—modelled on the WHO Framework Convention on Tobacco Control—committing countries to address obesity and undernutrition, explicitly excluding the food industry from policy development. They estimate the global cost of obesity $2 trillion a year, about or 2.8% of world GDP.Obesity prevention programs have been found to reduce the cost of treating obesity-related disease. However, the longer people live, the more medical costs they incur. Researchers, therefore, conclude that reducing obesity may improve the publics health, but it is unlikely to reduce overall health spending. Obesity can lead to social stigmatization and disadvantages in employment. When compared to their normal weight counterparts, obese workers on average have higher rates of absenteeism from work and take more disability leave, thus increasing costs for employers and decreasing productivity. A study examining Duke University employees found that people with a BMI over 40 kg/m2 filed twice as many workers compensation claims as those whose BMI was 18.5–24.9 kg/m2. They also had more than 12 times as many lost work days. The most common injuries in this group were due to falls and lifting, thus affecting the lower extremities, wrists or hands, and backs. The Alabama State Employees Insurance Board approved a controversial plan to charge obese workers $25 a month for health insurance that would otherwise be free unless they take steps to lose weight and improve their health. These measures started in January 2010 and apply to those state workers whose BMI exceeds 35 kg/m2 and who fail to make improvements in their health after one year.Some research shows that obese people are less likely to be hired for a job and are less likely to be promoted. Obese people are also paid less than their non-obese counterparts for an equivalent job; obese women on average make 6% less and obese men make 3% less.Specific industries, such as the airline, healthcare and food industries, have special concerns. Due to rising rates of obesity, airlines face higher fuel costs and pressures to increase seating width. In 2000, the extra weight of obese passengers cost airlines US$275 million. The healthcare industry has had to invest in special facilities for handling severely obese patients, including special lifting equipment and bariatric ambulances. Costs for restaurants are increased by litigation accusing them of causing obesity. In 2005 the US Congress discussed legislation to prevent civil lawsuits against the food industry in relation to obesity; however, it did not become law.With the American Medical Associations 2013 classification of obesity as a chronic disease, it is thought that health insurance companies will more likely pay for obesity treatment, counseling and surgery, and the cost of research and development of fat treatment pills or gene therapy treatments should be more affordable if insurers help to subsidize their cost. The AMA classification is not legally binding, however, so health insurers still have the right to reject coverage for a treatment or procedure.In 2014, The European Court of Justice ruled that morbid obesity is a disability. The Court said that if an employees obesity prevents them from "full and effective participation of that person in professional life on an equal basis with other workers", then it shall be considered a disability and that firing someone on such grounds is discriminatory. Size acceptance The principal goal of the fat acceptance movement is to decrease discrimination against people who are overweight and obese. However, some in the movement are also attempting to challenge the established relationship between obesity and negative health outcomes.A number of organizations exist that promote the acceptance of obesity. They have increased in prominence in the latter half of the 20th century. The US-based National Association to Advance Fat Acceptance (NAAFA) was formed in 1969 and describes itself as a civil rights organization dedicated to ending size discrimination.The International Size Acceptance Association (ISAA) is a non-governmental organization (NGO) which was founded in 1997. It has more of a global orientation and describes its mission as promoting size acceptance and helping to end weight-based discrimination. These groups often argue for the recognition of obesity as a disability under the US Americans With Disabilities Act (ADA). The American legal system, however, has decided that the potential public health costs exceed the benefits of extending this anti-discrimination law to cover obesity. Industry influence on research In 2015, the New York Times published an article on the Global Energy Balance Network, a nonprofit founded in 2014 that advocated for people to focus on increasing exercise rather than reducing calorie intake to avoid obesity and to be healthy. The organization was founded with at least $1.5M in funding from the Coca-Cola Company, and the company has provided $4M in research funding to the two founding scientists Gregory A. Hand and Steven N. Blair since 2008. Childhood obesity The healthy BMI range varies with the age and sex of the child. Obesity in children and adolescents is defined as a BMI greater than the 95th percentile. The reference data that these percentiles are based on is from 1963 to 1994 and thus has not been affected by the recent increases in rates of obesity. Childhood obesity has reached epidemic proportions in the 21st century, with rising rates in both the developed and the developing world. Rates of obesity in Canadian boys have increased from 11% in the 1980s to over 30% in the 1990s, while during this same time period rates increased from 4 to 14% in Brazilian children. In the UK, there were 60% more obese children in 2005 compared to 1989. In the US, the percentage of overweight and obese children increased to 16% in 2008, a 300% increase over the prior 30 years.As with obesity in adults, many factors contribute to the rising rates of childhood obesity. Changing diet and decreasing physical activity are believed to be the two most important causes for the recent increase in the incidence of child obesity. Antibiotics in the first 6 months of life have been associated with excess weight at age seven to twelve years of age. Because childhood obesity often persists into adulthood and is associated with numerous chronic illnesses, children who are obese are often tested for hypertension, diabetes, hyperlipidemia, and fatty liver disease. Treatments used in children are primarily lifestyle interventions and behavioral techniques, although efforts to increase activity in children have had little success. In the United States, medications are not FDA approved for use in this age group. Multi-component behaviour change interventions that include changes to dietary and physical activity may reduce BMI in the short term in children aged 6 to 11 years, although the benefits are small and quality of evidence is low. Other animals Obesity in pets is common in many countries. In the United States, 23–41% of dogs are overweight, and about 5.1% are obese. The rate of obesity in cats was slightly higher at 6.4%. In Australia the rate of obesity among dogs in a veterinary setting has been found to be 7.6%. The risk of obesity in dogs is related to whether or not their owners are obese; however, there is no similar correlation between cats and their owners. See also Portal-visceral hypothesis References Informational notes Citations Bibliography Further reading
Proctalgia fugax	Proctalgia fugax, a variant of levator ani syndrome, is a severe, episodic pain in the regions of the rectum and anus. It can be caused by cramping of the levator ani muscle, particularly in the pubococcygeal part. Signs and symptoms It most often occurs in the middle of the night and lasts from seconds to minutes; pain and aching lasting twenty minutes or longer would likely be diagnosed instead as levator ani syndrome. In a study published in 2007 involving 1809 patients, the attacks occurred in the daytime (33 percent) as well as at night (33 percent) and the average number of attacks was 13. Onset can be in childhood; however, in multiple studies the average age of onset was 45. Many studies showed that women are affected more commonly than men, but this can be at least partly explained by mens reluctance to seek medical advice concerning rectal pain. Data on the number of people affected vary, but prevalence may be as high as 8–18%. It is thought that only 17–20% of patients consult a physician, so obtaining accurate data on occurrence presents a challenge.During an episode, the patient feels spasm-like, sometimes excruciating, pain in the rectum or anus, often misinterpreted as a need to defecate. To be diagnosed as proctalgia fugax, the pain must arise de novo (meaning the absence of clear cause). As such, pain associated with constipation (either chronic, or acute), penetrative anal intercourse, trauma (such as tears or fissures of the rectal sphincter or anal canal), side-effects of some medications (particularly opiates), or rectal foreign body insertion preclude this diagnosis. The pain episode subsides by itself as the spasm disappears on its own, but may reoccur.Because of the high incidence of internal anal sphincter thickening with the disorder, it is thought to be a disorder of that muscle or that it is a neuralgia of pudendal nerves. It is not known to be linked to any disease process. Prevention High-voltage pulsed galvanic stimulation (HGVS) has been shown to be of prophylactic benefit, to reduce the incidence of attacks. The patient is usually placed in the left lateral decubitus position and a sterile probe is inserted into the anus. The negative electrode is used and the stimulator is set with a pulse frequency of 80 to 120 cycles per second. The voltage (intensity) is started at 0, progressively raised to a threshold of patient discomfort, and then is decreased to a level that the patient finds comfortable. As the patients tolerance increases, the voltage can be gradually increased to 250 to 350 Volts. Each treatment session usually lasts between 15 and 60 minutes. Several studies have reported short-term success rates that ranged from 65 to 91%.Low dose diazepam of around 2 mg or less, or similar muscle-relaxant, taken orally at bedtime has been suggested as preventative, but its benefits are limited. Treatment There is no known cure. The most common approach for mild cases is simply reassurance and topical treatment with calcium-channel blocker (diltiazem, nifedipine) ointment, salbutamol inhalation and topical nitroglycerine. For persistent cases, local anesthetic blocks, clonidine or botulinum toxin injections can be considered. Supportive treatments directed at aggravating factors include high-fiber diet, withdrawal of drugs which have gut effects (e.g., drugs that provoke or worsen constipation including narcotics and oral calcium channel blockers; drugs that provoke or worsen diarrhea including quinidine, theophylline, and antibiotics), warm baths, rectal massage, perineal strengthening exercises, anticholinergic agents, non-narcotic analgesics, sedatives or muscle relaxants such as diazepam. In patients who have frequent, severe, prolonged attacks, inhaled salbutamol has been shown in some studies to reduce their duration.Traditional remedies have ranged from warm baths (if the pain lasts long enough), warm to hot enemas, and relaxation techniques. References External links PatientPlus
Pilar sheath acanthoma	A pilar sheath acanthoma is a cutaneous condition most often found on the face, particularly above the upper lip in adults.: 675 See also Dilated pore Trichoadenoma Skin lesion == References ==
Membranous glomerulonephritis	Membranous glomerulonephritis (MGN) is a slowly progressive disease of the kidney affecting mostly people between ages of 30 and 50 years, usually white people (i.e., those of European, Middle Eastern, or North African ancestry.). It is the second most common cause of nephrotic syndrome in adults, with focal segmental glomerulosclerosis (FSGS) recently becoming the most common. Signs and symptoms Most people will present as nephrotic syndrome, with the triad of albuminuria, edema and low serum albumin (with or without kidney failure). High blood pressure and high cholesterol are often also present. Others may not have symptoms and may be picked up on screening, with urinalysis finding high amounts of protein loss in the urine. A definitive diagnosis of membranous nephropathy requires a kidney biopsy, though given the very high specificity of anti-PLA2R antibody positivity this can sometimes be avoided in patients with nephrotic syndrome and preserved kidney function Causes Primary/idiopathic 85% of MGN cases are classified as primary membranous glomerulonephritis—that is to say, the cause of the disease is idiopathic (of unknown origin or cause). This can also be referred to as idiopathic membranous nephropathy.One study has identified antibodies to an M-type phospholipase A2 receptor in 70% (26 of 37) cases evaluated. Testing for these anti-PLA2R has revolutionised diagnosis and treatment of this disease in antibody positive patients, and tracking titre level over time allows you to predict risk of disease progression and chance of spontaneous remissionIn 2014, a second autoantigen was discovered, the thrombospondin type 1 domain-containing 7A (THSD7A) system that might account for an additional 5-10% of membranous nephropathy cases, and appears to be associated with malignancies. New studies are identifying novel auto-antigens responsible for causing a membranous nephropathy pattern of injury continue to be published, with antibodies against NELL-1 and EXT1/EXT2 in 2019, Semaphorin3B and Protocadherin 7 (PCDH7) in 2020, and serine protease HTRA1 in 2021. Secondary The remainder is secondary due to: autoimmune conditions (e.g., systemic lupus erythematosus). infections (e.g., syphilis, malaria, hepatitis B, hepatitis C, HIV). drugs (e.g., captopril, NSAIDs, penicillamine, probenecid, Bucillamine, Anti-TNF therapy, Tiopronin). inorganic salts (e.g. gold, mercury). tumors, frequently solid tumors of the lung and colon; hematological malignancies such as chronic lymphocytic leukemia are less common. Pathogenesis MGN is caused by immune complex formation in the glomerulus. The immune complexes are formed by binding of antibodies to antigens in the glomerular basement membrane. The antigens may be part of the basement membrane, or deposited from elsewhere by the systemic circulation.The immune complex serves as an activator that triggers a response from the C5b - C9 complements, which form a membrane attack complex (MAC) on the glomerular epithelial cells. This, in turn, stimulates release of proteases and oxidants by the mesangial and epithelial cells, damaging the capillary walls and causing them to become "leaky". In addition, the epithelial cells also seem to secrete an unknown mediator that reduces nephrin synthesis and distribution.Within membranous glomerulonephritis, especially in cases caused by viral hepatitis, serum C3 levels are low.Similar to other causes of nephrotic syndrome (e.g., focal segmental glomerulosclerosis or minimal change disease), membranous nephropathy is known to predispose affected individuals to develop blood clots such as pulmonary emboli. Membranous nephropathy in particular is known to increase this risk more than other causes of nephrotic syndrome though the reason for this is not yet clear. Morphology The defining point of MGN is the presence of subepithelial immunoglobulin-containing deposits along the glomerular basement membrane (GBM). By light microscopy, the basement membrane is observed to be diffusely thickened. Using Jones stain, the GBM appears to have a "spiked" or "holey" appearance. On electron microscopy, subepithelial deposits that nestle against the glomerular basement membrane seems to be the cause of the thickening. Also, the podocytes lose their foot processes. As the disease progresses, the deposits will eventually be cleared, leaving cavities in the basement membrane. These cavities will later be filled with basement membrane-like material, and if the disease continues even further, the glomeruli will become sclerosed and finally hyalinized. Immunofluorescence microscopy will reveal typical granular deposition of immunoglobulins and complement along the basement membrane.Although it usually affects the entire glomerulus, it can affect parts of the glomerulus in some cases. Treatment Treatment of secondary membranous nephropathy is guided by the treatment of the original disease. For treatment of idiopathic membranous nephropathy, the treatment options include immunosuppressive drugs and non-specific anti-proteinuric measures such as ACE inhibitors or angiotensin II receptor blockers. Given spontaneous remission is common, international guidelines recommend a period of watchful waiting before considering immunosuppressive treatment. Likelihood of achieving spontaneous remission is much higher if anti-proteinuric therapy with ace inhibitors or angiotensin II receptor blockers is commenced.Recommended first line immunosuppressive therapy often includes: cyclophosphamide alternating with a corticosteroid, also known as the Ponticelli regime. Immunosuppressive therapy options Corticosteroids: They have been tried with mixed results, with one study showing prevention of progression to kidney failure without improvement in proteinuria. Chlorambucil Cyclosporine Tacrolimus Cyclophosphamide Mycophenolate mofetil RituximabPerhaps the most difficult aspect of membranous glomerulonephritis is deciding which people to treat with immunosuppressive therapy as opposed to simple "background" or anti-proteinuric therapies. A large part of this difficulty is due to a lack of ability to predict which people will progress to end-stage kidney disease, or kidney disease severe enough to require dialysis. Because the above medications carry risk, treatment should not be initiated without careful consideration as to risk/benefit profile. Of note, corticosteroids (typically Prednisone) alone are of little benefit. They should be combined with one of the other 5 medications, each of which, along with prednisone, has shown some benefit in slowing down progression of membranous nephropathy. It must be kept in mind, however, that each of the 5 medications also carry their own risks, on top of prednisone.The twin aims of treating membranous nephropathy are first to induce a remission of the nephrotic syndrome and second to prevent the development of end-stage kidney failure. A meta-analysis of four randomized controlled trials comparing treatments of membranous nephropathy showed that regimes comprising chlorambucil or cyclophosphamide, either alone or with steroids, were more effective than symptomatic treatment or treatment with steroids alone in inducing remission of the nephrotic syndrome. Prognosis About a third of untreated patients have spontaneous remission, another third progress to require dialysis and the last third continue to have proteinuria, without progression of kidney failure. Terminology The closely related terms membranous nephropathy (MN) and membranous glomerulopathy both refer to a similar constellation but without the assumption of inflammation. Membranous nephritis (in which inflammation is implied, but the glomerulus not explicitly mentioned) is less common, but the phrase is occasionally encountered. These conditions are usually considered together. By contrast, membranoproliferative glomerulonephritis has a similar name, but is considered a separate condition with a distinctly different causality. Membranoproliferative glomerulonephritis involves the basement membrane and mesangium, while membranous glomerulonephritis involves the basement membrane but not the mesangium. (Membranoproliferative glomerulonephritis has the alternate name "mesangiocapillary glomerulonephritis", to emphasize its mesangial character.) References == External links ==
Genitopatellar syndrome	Genitopatellar syndrome is a rare disorder consisting of congenital flexion contractures of the lower extremities, abnormal or missing patellae, and urogenital anomalies. Additional symptoms include microcephaly, severe psychomotor disability. In 2012, it was shown that mutations in the gene KAT6B cause the syndrome. Genitopatellar syndrome (GTPTS) can be caused by heterozygous mutation in the KAT6B gene on chromosome 10q22. The Say-Barber-Biesecker variant of Ohdo syndrome, which has many overlapping features with GTPTS, can also be caused by heterozygous mutation in the KAT6B gene. Signs and symptoms Genitopatellar syndrome is characterized by genital abnormalities, missing or underdeveloped kneecaps (patellae), intellectual disability and abnormalities affecting other parts of the body. It is also associated with delayed development and intellectual disability, which are often severe. Affected individuals may have an unusually small head (microcephaly) and structural brain abnormalities, including agenesis of the corpus callosum.Major features include: Patellar hypoplasia/agenesis Flexion contractures at the hips and knees Agenesis of the corpus callosum with microcephaly Hydronephrosis and/or multiple kidney cysts Atrial septal defect Intestinal malrotation Talipes equinovarus (including club feet) Feeding difficultiesOther features may include: Dental anomalies (delayed eruption of teeth) Hearing loss Thyroid anomalies Anal anomalies Hypotonia Global developmental delay/intellectual disability Cause Genitopatellar syndrome is inherited in an autosomal dominant fashion. The mutation responsible for the syndrome occurs in the KAT6B gene. This gene is located on the long arm of chromosome 10 (10q22.2).The KAT6B gene gene product is an enzyme called histone acetyltransferase which functions in regulating and making of histone which are proteins that attach to DNA and give the chromosomes their shape. The function of histone acetyltransferase produced from KAT6B is unknown but it is considered as a regulator of early development. There is little known about how the mutation in the KAT6B causes the syndrome but researchers suspects that the mutations occur near the end of the KAT6B gene and causes it to produce shortened acetyltransferase enzyme. The shortened enzyme alters the regulation of other genes. On the other hand, the mutation of KAT6B leading to the specific features of genitopatellar syndrome is still not surely proven. Diagnosis Even though clinical diagnostic criteria have not been 100 percent defined for genitopatellar syndrome, the researchers stated that the certain physical features could relate to KAT6B mutation and result in the molecular genetic testing. The researchers stated that the Individuals with two major features or one major feature and two minor features are likely to have a KAT6B mutation. To diagnose the Genitopatellar Syndrome, there are multiple ways to evaluate. The primary method of diagnosing Genitopatellar Syndrome is through molecular genetic testing. Evaluation by developmental specialist Feeding evaluation Baseline hearing evaluation Thyroid function tests Evaluation of males for cryptorchidism Orthopedic evaluation if contractures are present or feet/ankles are malpositioned Hip X-rays to evaluate for femoral head dislocation Kidney ultrasound examination for hydronephrosis and cysts Echocardiogram for congenital heart defects Evaluation for laryngomalacia if respiratory issues are present Evaluation by gastroenterologist as needed, particularly if bowel malrotation is suspected Treatment There is no cure for genitopatellar syndrome. However, there are treatments for the different symptoms. For the developmental symptoms, Educational intervention and speech therapy beginning in infancy could help to reduce the high risk for motor, cognitive, speech, and language delay. For the skeletal features, referral to an orthopedist for consideration of surgical release of contractures. In addition, early referral to physical therapy could help increase joint mobility. Lastly, thyroid hormone replacement could help out the thyroid dysfunction. History In 1988, Goldblatt et al. first reported a 4-year-old boy with hypoplastic patellae, mental retardation, scrotal hypoplasia, skeletal deformities, kidney anomalies, flattened nasal bridge, and short stature. Later in 2000, Cormier-Daire et al. reported seven patients with genital anomalies (scrotal hypoplasia and cryptorchidism in the boys and clitoral hypertrophy in the girls), facial dysmorphism, kidney anomalies, absent patellae, and severe mental retardation in the two survivors. The condition is now known as genitopatellar syndrome. See also Say-Barber-Biesecker-Young-Simpson syndrome KAT6B References == External links ==
Diplegia	Diplegia, when used singularly, refers to paralysis affecting symmetrical parts of the body. This is different from hemiplegia which refers to spasticity restricted to one side of the body, paraplegia which refers to paralysis restricted to the legs and hip, and quadriplegia which requires the involvement of all four limbs but not necessarily symmetrical. Diplegia is the most common cause of crippling in children, specifically in children with cerebral palsy. Other causes may be due to injury of the spinal cord. There is no set course of progression for people with diplegia. Symptoms may get worse but the neurological part does not change. The primary parts of the brain that are affected by diplegia are the ventricles, fluid filled compartments in the brain, and the wiring from the center of the brain to the cerebral cortex. There is also usually some degeneration of the cerebral neurons, as well as problems in the upper motor neuron system. The term diplegia can refer to any bodily area, such as the face, arms, or legs. Facial diplegia Facial diplegia refers to people with paralysis of both sides of their face. Bilateral occurs when the onset of the second side occurs within one month of the onset of the first side. Facial diplegia occurs in 50% of patients with Guillain–Barré syndrome. Facioscapulohumeral muscular dystrophy (FSHD) is the second most common adult-onset muscular dystrophy with facial weakness being a distinct feature of FSHD in over 90% of cases. Causes Facial paralysis is usually caused by traumatic, infectious, neurological, metabolic, toxic, vascular, and idiopathic conditions. While over 50% of the cases of unilateral facial paralysis are caused by idiopathic conditions, less than 20% of bilateral cases are idiopathic. The most common infectious cause of facial diplegia is Lyme disease. Treatment The treatment for facial diplegia depends on the underlying cause. Some causes are usually treatable such as infectious, toxic, and vascular by treating the main problem first. After the underlying problem is cured, the facial paralysis usually will go away. Diplegia of the arms People with diplegia in their arms experience difficulties in reaching, pointing, grasping, releasing, manipulating objects and many other motor functions performed by the hands and arms. Causes There are several ways of getting diplegia in the arms. It is very common for people with cerebral palsy to have diplegia of the arms. Although most people with cerebral palsy have diplegia in their legs, some people have diplegia in their arms. Other ways of getting paralysis of both arms is through a traumatic event or injury. Treatment There are several different modes of treatment for people with paralysis in their upper limbs. For example, behavioral and environmental treatments may include physiotherapy, occupational therapy, motor learning, strength training, and neurodevelopment treatment. Another treatment may be through the use of splints and casts. Electrophysical agents may be used such as neuromuscular electrical stimulation (NMES). Sometimes pharmacological treatments are necessary such as Botulinum toxin type A. On more severe cases surgery of the upper limbs may be required. Diplegia in the legs Diplegia of the legs consists of paralysis of both legs. There are 3 levels of severity. Mild diplegia means the person can usually walk but might walk a little differently, can usually play and run to a limited extent. Moderate diplegia means the person can usually walk but with a slight bend in the knees. They usually cant run and have to use the handrails to go up and down steps. People with severe diplegia usually need crutches, a walker, or a wheelchair to be able to get around.Children with diplegia in the legs have a delayed growth in their leg muscles which causes the muscles to be short. This then causes the joints to become stiff and the range of motion to decrease as the child grows. “For the majority of children with diplegia, growth and development are not a problem. Children with diplegia are eventually able to walk, just normally later; they generally attend regular schools and become independently functioning adults.” Causes The most common cause of diplegia in the legs is cerebral palsy. Paralysis of the legs may also be caused by trauma, injury, or genetics, but this is very rare. Age of onset Usually occurs within 2 periods: With premature babies full diagnosis usually between ages 2–5 yearsDiplegia is usually not diagnosed before the age of 2 years yet the symptoms and signs of the earlier stages are typical and should enable the diagnosis to be made before the contractures have occurred. Parents suspecting diplegia should take their child to the doctor to potentially get an earlier diagnosis. Treatment and care This is broken up by age categories. Different ages require different forms of treatment which may include: therapy, bracing, walkers, wheelchairs, and surgery. Currently the treatments for children are concentrated primarily on independent walking but instead a more independence-oriented therapeutic approach would be more beneficial. This way the child can still focus on walking but at the same time be taught to do things for themselves while using the best method of walking for them. This could include using a walker or wheelchair to get around and do things easier than focusing all the attention on walking so early. For people requiring surgery, distal hamstring lengthening is the most common operation performed because it reduces knee flexion and improves knee motion. Birth to 1 year “This first year sees the development of many milestones, such as head control, reaching out for a toy, sitting, starting to vocalize sounds, and finger feeding.” Most parents want their children to excel very fast, but there is a wide upper and lower range of development time for premature babies so its very hard to diagnose cerebral palsy or diplegia this early. The most common symptom of a child with diplegia is stiff lower extremities. This should become apparent by the six month mark which means he or she does not have severe diplegia. During this age if a child is not moving his legs on his own then it is recommended to do some exercise, especially gentle stretching with the child. 1 to 3 years “This is the age at which the characteristics of diplegia become more noticeable, mainly because, unlike other children at this age, the child with diplegia is not walking.” By the age of three, it is important for the child to be in a specialized school environment so the child can participate in physical therapy and learn social skills. Parents should not force the child to sit, crawl, or walk a certain way during this age period. Let the child do whats comfortable for them and allow the therapist to correct this problem. If you want to help your child walk more, then push toys are recommended for walking aids. Regular exams should be done to make sure the childs legs are growing normally and he or she is not having any problems with the hip. 4 to 6 years “This is the age range at which the child with diplegia makes the most significant physical improvement in motor function.” During this time period the child makes major improvements in motor function. He or she should be in a regular school and focus on cognitive issues not therapy. A child using a walking aid for mobility to move around with the other children is not a bad thing. If a child is not walking yet, then this is usually caused by a problem in balance, muscle coordination, spasticity, or leg alignment. Each of these reasons should be looked into closely so the problem can be addressed and fixed. 7 to 12 years “By the time a child reaches this age the rate of physical improvement has leveled off in areas such as balance and coordination, and its a good idea to refocus the child’s attention away from additional physical improvement and toward intellectual learning.” During this time period a child should lean away from physical therapy and do more outdoor or social exercises such as sports and adaptive P.E. Usually by age 8-10 a child has reached maximum walking ability. This will usually decrease a little when a child hits puberty and gains height and weight because walking becomes harder during this changing period. Any significant problems in walking should be addressed with surgery at this stage. 13 to 18 years “During this time period of a child’s development, a major issue is separating from the family.” Parents should learn how to cope with their child growing up and give them more freedom and independence. Teenagers need to make their own decisions and learn from them. One way to do this is for parents to compromise and let the child make smaller decisions so they feel important. Parents should also understand that their child may regress in walking some from increase in height and weight. Going back to therapy during puberty is recommended so the teenager can adjust to the increase in height and weight and not regress as much. History of the term diplegia In 1890 Sachs and Peterson first referenced to the term diplegia, along with the word paraplegia, for their cerebral palsy classification. In 1955 the word diplegia was used in the clinical field to describe a patient whose limbs were affected in a symmetrical way. This included limbs on the same side of the body thus including hemiplegia. Later in 1956 diplegia was presented as a form of bilateral cerebral palsy affecting like parts on either side of the body. In 1965 Milani Comparetti distinguished diplegia from tetraplegia by considering the patients upper limbs ability to express a sufficient support reaction. Thus diplegia usually refers to just symmetry of one body part or limb, as the legs, or arms. While tetraplegia or quadriplegia refers to paralysis of all 4, both arms and legs. == References ==
Chronic pulmonary aspergillosis	Chronic pulmonary aspergillosis is a long-term fungal infection caused by members of the genus Aspergillus—most commonly Aspergillus fumigatus. The term describes several disease presentations with considerable overlap, ranging from an aspergilloma—a clump of Aspergillus mold in the lungs—through to a subacute, invasive form known as chronic necrotizing pulmonary aspergillosis which affects people whose immune system is weakened. Many people affected by chronic pulmonary aspergillosis have an underlying lung disease, most commonly tuberculosis, allergic bronchopulmonary aspergillosis, asthma, or lung cancer. Classification Chronic pulmonary aspergillosis as a term encompasses a number of different presentations of varying severity. There is considerable overlap between disease forms which adds to confusion during diagnosis. The primary differentiation comes from radiological findings and serology. Aspergilloma An aspergilloma is a fungus ball composed of Aspergillus hypha - the long filamentous strands which extend from the fungus to enable growth and reproduction. They can arise within any bodily cavity, though in chronic pulmonary aspergillosis they form within pulmonary cavities that have been colonized by Aspergillus spp. If there is a single, stable cavity that provides minimal symptoms, the term simple aspergilloma is commonly used to distinguish it from more severe forms of chronic pulmonary aspergillosis. Aspergillus nodule Aspergillus can form single or multiple nodules which may or may not form a cavity. Whilst usually benign in nature, they can sometimes cause symptoms such as cough or an exacerbation of existing disease such as asthma. Histologically, there is necrosis surrounded by granulomatous inflammation with some multinucleated giant cells present. Chronic cavitary pulmonary aspergillosis When people without immunocompromise undergo formation of one or more pulmonary cavities, this is called chronic cavitary pulmonary aspergillosis. Historically it was also known as "complex aspergilloma" in contrast to a "simple aspergilloma"; this is now considered inaccurate as many cases do not have a visible aspergilloma on imaging. In contrast to aspergilloma and Aspergillus nodules, the vast majority of people with chronic cavitary pulmonary aspergillosis have positive tests for IgG antibodies. Chronic fibrosing pulmonary aspergillosis When chronic cavitary pulmonary aspergillosis is left untreated, it can progress to a form of aspergillosis known as chronic fibrosing pulmonary aspergillosis). As a result of the ongoing inflammation over an extended period of time, extensive fibrosis of the lung parenchyma occurs. This leads to a state known colloquially as "destroyed lung", and has features resembling treated pulmonary tuberculosis. Chronic necrotizing pulmonary aspergillosis Also known as subacute invasive pulmonary aspergillosis, this form of chronic pulmonary aspergillosis leads to progressive features over the course of one to three months—usually in people with some degree of immunocompromise. It is more common in people who are elderly or dependent on alcohol, or with diseases such as diabetes, malnutrition, chronic obstructive pulmonary disease or HIV/AIDS. In contrast to chronic cavitary pulmonary aspergillosis, for example, IgG antibodies for Aspergillus or an antigen called galactomannan may be found in the blood as well as in sputum samples. Signs and symptoms People with chronic pulmonary aspergillosis typically present with a prolonged, several month history of unintentional weight loss, chronic cough which is normally productive of sputum, shortness of breath and haemoptysis. One small case series of 18 people found these to be the most common presenting symptoms. Less common symptoms include severe fatigue or malaise, chest pain, sputum production without cough, and fever. Fever would not typically be expected unless they had the subacute invasive subtype. Furthermore, it is possible for less severe subtypes to be asymptomatic. Beyond the direct symptoms, it is possible to have general signs of underlying lung pathology such as digital clubbing—especially when there has been an underlying disease such as tuberculosis or where disease has caused heart failure (known as cor pulmonale). Complications Chronic pulmonary aspergillosis can cause bleeding into the lung parenchyma which can range from mild to life-threatening. If left untreated, as the disease progresses the fungus can spread into the bloodstream causing a state known as fungemia. This widespread infection can distribute fungal spores to other parts of the body, and lead to areas of infarction, and cause haemorrhages. Causes Aspergillosis is an infection caused by fungi from the genus Aspergillus. The vast majority of cases are caused by Aspergillus fumigatus—a filamentous fungus found ubiquitously on every continent including Antarctica. Other species of Aspergillus include A. flavus and A. terreus.The major risk factors for chronic pulmonary aspergillosis are previous cavity formation from other respiratory conditions. Examples include collapsed lungs which have formed bullae, chronic obstructive lung disease, lung cancer, and fibrocavitary sarcoidosis. Another risk factor is immunosuppression; most commonly, this includes allogeneic stem cell transplantation, prolonged neutropaenia, immunosuppressive drug therapy, chronic granulomatous disease and haematological malignancies. Certain demographics are also at higher risk, including the elderly, male gender and those with a low body mass index.There appears to be increasing evidence for complex genetic factors increasing the risk of developing chronic pulmonary aspergillosis, such as defects to toll-like receptor (TLR) 4, IL1 and IL15, TLR3, TLR10, TREM1, VEGFA, DENND1B, and PLAT. Mechanism The full underlying pathogenesis is not completely understood. Most people with chronic pulmonary aspergillosis have functional immune status, but usually have underlying structural damage to the lungs from an underlying process or disease. Most commonly, pre-existing pulmonary cavities from other diseases such as tuberculosis become colonised with Aspergillus conidia which have been inhaled—humans inhale between 1,000 and 10 billion spores per day, of which A. fumigatus is the most common.Aspergillomas themselves usually form in existing cavities but the cavities may form directly from chronic pulmonary aspergillosis. People with pulmonary tuberculosis with a cavity larger than 2 cm appear to have a 20% increased risk of developing chronic pulmonary aspergillosis.It is postulated that conidia, once inhaled, are attacked by the host immune defences—specifically phagocytes and alveolar macrophage resident in the small airways. It is unknown whether these defences are sufficient to clear conidia or whether they are directly responsible for the inflammation leading to chronic pulmonary aspergillosis. Some Aspergillus have the ability to inhibit phagocyte nicotinamide adenine dinucleotide phosphate oxidase activation which is one of the core defence systems against filamentous fungi, which may increase susceptibility of the host to chronic pulmonary aspergillosis. Diagnosis The diagnosis of chronic pulmonary aspergillosis is often initially considered when patients present with a history of unintentional weight loss and fatigue. Confirmation of this suspicion is normally achieved with a combination of radiological imaging and serological testing, with the goal of excluding other diagnoses like tuberculosis and finding evidence of fungus present. Whilst cavities seen on chest X-rays can raise suspicion, positive IgG testing for Aspergillus is required for confirmation.Sputum samples can be sent for culture, but where these return negative patients should undergo bronchoscopy and bronchoalveolar lavage for further culture samples. Concurrent infections with non-tuberculous mycobacteria, or atypical infections such as MRSA or Pseudomonas aeruginosa are common and these can also form cavities.To confirm the presence of an aspergilloma, there needs to be radiological evidence of a round mass in the lungs with confirmatory evidence either from culture or IgG testing. The distinction between simple aspergilloma, and more advanced chronic cavitary pulmonary aspergillosis, will depend on the severity of inflammation, radiological evidence, and changes over time. To confirm chronic pulmonary aspergillosis, the current criteria is one large cavity or more than two small cavities, either with or without aspergilloma. This must be accompanied by at least one symptom of fever, weight loss, fatigue, cough, sputum production, haemoptysis or shortness of breath for at least 3 months. Furthermore, as with aspergilloma, there must be positive IgG testing but this can be with or without culture. To confirm Aspergillus nodules as opposed to aspergilloma, these must be seen directly on imaging or confirmed by percutaneous or surgical biopsy.The fibrosing form—chronic fibrosing pulmonary aspergillosis—has similar criteria to chronic cavitary pulmonary aspergillosis but will be accompanied by significant fibrosis seen on either biopsy, tomosynthesis, or high resolution computed tomography.If chronic pulmonary aspergillosis has progressed to subacute invasive pulmonary aspergillosis, there must be a degree of immunosuppression. The microbiological criteria are similar to those of invasive aspergillosis but normally slower in progression, i.e. months rather than weeks. Furthermore, there must be evidence of IgG or galactomannan in the blood and a confirmatory biopsy of affected tissue. Treatment People with single aspergillomas generally do well with surgery to remove the aspergilloma, and are best given pre-and post-operative antifungal medications. Often, no treatment is necessary; however, if a person coughs up blood (haemoptysis), treatment may be required using surgery or injection of dye to locate the bleeding combined with embolisation using chemicals or tiny material meant to block the bleeding blood vessel. Studies of tranexamic acid for treating haemoptysis do not provide strong evidence for long-term benefit.For chronic cavitary pulmonary aspergillosis and chronic fibrosing pulmonary aspergillosis, lifelong use of antifungal medications is commonplace. Itraconazole and voriconazole are first- and second-line antifungal agents respectively. Posaconazole or isavuconazole can be used as third-line agent for people with chronic pulmonary aspergillosis who are intolerant of or developed resistance to the first- and second-line agents. Regular chest X-rays, serological and mycological parameters, and quality of life questionnaires are used to monitor treatment progress. It is important to monitor the blood levels of antifungals to ensure optimal dosing as individuals vary in their absorption levels of these medications. Prognosis References == External links ==
45,X/46,XY mosaicism	45,X/46,XY mosaicism, also known as X0/XY mosaicism and mixed gonadal dysgenesis, is a mutation of sex development in humans associated with sex chromosome aneuploidy and mosaicism of the Y chromosome. This is called a mosaic karyotype because, like tiles in mosaic floors or walls, there is more than one type of cell. It is a fairly rare chromosomal disorder at birth, with an estimated incidence rate of about 1 in 15,000 live births. Mosaic loss of the Y chromosome in previously non-mosaic men grows increasingly common with age.The clinical manifestations are highly variable, ranging from partial virilisation and ambiguous genitalia at birth, to patients with completely male or female gonads. Most individuals with this karyotype have apparently normal male genitalia, and a minority have female genitalia, with a significant number of individuals showing genital abnormalities or intersex characteristics. A significantly higher than normal number of other developmental abnormalities are also found in individuals with X0/XY mosaicism. Psychomotor development is normal. Signs and symptoms Although similar in some ways to true hermaphroditism, the conditions can be distinguished histologically and by karyotyping. The observable characteristics (phenotype) of this condition are highly variable, ranging from gonadal dysgenesis in males, to Turner-like females and phenotypically normal males. The phenotypical expression may be ambiguous, male or female depending on the extent of the mosaicism. The most common presentation of 45,X/46,XY karyotype is phenotypically normal male, next being genital ambiguity.There is a range of chromosomal anomalies within 45,X/46,XY where the variations are very complex, and the actual result in living individuals is often not a simple picture. Most patients with this karyotype are known to have abnormal gonadal histology and heights considerably below their genetic potential. High gonadotropin levels have been described in both male and female patients, as well as low levels of testosterone in male patients. Dosage loss of SHOX gene is commonly associated with short stature. Psychomotor development is normal. As the gonads may not be symmetrical, the development of the Müllerian duct and Wolffian duct may be asymmetrical, too. Because of the presence of dysgenetic gonadal tissue and Y chromosome material, there is a high risk of the development of a gonadoblastoma. Causes In a normal situation, all the cells in an individual will have 46 chromosomes with one being an X and one a Y or with two Xs. However, sometimes during this complicated early copying process (DNA replication and cell division), one chromosome can be lost. In 45,X/46,XY, most or all of the Y chromosome is lost in one of the newly created cells. All the cells then made from this cell will lack the Y chromosome. All the cells created from the cells that have not lost the Y chromosome will be XY. The 46,XY cells will continue to multiply at the same time as the 45,X cells multiply. The embryo, then the fetus and then the baby will have what is called a 45,X/46,XY constitution. This is called a mosaic karyotype because, like tiles in mosaic floors or walls, there is more than one type of cell.There are many chromosomal variations that cause the 45,X/46,XY karyotype, including malformation (isodicentricism) of the Y chromosomes, deletions of Y chromosome or translocations of Y chromosome segments. These rearrangements of the Y chromosome can lead to partial expression of the SRY gene which may lead to abnormal genitals and testosterone levels. Diagnosis Identification of 45,X/46,XY karyotype has significant clinical implications due to known effects on growth, hormonal balance, gonadal development and histology. 45,X/46,XY is diagnosed by examining the chromosomes in a blood sample. The age of diagnosis varies depending on manifestations of disease prompting reason for cytogenetic testing. Many patients are diagnosed prenatally due to fetal factors (increased nuchal fold, or abnormal levels of serum), maternal age or abnormal ultrasounds, while others will be diagnosed postnatal due to external genital malformation. It is not uncommon for patients to be diagnosed later in life due to short stature or delayed puberty, or a combination of both.45,X/46,XY mosaicism can be detected prenatally through amniocentesis however, it was determined that the proportion of 45,X cells in the amniotic fluid cannot predict any phenotypic outcomes, often making prenatal genetic counselling difficult. Management See also Gonadal dysgenesis Mosaic (genetics) Turner syndrome References == External links ==
Acne conglobata	Acne conglobata is a highly inflammatory disease presenting with comedones, nodules, abscesses, and draining sinus tracts.This condition generally begins between the ages of 18 and 30. It usually persists for a very long time, and often until the patient is around 40 years old. Although it often occurs where there is already an active acne problem, it can also happen to people whose acne has subsided. Although the cause of this type of acne is unknown, it is associated with testosterone and thus appears mainly in males. It can be caused by anabolic steroid abuse and sometimes appears in males after stopping testosterone therapy. It can also happen to someone who has a tumor that is releasing large amounts of androgens, or to people in remission from diseases, such as leukemia. In certain persons, the condition may be triggered by exposure to aromatic hydrocarbons or ingestion of halogens. Presentation Acne conglobata is a severe, inflammatory variant of acne. Inflammatory papules, papulonodules, nodules and pustules may coalesce, and abscesses in the skin may form sinuses that interconnect. Bleeding or draining of acneiform plaques may be present. The systemic findings seen in acne fulminans are not present. A component of the follicular occlusion tetrad, acne conglobata may be seen with hidradenitis suppurativa, pilonidal disease and dissecting cellulitis of the scalp. The face, chest, back and buttocks may be involved. Treatment The most common treatment is the acne medication isotretinoin. It may be combined with prednisone. Antibiotics such as dapsone, tetracycline or erythromycin may also be prescribed. An option to treat with carbon dioxide laser therapy, followed by topical tretinoin therapy has been described.Surgery may be necessary to remove large nodules. Alternatively, nodules can be injected with corticosteroids such as triamcinolone. See also List of cutaneous conditions References == External links ==
Tetra-amelia syndrome	Tetra-amelia syndrome (tetra- + amelia), also called autosomal recessive tetraamelia, is an extremely rare autosomal recessive congenital disorder characterized by the absence of all four limbs. Other areas of the body are also affected by malformations, such as the face, skull, reproductive organs, anus, lungs and pelvis. The disorder can be caused by recessive mutations in the WNT3 or RSPO2 genes. Presentation Tetra-amelia syndrome is characterized by the complete absence of all four limbs. The syndrome causes severe malformations of various parts of the body, including the face and head, heart, nervous system, skeleton, and genitalia. In many cases, the lungs are underdeveloped, which makes breathing difficult or impossible. Because children with tetra-amelia syndrome have such serious medical problems, most are stillborn or die shortly after birth. Cause RSPO2 and WNT3 genes Researchers have found loss-of-function mutations in the WNT3 or the RSPO2 genes in people with tetra-amelia syndrome from several consanguineous families. These two gene encode proteins belonging to the WNT pathway which plays critical roles during development. The protein produced from the WNT3 and RSPO2 genes are involved in the formation of the limbs and other body systems during embryonic development. Mutations in the WNT3 or RSPO2 genes prevent cells from producing functional WNT3 and RSPO2 proteins, which disrupts normal limb formation and leads to the other serious birth defects associated with tetra-amelia syndrome. According to a 2018 study by Bruno Reversade, the loss of RSPO2, unlike WNT3, also prevents formation of the lungs causing a lethal syndrome of tetra-amelia. Inheritance within families In most of the families reported so far, tetra-amelia syndrome appears to have an autosomal recessive pattern of inheritance. This means the defective gene responsible for the disorder is located on an autosome , and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. Epidemiology Tetra-amelia syndrome has been reported in only a few families worldwide. According to a 2011 study by Bermejo-Sanchez, amelia – that is, the lacking of one or more limbs – occurs in roughly 1 out of every 71,000 pregnancies. People with tetra-amelia syndrome Joanne ORiordan of Millstreet, Cork, Ireland. At the age of 16 she addressed the United Nations in New York. She appeared before the International Telecommunication Union’s conference ‘Girls in Technology’, receiving a standing ovation after delivering the keynote speech. Hirotada Ototake Nick Vujicic, founder of Life Without Limbs. Prince Randian Violetta (entertainer) Kent Bell (1965-2015) of Jacksonville, FL, scoreboard operator and disabled rights advocate, appeared on Oprah Winfrey show and in numerous print articles over the course of his life. Rob Mendez, varsity football team offensive coordinator at Francis Parker School (San Diego). Christian Arndt of Germany, media presenter. References External links "Tetra-amelia syndrome - Genetics Home Reference". U.S. National Library of Medicine. Retrieved 2009-01-09.
Rasmussen syndrome	Rasmussen syndrome is a condition characterized by multiple skin growths called trichoepitheliomas. See also List of cutaneous neoplasms associated with systemic syndromes List of cutaneous conditions == References ==
Alezzandrini syndrome	Alezzandrini syndrome is a very rare syndrome characterized by a unilateral degenerative retinitis, followed after several months by ipsilateral vitiligo on the face and ipsilateral poliosis.: 864 Deafness may also be present.: 864 See also List of cutaneous conditions Skin lesion References == External links ==
Meralgia paraesthetica	Meralgia paresthetica or meralgia paraesthetica is numbness or pain in the outer thigh not caused by injury to the thigh, but by injury to a nerve that extends from the spinal column to the thigh. This chronic neurological disorder involves a single nerve—the lateral cutaneous nerve of the thigh, which is also called the lateral femoral cutaneous nerve (and hence the syndrome lateral femoral cutaneous neuropathy). The term "meralgia paraesthetica" combines four Greek roots to mean "thigh pain with anomalous perception". The disorder has also been nicknamed bikini brief syndrome and skinny pants syndrome, because it can be caused by wearing tight clothing. Signs and symptoms Pain on the outer side of the thigh, occasionally extending to the outer side of the knee, usually constant. A burning sensation, tingling, or numbness in the same area Multiple bee-sting like pains in the affected area Occasionally, aching in the groin area or pain spreading across the buttocks Usually more sensitive to light touch than to firm pressure Hypersensitivity to heat (warm water from shower feels like it is burning the area) Occasionally, patients may complain of itching or a bothersome sensation rather than pain in the affected area.The entire distribution of the nerve is rarely affected. Usually, the unpleasant sensation(s) affect only part of the skin supplied by the nerve. Cause The lateral femoral cutaneous nerve most often becomes injured by entrapment or compression where it passes between the upper front hip bone (ilium) and the inguinal ligament near the attachment at the anterior superior iliac spine (the upper point of the hip bone). Less commonly, the nerve may be entrapped by other anatomical or abnormal structures, or damaged by diabetic or other neuropathy or trauma such as from seat belt injury in an accident.The nerve may become painful over a period of time as weight gain makes underwear, belting or the waistband of pants gradually exert higher levels of pressure. Pain may be acute and radiate into the rib cage, and into the groin, thigh, and knee. Alternately, weight loss or aging may remove protective fat layers under the skin, so the nerve can compress against underwear, outer clothing, and—most commonly— by belting. Long periods of standing or leg exercise that increases tension on the inguinal ligament may also cause pressure.The lateral cutaneous nerve of the thigh can occasionally be damaged during laparoscopic hernia repair, or scarring from the operation can lead to meralgia paraesthetica. Diagnosis Diagnosis is largely based on patient description and relevant details about recent surgeries, hip injuries, or repetitive activities that could irritate the nerve. Examination checks for sensory differences between the affected leg and the other leg.Differentiation of meralgia paraesthetica from a second lumbar root lesion remains the greatest problem in diagnosis and relies on the careful delineation of the paraesthetic area, the degree of numbness and a negative MR scan of the lumbar spine. Although the L2 area and the area supplied by the lateral cutaneous nerve correspond well laterally, the second root also contributes to the innervation of the groin and the inner aspect of the thigh. Furthermore, in L2 root lesions the analgesia is very slight because of the overlap between L2 and L3, whereas in lesions of the lateral cutaneous nerve, there is almost full anaesthesia, with a clear-cut border.Accurate diagnosis may require an abdominal and pelvic examination to exclude problems in those areas.Electromyographic (EMG) nerve-conduction studies may be required.X-rays may be needed to exclude bone abnormalities that might put pressure on the nerve; likewise CT or MRI scans to exclude soft tissue causes such as a tumor. Treatment Treatment varies. In most cases, the best treatment is to remove the cause of compression by modifying patient behavior, in combination with medical treatment to relieve inflammation and pain. Whatever the cause, typical treatment takes several weeks to months—depending on the degree of nerve damage. Typical treatment options include: Active Release Technique (ART) soft tissue treatment Wearing looser clothing and suspenders rather than belts Weight loss if obesity is present Non-steroidal anti-inflammatory drugs (NSAIDs) to reduce inflammatory pain if pain level limits motion and prevents sleep Reducing physical activity in relation to pain level. Acute pain may require absolute bed rest Deep tissue massage to reduce tension in the gluteal muscles, most commonly the gluteus maximus. The tensor fasciae latae may also be implicated.For lower pain levels, treatment may involve having the patient: Seek appropriate physical therapy, such as stretching and massage, which plays a large role in the management of pain Learn to perform inguinal ligament stretching (from a physical therapist) which can rapidly relieve symptoms Use rest periods to interrupt long periods of standing, walking, cycling, or other aggravating activity Lose weight, and exercise to strengthen abdominal muscles Wear clothing that is loose at the upper front hip area Apply heat, ice, or electrical stimulation Take nonsteroidal anti-inflammatory medications for 7–10 days Remove hair in affected area (shave) Lidocaine patches (after shaving area) Titanium dioxide patches to interfere with the electrostatic effect of the nerves on the surface of the skinPain may take significant time (weeks) to stop and, in some cases, numbness persists despite treatment. In severe cases, the physician might perform a local nerve block at the inguinal ligament, using a combination of local anaesthetic (lidocaine) and corticosteroids to provide relief that may last several weeks.Pain modifier drugs for neuralgic pain (such as amitriptyline, carbamazepine or gabapentin) may be tried, but are often not as helpful in the majority of patients.Persistent and severe cases may require surgery to decompress the nerve or, as a last resort, to resect the nerve. The latter treatment leaves permanent numbness in the area. See also References External links Meralgia Paresthetica at eMedicine.com
Perlman syndrome	Perlman syndrome (PS) (also called renal hamartomas, nephroblastomatosis and fetal gigantism) is a rare overgrowth disorder present at birth. It is characterized by polyhydramnios and fetal overgrowth, including macrocephaly, neonatal macrosomia, visceromegaly, dysmorphic facial features, and an increased risk for Wilms tumor at an early age. The prognosis for Perlman syndrome is poor and it is associated with a high neonatal mortality. Perlman syndrome is an uncommon genetic disorder grouped with overgrowth syndrome in which an abnormal increase is often noted at birth in the size of the body or a body part of the infant. The disorder, also called renal hamartomas, nephroblastomatosis and fetal gigantism, has also been grouped with Renal cell carcinoma. The characteristic features include polyhydramnios, fetal overgrowth, including macrocephaly, neonatal macrosomia, visceromegaly, dysmorphic facial features, and an increased risk for Wilms tumor at an early age. Signs and symptoms Genetics The gene thought to cause some of the cases of Perlman syndrome is DIS3L2 found on chromosome 2 at 2q37.2 and is thought to have an important role in the mitotic cell cycle. Although both sexes are affected, the sex ratio of male to female is 2:1. The syndrome has been described in both consanguineous and non-consanguineous couplings. No chromosomal abnormalities have been observed, except for in the case of Chernos et al., which showed a de novo mutation — an extra G positive band, a genetic mutation that neither parent possessed nor transmitted — on the tip of the short arm of chromosome 11. Diagnosis The diagnosis of Perlman syndrome is based on observed phenotypic features and confirmed by histological examination of the kidneys. Prenatal diagnosis is possible for families that have a genetic disposition for Perlman syndrome although there is no conclusive laboratory test to confirm the diagnosis. Fetal overgrowth, particularly with an occipitofrontal circumference (OFC) greater than the 90th centile for gestational age, as well as an excess of amniotic fluid in the amniotic sac (polyhydramnios), may be the first signs of Perlman. Using ultrasound diagnosis, Perlman syndrome has been detected at 18 weeks. During the first trimester, the common abnormalities of the syndrome observed by ultrasound include cystic hygroma and a thickened nuchal lucency. Common findings for the second and third trimesters include macrosomia, enlarged kidneys, renal tumors (both hamartoma and Wilms), cardiac abnormalities and visceromegaly.Prompt recognition and identification of the disorder along with accurate follow-up and clinical assistance is recommended as the prognosis for Perlman is severe and associated with a high neonatal death rate. Differential diagnosis Perlman syndrome shares clinical overlaps with other overgrowth disorders, with similarities to Beckwith–Wiedemann syndrome and Simpson–Golabi–Behmel syndrome having been particularly emphasized in scientific study. Similarities with Beckwith-Wiedemann syndrome include polyhydramnios, macrosomia, nephromegaly and hypoglycaemia. It is the distinctive facial dysmorphology of Perlman, including deep-set eyes, depressed nasal bridge, everted upper lip, and macrocephaly which allows the two conditions to be distinguished from one another. Diagnosis of Perlman syndrome also overlaps with other disorders associated with Wilms tumor, namely, Sotos syndrome and Weaver syndrome. Treatment Epidemiology Perlman syndrome is a rare disease with an estimated incidence of less than 1 in 1,000,000. As of 2008, fewer than 30 patients had ever been reported in the world literature. See also Beckwith–Wiedemann syndrome Multiple abnormalities Renal cell carcinoma References == External links ==
Starvation	Starvation is a severe deficiency in caloric energy intake, below the level needed to maintain an organisms life. It is the most extreme form of malnutrition. In humans, prolonged starvation can cause permanent organ damage and eventually, death. The term inanition refers to the symptoms and effects of starvation. Starvation may also be used as a means of torture or execution. According to the World Health Organization (WHO), hunger is the single gravest threat to the worlds public health. The WHO also states that malnutrition is by far the biggest contributor to child mortality, present in half of all cases. Undernutrition is a contributory factor in the death of 3.1 million children under five every year. Figures on actual starvation are difficult to come by, but according to the Food and Agriculture Organization, the less severe condition of undernourishment currently affects about 842 million people, or about one in eight (12.5%) people in the world population.The bloated stomach represents a form of malnutrition called kwashiorkor. The exact pathogenesis of kwashiorkor is not clear, as initially it was thought to relate to diets high in carbohydrates (e.g. maize) but low in protein. While many patients have low albumin, this is thought to be a consequence of the condition. Possible causes such as aflatoxin poisoning, oxidative stress, immune dysregulation, and altered gut microbiota have been suggested. Treatment can help mitigate symptoms such as the pictured weight loss and muscle wasting, however prevention is of utmost importance.Without any food, humans usually die in around 2 months. There was a surprising case when someone survived 382 days. Lean people can usually survive with a loss of up to 18% of their body mass. Obese people can tolerate more, possibly over 20%. Females survive longer than males. Signs and symptoms The following are some of the symptoms of starvation: Changes in behaviour or mental status The beginning stages of starvation impact mental status and behaviours. These symptoms show up as irritable mood, fatigue, trouble concentrating, and preoccupation with food thoughts. People with those symptoms tend to be easily distracted and have no energy. Physical signs As starvation progresses, the physical symptoms set in. The timing of these symptoms depends on age, size, and overall health. It usually takes days to weeks, and includes weakness, fast heart rate, shallow breaths that are slowed, thirst, and constipation. There may also be diarrhea in some cases. The eyes begin to sink in and glass over. The muscles begin to become smaller and muscle wasting sets in. One prominent sign in children is a swollen belly. Skin loosens and turns pale in color, and there may be swelling of the feet and ankles. Weakened immune system Symptoms of starvation may also appear as a weakened immune system, slow wound healing, and poor response to infection. Rashes may develop on the skin. The body directs any nutrients available to keeping organs functioning. Other symptoms Other effects of starvation may include: Anemia Gallstones Hypotension Stomach disease Cardiovascular and respiratory diseases Irregular or absent menstrual periods in women Kidney disease or failure Electrolyte imbalance Emaciation Oliguria Stages of starvation The symptoms of starvation show up in three stages. Phase one and two can show up in anyone that skips meals, diets, and goes through fasting. Phase three is more severe, can be fatal, and results from long-term starvation. Phase one: When meals are skipped, the body begins to maintain blood sugar levels by producing glycogen in the liver and breaking down stored fat and protein. The liver can provide glycogen for the first few hours. After that, the body begins to break down fat and protein. The body uses Fatty acids as an energy source for muscles but lowers the amount of glucose sent to the brain. Another chemical that comes from fatty acids is glycerol. It can be used as glucose for energy but eventually runs out. Phase two: Phase two can last for weeks at a time. In this phase, the body mainly uses stored fat for energy. The breakdown occurs in the liver and turns fat into ketones. After fasting for one week, the brain will use these ketones and any available glucose. Using ketones lowers the need for glucose, and the body slows the breakdown of proteins. Phase three: By this point, the fat stores are gone, and the body begins to turn to stored protein for energy. This means it needs to break down muscle tissues full of protein; the muscles break down very quickly. Protein is essential for cells to work correctly, and when it runs out, the cells can no longer function. The cause of death due to starvation is usually an infection or the result of tissue breakdown. This is due to the body becoming unable to produce enough energy to fight off bacteria and viruses. The final stage of starvation includes signals like hair color loss, skin flaking, swelling in the extremities, and a bloated belly. Even though they may feel hunger, people in the final stage of starvation usually cannot eat enough food to recover. Causes The body expends more energy than it takes in. This imbalance can arise from one or more medical conditions or circumstantial situations, which can include: Medical reasons Anorexia nervosa Bulimia nervosa Eating disorder, not otherwise specified Celiac disease Coma Major depressive disorder Diabetes mellitus Digestive disease Constant vomitingCircumstantial causes Child, elder, or dependant abuse Famine for any reason, such as political strife and war Hunger striking Excessive fasting Poverty Torture Biochemistry With a typical high-carbohydrate diet, the human body relies on free blood glucose as its primary energy source. Glucose can be obtained directly from dietary sugars and by the breakdown of other carbohydrates. In the absence of dietary sugars and carbohydrates, glucose is obtained from the breakdown of stored glycogen. Glycogen is a readily-accessible storage form of glucose, stored in notable quantities in the liver and skeletal muscle. After the exhaustion of the glycogen reserve, and for the next two to three days, fatty acids become the principal metabolic fuel. At first, the brain continues to use glucose. If a non-brain tissue is using fatty acids as its metabolic fuel, the use of glucose in the same tissue is switched off. Thus, when fatty acids are being broken down for energy, all of the remaining glucose is made available for use by the brain.After two or three days of fasting, the liver begins to synthesize ketone bodies from precursors obtained from fatty acid breakdown. The brain uses these ketone bodies as fuel, thus cutting its requirement for glucose. After fasting for three days, the brain gets 30% of its energy from ketone bodies. After four days, this may increase to 70% or more. Thus, the production of ketone bodies cuts the brains glucose requirement from 80 g per day to 30 g per day, about 35% of normal, with 65% derived from ketone bodies. But of the brains remaining 30 g requirement, 20 g per day can be produced by the liver from glycerol (itself a product of fat breakdown). This still leaves a deficit of about 10 g of glucose per day that must be supplied from another source; this other source will be the bodys own proteins. After exhaustion of fat stores, the cells in the body begin to break down protein. This releases alanine and lactate produced from pyruvate, which can be converted into glucose by the liver. Since much of human muscle mass is protein, this phenomenon is responsible for the wasting away of muscle mass seen in starvation. However, the body is able to choose which cells will break down protein and which will not. About 2–3 g of protein has to be broken down to synthesize 1 g of glucose; about 20–30 g of protein is broken down each day to make 10 g of glucose to keep the brain alive. However, this number may decrease the longer the fasting period is continued, in order to conserve protein. Starvation ensues when the fat reserves are completely exhausted and protein is the only fuel source available to the body. Thus, after periods of starvation, the loss of body protein affects the function of important organs, and death results, even if there are still fat reserves left. In a leaner person, the fat reserves are depleted faster, and the protein, sooner, therefore death occurs sooner.) Ultimately, the cause of death is in general cardiac arrhythmia or cardiac arrest, brought on by tissue degradation and electrolyte imbalances. Conditions like metabolic acidosis may also kill starving people. Prevention Starvation can be caused by factors beyond the control of the individual. The Rome Declaration on World Food Security outlines several policies aimed at increasing food security and, consequently, preventing starvation. These include: Poverty reduction Prevention of wars and political instability Food aid Agricultural sustainability Reduction of economic inequalitySupporting farmers in areas of food insecurity through such measures as free or subsidized fertilizers and seeds increases food harvest and reduces food prices. Treatment Patients that suffer from starvation can be treated, but this must be done cautiously to avoid refeeding syndrome. Rest and warmth must be provided and maintained. Food can be given gradually in small quantities. The quantity of food can be increased over time. Proteins may be administered intravenously to raise the level of serum proteins. For worse situations, hospice care and opioid medications can be used. Organizations Many organizations have been highly effective at reducing starvation in different regions. Aid agencies give direct assistance to individuals, while political organizations pressure political leaders to enact more macro-scale policies that will reduce famine and provide aid. Statistics According to estimates by the Food and Agriculture Organization, between 720 and 811 million people were affected by hunger globally in 2020. This was a decrease from estimated 925 million in 2010 and roughly 1 billion in 2009. In 2007, 923 million people were reported as being undernourished, an increase of 80 million since 1990–92. An estimated 820 million people did not have enough to eat in 2018, up from 811 million in the previous year, which is the third year of increase in a row.As the definitions of starving and malnourished people are different, the number of starving people is different from that of malnourished. Generally, far fewer people are starving than are malnourished. The proportion of malnourished and starving people in the world has been more or less continually decreasing for at least several centuries. This is due to an increasing supply of food and to overall gains in economic efficiency. In 40 years, the proportion of malnourished people in the developing world has been more than halved. The proportion of starving people has decreased even faster. Capital punishment Historically, starvation has been used as a death sentence. From the beginning of civilization to the Middle Ages, people were immured, and died for want of food. In ancient Greco-Roman societies, starvation was sometimes used to dispose of guilty upper-class citizens, especially erring female members of patrician families. In the year 31, Livilla, the niece and daughter-in-law of Tiberius, was discreetly starved to death by her mother for her adulterous relationship with Sejanus and for her complicity in the murder of her own husband, Drusus the Younger. Another daughter-in-law of Tiberius, named Agrippina the Elder (a granddaughter of Augustus and the mother of Caligula), also died of starvation, in 33 AD; however, it is unclear if her starvation was self-inflicted. A son and daughter of Agrippina were also executed by starvation for political reasons; Drusus Caesar, her second son, was put in prison in 33 AD, and starved to death by orders of Tiberius (he managed to stay alive for nine days by chewing the stuffing of his bed); Agrippinas youngest daughter, Julia Livilla, was exiled on an island in 41 by her uncle, Emperor Claudius, and her death by starvation was arranged by the empress Messalina. It is also possible that Vestal Virgins were starved when found guilty of breaking their vows of celibacy. Ugolino della Gherardesca, his sons, and other members of his family were immured in the Muda, a tower of Pisa, and starved to death in the thirteenth century. Dante, his contemporary, wrote about Gherardesca in his masterpiece The Divine Comedy. In Sweden in 1317, King Birger of Sweden imprisoned his two brothers for a coup they had staged several years earlier (Nyköping Banquet). According to legend they died of starvation a few weeks later, since their brother had thrown the prison key in the castle moat. In Cornwall in the UK in 1671, John Trehenban from St Columb Major was condemned to be starved to death in a cage at Castle An Dinas for the murder of two girls. The Makah, a Native American tribe inhabiting the Pacific Northwest near the modern border of Canada and the United States, practiced death by starvation as a punishment for slaves. Concentration camps and ghettos Many of the prisoners in the Nazi concentration camps were murdered through deliberate maltreatment, disease, starvation, and overwork, or were executed as unfit for labor. Many occupants of ghettos in eastern Europe also starved to death, most notoriously in the Warsaw Ghetto in German-occupied Poland. Prisoners were transported in inhumane conditions by rail freight cars, in which many died before reaching their destination. The prisoners were confined to the cattle cars for days or even weeks, with little or no food or water. Many died of dehydration in the intense heat of summer or froze to death in winter. Nazi concentration camps in Europe from 1933 to 1945 deliberately underfed prisoners, who were at the same time forced to perform heavy labour. Their diet was restricted to watery vegetable soup and a little bread, with little to no dietary fats, proteins or other essential nutrients. Such treatment led to loss of body tissues, and when prisoners became skeletal, the so-called Muselmann were murdered by gas or bullets when examined by camp doctors. Starvation was also used as a punishment where victims were locked into a small cell until dead, a process which could take many days. Saint Maximilian Kolbe, a martyred Polish friar, underwent a sentence of starvation in Auschwitz concentration camp in 1941. Ten prisoners had been condemned to death by starvation in the wake of a successful escape from the camp. Kolbe volunteered to take the place of a man with a wife and children. After two weeks of starvation, Kolbe and three other inmates remained alive; they were then executed with injections of phenol. See also References Further reading Online books, and library resources in your library and in other libraries about Starvation U.N. Chief: Hunger Kills 17,000 Kids Daily - by CNN Wilson, DE; Zeikus, R; Chan, IF (Apr 1987). "Relationship of organ lipoprotein lipase activity and ketonuria to hypertriglyceridemia in starved and streptozocin-induced diabetic rats". Diabetes. 36 (4): 485–90. doi:10.2337/diabetes.36.4.485. PMID 3817303. Swaner, JC; Connor, WE (Aug 1975). "Hypercholesterolemia of total starvation: its mechanism via tissue mobilization of cholesterol". The American Journal of Physiology. 229 (2): 365–9. doi:10.1152/ajplegacy.1975.229.2.365. PMID 169705.
Platinosis	Platinosis is an allergy-like reaction to exposure to soluble salts of platinum. The symptoms of platinosis may include asthma, dermatitis, dyspnea, conjunctival vasodilatation, and rhinopharyngitis. The symptoms are progressive, sometimes taking months to years to appear. Platinosis is usually associated with workers in industries related to platinum production. The effects are permanent. Halogeno-platinum compounds are among the most potent respiratory and skin sensitisers known, therefore it is vital that exposure via the skin and by breathing contaminated air is carefully controlled. In practice, the compounds mainly responsible for platinum sensitisation are typically the soluble, ionic, platinum-chloro compounds such as ammonium hexachloroplatinate and tetrachloroplatinate, and hexachloroplatinic acid. Other ionic halogeno compounds are also sensitisers, the order of allergenicity being Cl > Br > I. Neutral compounds such as cis-platin and ammine and nitro complexes such as [Pt(NH3)4]Cl2, K2[Pt(NO2)4] and platinum nitrate are not considered to be allergenic; neither is the metal. See also Heavy metal poisoning References Parrot, Jl; Hébert, R; Saindelle, A; Ruff, F (Nov 1969). "Platinum and platinosis. Allergy and histamine release due to some platinum salts". Archives of Environmental Health. 19 (5): 685–91. doi:10.1080/00039896.1969.10666910. PMID 4187030. Saindelle, A; Ruff, F; Hébert, R; Parrot, Jl (Oct 1968). "A new histamine liberator: chloroplatinate. An occupational allergy: platinosis" [A new histamine liberator: chloroplatinate. An occupational allergy: platinosis]. Revue Française dAllergologie (in French). 8 (4): 205–14. doi:10.1016/S0370-4688(68)80018-3. PMID 4180839. Parrot, Jl; Saindelle, A; Ruff, F (Dec 1967). "Platinum and platinosis. Histamine release by some platinum salts and platinum allergy" [Platinum and platinosis. Histamine release by some platinum salts and platinum allergy]. La Presse Médicale (in French). 75 (55): 2817–20. PMID 4171373. Parrot, Jl; Saindelle, A; Tazi, T (Jun 1963). "Histamine Liberation by Platinum Salts and the Mechanism of Platinosis" [HISTAMINE LIBERATION BY PLATINUM SALTS AND THE MECHANISM OF PLATINOSIS.]. Bulletin de lAcadémie Nationale de Médecine (in French). 147: 458–62. PMID 14054203. Roberts, Ae (Dec 1951). "Platinosis; a five-year study of the effects of soluble platinum salts on employees in a platinum laboratory and refinery". AMA Archives of Industrial Hygiene and Occupational Medicine. 4 (6): 549–59. PMID 14877314.
Pemphigus	Pemphigus ( or ) is a rare group of blistering autoimmune diseases that affect the skin and mucous membranes. The name is derived from the Greek root pemphix, meaning "pustule".In pemphigus, autoantibodies form against desmoglein, which forms the "glue" that attaches adjacent epidermal cells via attachment points called desmosomes. When autoantibodies attack desmogleins, the cells become separated from each other and the epidermis becomes detached, a phenomenon called acantholysis. This causes blisters that slough off and turn into sores. In some cases, these blisters can cover a large area of the skin.Originally, the cause of this disease was unknown, and "pemphigus" was used to refer to any blistering disease of the skin and mucosa. In 1964, researchers found that the blood of patients with pemphigus contained antibodies to the layers of skin that separate to form the blisters. In 1971, an article investigating the autoimmune nature of this disease was published. Types The several types of pemphigus (pemphigus vulgaris, pemphigus foliaceus, intraepidermal neutrophilic IgA dermatosis, and paraneoplastic pemphigus) vary in severity. Skin lesions caused by pemphigus can lead to fatal infections, so treatment is extremely important. Pemphigus vulgaris (PV - ICD-10 L10.0) is the most common form of the disorder and occurs when antibodies attack desmoglein 3. Sores often originate in the mouth, making eating difficult and uncomfortable. Although PV may occur at any age, it is most common among people between 40 and 60. It is more frequent among Ashkenazi Jews. Rarely, it is associated with myasthenia gravis. Nail disease may be the only finding and has prognostic value in management. Pemphigus foliaceus (PF) is the least severe of the three varieties. Desmoglein 1, the protein that is targeted by the autoantibodies, is enriched in the upper skin layers. PF is characterized by crusty sores that often begin on the scalp, and may move to the chest, back, and face. Mouth sores do not occur. This form is also frequent among Ashkenazi Jews. It is not as painful as PV, and is often misdiagnosed as dermatitis or eczema Intraepidermal neutrophilic IgA dermatosis is characterized histologically by intraepidermal bullae with neutrophils, some eosinophils, and acantholysis. The least common and most severe type of pemphigus is paraneoplastic pemphigus (PNP). This disorder is a complication of cancer, usually lymphoma or Castlemans disease. It may precede the diagnosis of the tumor. Painful sores appear on the mouth, lips, and the esophagus. In this variety of pemphigus, the disease process often involves the lungs, causing bronchiolitis obliterans (constrictive bronchiolitis). Though much less frequent, it is still found the most in the Ashkenazi Jewish population. Complete removal of and/or cure of the tumor may improve the skin disease, but lung damage is generally irreversible. Endemic pemphigus foliaceus includes fogo selvagem, the new variant of endemic pemphigus foliaceus in El Bagre, Colombia, and the Tunisian endemic pemphigus in North Africa.Hailey-Hailey disease, also called familial benign pemphigus, is an inherited skin disease, not an autoimmune disease, so it is not considered part of the pemphigus group of diseases. Diagnosis Pemphigus defines a group of autoimmune intraepithelial blistering diseases that are characterized by loss of normal cell-cell adhesion (acantholysis), and by the presence of pathogenic (predominantly IgG) autoantibodies reacting against epithelial adhesion molecules. Pemphigus is further divided in two major subtypes: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). However, several other disorders such as IgA pemphigus, IgE pemphigus, pemphigus herpetiformis, drug-induced pemphigus, Senear Usher syndrome, and endemic pemphigus foliaceus exist, and are recognized by a dermatologist from the appearance and distribution of the skin lesions. It is also commonly diagnosed by specialists practicing otolaryngology- head and neck surgery, periodontists, oral and maxillofacial surgeons, and eye doctors, as lesions can affect the eyes and mucous membranes of the oral cavity. Intraorally, it resembles the more common diseases lichen planus and mucous membrane pemphigoid. Definitive diagnosis requires examination of a skin or mucous membrane biopsy by a dermatopathologist or oral pathologist. The skin biopsy is taken from the edge of a blister, prepared for histopathology and examined with a microscope. The pathologist looks for an intraepidermal vesicle caused by the breaking apart of epidermal cells (acantholysis). Thus, the superficial (upper) portion of the epidermis sloughs off, leaving the bottom layer of cells on the "floor" of the blister. This bottom layer of cells is said to have a "tombstone" appearance. Definitive diagnosis also requires the demonstration of antidesmoglein autoantibodies by direct immunofluorescence on the skin biopsy. These antibodies appear as IgG deposits along the desmosomes between epidermal cells, a pattern reminiscent of chicken wire. Antidesmoglein antibodies can also be detected in a blood sample using the ELISA technique. Classification Pemphigus is a group of autoimmune blistering diseases that may be classified into these types: Pemphigus vulgaris Pemphigus vegetans Pemphigus vegetans of Hallopeau Pemphigus vegetans of Neumann Pemphigus foliaceus, of which there several forms: Pemphigus erythematosus or Senear–Usher Syndrome Endemic pemphigus foliaceus with its three variants, Fogo Selvagem, the new variant endemic pemphigus Foliaeus and Tunisian endemic pemphigus foliaceus Paraneoplastic pemphigus IgA pemphigus, of which there several forms: Subcorneal pustular dermatosis Intraepidermal neutrophilic IgA dermatosis Drug induced pemphigus Treatment If not treated, pemphigus can be fatal, usually from overwhelming opportunistic infection of lesions. The most common treatment is the administration of oral steroids, especially prednisone, often in high doses. The side effects of corticosteroids may require the use of so-called steroid-sparing or adjuvant drugs. One of the most dangerous side effects of high-dosage steroid treatments is intestinal perforations, which may lead to sepsis. Steroids and other medications being taken to treat pemphigus may also mask the effects of the perforations. Patients on high dosages of oral steroids should closely monitor their gastrointestinal health. As lesions are usually terribly painful, pain medication likely complicate and exacerbate the gastrointestinal issues caused by steroids. Treatment options Topical steroids, such as clobetasol Intralesional injection of steroids, such as dexamethasone Immunosuppressant drugs, such as CellCept (mycophenolic acid): In recent years, adjuvant drugs, especially biologics, have shown great promise. Serum- or plasma-pooled products, such as intravenous gamma globulin (IVIG) may be useful in severe cases, especially paraneoplastic pemphigus. Biologics such as Rituximab, an anti-CD20 antibody, which was found to improve otherwise severe cases of recalcitrant pemphigus vulgaris.All of these drugs may cause severe side effects, so patients should be closely monitored by doctors. Once the outbreaks are under control, dosage is often reduced, to lessen side effects. A meta-analysis of the literature found insufficient evidence to determine the optimal treatment regimen for pemphigus vulgaris and pemphigus foliaceus, but it found that adding cyclophosphamid and azathioprine to a glucocorticoid regimen reduced the amount of glucocorticoid needed for treatment, and topical epidermal growth factor significantly reduced lesion healing time.If skin lesions do become infected, antibiotics may be prescribed. Tetracycline antibiotics have a mildly beneficial effect on the disease and are sometimes enough for pemphigus foliaceus. In addition, talcum powder is helpful to prevent oozing sores from adhering to bedsheets and clothes. Wound care and treatments are often akin to those used in burn units, including careful use of dressings that dont stick to the wounds, etc. If paraneoplastic pemphigus is diagnosed with pulmonary disease, a powerful cocktail of immunosuppressant drugs is sometimes used in an attempt to halt the rapid progression of bronchiolitis obliterans, including methylprednisolone, ciclosporin, azathioprine, and thalidomide. Plasmapheresis may also be useful. Animals affected Pemphigus foliaceus has been recognized in pet dogs, cats, and horses, and is the most common autoimmune skin disease diagnosed in veterinary medicine. PF in animals produces clusters of small vesicles that quickly evolve into pustules. Pustules may rupture, forming erosions or become crusted. Left untreated, PF in animals is life-threatening, leading to not only loss of condition, but also secondary infection. PV is a very rare disorder described in pet dogs and cats. Paraneoplastic pemphigus has been identified in pet dogs. See also List of conditions caused by problems with junctional proteins List of cutaneous conditions List of immunofluorescence findings for autoimmune bullous conditions List of target antigens in pemphigus Pemphigoid Pemphigus herpetiformis References External links National Organization of Rare Diseases: Pemphigus
Mohr–Tranebjærg syndrome	Mohr–Tranebjærg syndrome (MTS) is a rare X-linked recessive syndrome also known as deafness–dystonia syndrome and caused by mutation in the TIMM8A gene. It is characterized by clinical manifestations commencing with early childhood onset hearing loss, followed by adolescent onset progressive dystonia or ataxia, visual impairment from early adulthood onwards and dementia from the 4th decade onwards. The severity of the symptoms may vary, but they progress usually to severe deafness and dystonia and sometimes are accompanied by cortical deterioration of vision and mental deterioration. Signs and Symptoms Mohr-Tranebjærg is characterized by a variety of symptoms affecting hearing loss. In the span of a subject with Mohr-Tranebjærg, by the age of early childhood, around 18 months, the development of quickly progressive prelingual or postlingual sensorineural hearing loss. The presence of auditory symptoms is characterized by preserved oto-acoustic emissions, abnormal auditory brain stem response, poor speech, and worsening in auditory symptoms even with auditory devices. Also, neuropsychological manifestations, possibly consisting of personality changes, paranoia, and mild intellectual deficit could emerge. During adolescence, there is a possibility that a slowly progressive movement disorder, similar to gegenhalten, dystonia, or ataxia could develop. Patients with Mohr-Tranebjærg experience reduced visual acuity, photophobia, acquired color vision defect and central scotomas developing at around 20 years of age, and leading to more severe blindness by age 30 or 40.The first symptom of DDON syndrome is hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss), which begins in early childhood. The hearing impairment worsens over time, and most affected individuals have profound hearing loss by age 10.Individuals with Mohr Tranebjærg syndrome have normal vision during childhood, but they may develop vision problems due to breakdown of the nerves that carry information from the eyes to the brain (optic atrophy). Affected individuals can develop an increased sensitivity to light (photophobia) or other vision problems beginning in adolescence. Their sharpness of vision (visual acuity) slowly worsens, often leading to legal blindness in mid-adulthood. Genetics This condition is caused by mutations in the TIMM8A gene. This gene is located on the long arm of X chromosome (Xq22). The protein encoded by this gene localizes to the intermembrane space in mitochondria where it functions in the import of nuclear encoded proteins into the mitochondrial inner membrane. How this produces the clinical picture is not yet clear. The pattern of inheritance is X-linked recessive. Where the female is a carrier, male offspring have a 50 percent chance of inheriting the disease and female offspring have a 50 percent chance of being a carrier. Where the male is affected, male offspring do not inherit the pathogenic mutation and females are obligate carriers.TIMM8A is also referred to as DDP. Koehler determined the function of the DDP gene and concluded that the Mohr-Tranebjaerg syndrome is a novel type of mitochondrial disease that is most likely caused by a defective mitochondrial protein-import system. Diagnosis A combination of hearing impairment and recurrent infections due to XLA in a male patient should elicit sequencing of the TIMM8A gene. Neuroimaging is employed to verify the presence of cerebral atrophy. In cases of suspected CGS; testing for XLA is possible. Differential diagnosis This is long and includes Arts syndrome Autosomal recessive nonsyndromic sensorineural deafness type DFNB Friedreich ataxia MELAS syndrome Mitochondrial DNA depletion syndrome (encephalomyopathic form with methylmalonic aciduria) McLeod neuroacanthocytosis syndrome Pendred syndrome Usher syndrome type 1 and 2 Wolfram syndrome X-linked spinocerebellar ataxia type 3 and 4 Treatment Symptomatic Treatment The treatment for Mohr-Tranebjærg vary depending on the symptoms and the evolution of these symptoms over time. Since hearing loss is prevalent in those with Mohr-Tranebjærg, hearing aids, devices, or cochlear implants are considered for increasingly serious cases. Immunoglobin In those patients with secondary complications from the syndrome, intravenous immunoglobin may act to prevent infections in X-linked agammaglobulinemia, an inherited immune system disorder that can reduce the ability to fight infections. Similarly, those with XLA should avoid live viral vaccines. Patients that reach adulthood should seek regular evaluations from a neurologist to test the advancement of possible dementia and psychiatric manifestations Genetic Counseling Since the pattern of inheritance for Mohr-Tranebjærg is known to be X-linked recessive, genetic counseling is considered beneficial to families with known carriers. In the case that a female is a carrier, the statistical risk of male offspring inheriting the disease is 50%, while the probability that a female offspring will be a carrier is 50%. However, when a male is the carrier, the probability of having a female carrier offspring is 100%, and male offspring will not have any chance of inheriting the syndrome. Because of the statistical probabilities that each sex inherits the syndrome, males are affected by Mohr-Tranebjærg more frequently than females are. Females who carry one copy of the TIMM8A gene (described in Genetics) are usually unaffected, however, may develop mild hearing loss and dystonia. Prognosis Prognosis is poor. The combination of deafness and blindness severely affects communication, while the ongoing movement disorder results in an increasingly unstable gait. Life expectancy is highly variable and can range from death in the teenage years (after a rapidly progressive dystonia) to those that live into their 60s. History This condition was first described in 1960. Epidemiology Mohr-Tranebjᴂrg syndrome (MTS) prevalence is unknown. More than 90 cases (in 37 families) are known, but not all cases have been reported in the literature. See also Mitochondrial disorders TIMM13 and TIMM8A References External links GeneReviews/NCBI/NIH/UW entry on Deafness–Dystonia–Optic Neuronopathy Syndrome MTS — a page at NIH website
Pelvic fracture	A pelvic fracture is a break of the bony structure of the pelvis. This includes any break of the sacrum, hip bones (ischium, pubis, ilium), or tailbone. Symptoms include pain, particularly with movement. Complications may include internal bleeding, injury to the bladder, or vaginal trauma.Common causes include falls, motor vehicle collisions, a vehicle hitting a pedestrian, or a direct crush injury. In younger people significant trauma is typically required while in older people less significant trauma can result in a fracture. They are divided into two types: stable and unstable. Unstable fractures are further divided into anterior posterior compression, lateral compression, vertical shear, and combined mechanism fractures. Diagnosis is suspected based on symptoms and examination with confirmation by X-rays or CT scan. If a person is fully awake and has no pain of the pelvis medical imaging is not needed.Emergency treatment generally follows advanced trauma life support. This begins with efforts to stop bleeding and replace fluids. Bleeding control may be achieved by using a pelvic binder or bed-sheet to support the pelvis. Other efforts may include angiographic embolization or preperitoneal packing. After stabilization, the pelvis may require surgical reconstruction.Pelvic fractures make up around 3% of adult fractures. Stable fractures generally have a good outcome. The risk of death with an unstable fracture is about 15%, while those who also have low blood pressure have a risk of death approaching 50%. Unstable fractures are often associated with injuries to other parts of the body. Signs and symptoms Symptoms include pain, particularly with movement. Complications Complications are likely to result in cases of excess blood loss or puncture to certain organs, possibly leading to shock. Swelling and bruising may result, more so in high-impact injuries. Pain in the affected areas may differ where severity of impact increases its likelihood and may radiate if symptoms are aggravated when one moves around. Causes Common causes include falls, motor vehicle collisions, a vehicle hitting a pedestrian, or a direct crush injury. In younger people significant trauma is typically required while in older people less significant trauma can result in a fracture. Pathophysiology The bony pelvis consists of the ilium (i.e., iliac wings), ischium, and pubis, which form an anatomic ring with the sacrum. Disruption of this ring requires significant energy. When it comes to the stability and the structure of the pelvis, or pelvic girdle, understanding its function as support for the trunk and legs helps to recognize the effect a pelvic fracture has on someone. The pubic bone, the ischium and the ilium make up the pelvic girdle, fused together as one unit. They attach to both sides of the spine and circle around to create a ring and sockets to place hip joints. Attachment to the spine is important to direct force into the trunk from the legs as movement occurs, extending to ones back. This requires the pelvis to be strong enough to withstand pressure and energy. Various muscles play important roles in pelvic stability. Because of the forces involved, pelvic fractures frequently involve injury to organs contained within the bony pelvis. In addition, trauma to extra-pelvic organs is common. Pelvic fractures are often associated with severe hemorrhage due to the extensive blood supply to the region. The veins of the presacral pelvic plexus are particularly vulnerable. Greater than 85 percent of bleeding due to pelvic fractures is venous or from the open surfaces of the bone. Diagnosis If a person is fully awake and has no pain in the pelvis, medical imaging of the pelvis is not needed. Classification Pelvic fractures are most commonly described using one of two classification systems. The different forces on the pelvis result in different fractures. Sometimes they are determined based on stability or instability. Tile classification The Tile classification system is based on the integrity of the posterior sacroiliac complex.In type A injuries, the sacroiliac complex is intact. The pelvic ring has a stable fracture that can be managed nonoperatively. Type B injuries are caused by either external or internal rotational forces resulting in partial disruption of the posterior sacroiliac complex. These are often unstable. Type C injuries are characterized by complete disruption of the posterior sacroiliac complex and are both rotationally and vertically unstable. These injuries are the result of great force, usually from a motor vehicle crash, fall from a height or severe compression. Young-Burgess classification The Young-Burgess classification system is based on mechanism of injury: anteroposterior compression type I, II and III, lateral compression types I, II and III, and vertical shear, or a combination of forces. Lateral compression (LC) fractures involve transverse fractures of the pubic rami, either ipsilateral or contralateral to a posterior injury. Grade I – Associated sacral compression on side of impact Grade II – Associated posterior iliac ("crescent") fracture on side of impact Grade III – Associated contralateral sacroiliac joint injuryThe most common force type, lateral compression (LC) forces, from side-impact automobile accidents and pedestrian injuries, can result in an internal rotation. The superior and inferior pubic rami may fracture anteriorly, for example. Injuries from shear forces, like falls from above, can result in disruption of ligaments or bones. When multiple forces occur, it is called combined mechanical injury (CMI). The best imaging modality to use for this classification is probably a pelvic CT scan. Open book fracture One specific kind of pelvic fracture is known as an open book fracture. This is often the result of a heavy impact to the groin (pubis), a common motorcycling accident injury. In this kind of injury, the left and right halves of the pelvis are separated at front and rear, the front opening more than the rear, i.e. like an open book that falls to the ground and splits in the middle. Depending on the severity, this may require surgical reconstruction before rehabilitation. Forces from an anterior or posterior direction, like head-on car accidents, usually cause external rotation of the hemipelvis, an “open-book” injury. Open fractures have an increased risk of infection and hemorrhaging from vessel injury, leading to higher mortality. Prevention As the human body ages, the bones become weaker and brittle and are therefore more susceptible to fractures. Certain precautions are crucial in order to lower the risk of getting pelvic fractures. The most damaging is one from a car accident, cycling accident, or falling from a high building which can result in a high energy injury. This can be very dangerous because the pelvis supports many internal organs and can damage these organs. Falling is one of the most common causes of pelvic fracture. Therefore, proper precautions should be taken to prevent this from happening. Treatment A pelvic fracture is often complicated and treatment can be a long and painful process. Depending on the severity, pelvic fractures can be treated with or without surgery. Initial A high index of suspicion should be held for pelvic injuries in anyone with major trauma. The pelvis should be stabilized with a pelvic binder. This can be a purpose-made device, but improvised pelvic binders have also been used around the world to good effect. Stabilisation of the pelvic ring reduces blood loss from the pelvic vessels and reduced the risk of death. Surgery Surgery is often required for pelvic fractures. Many methods of pelvic stabilization are used including external fixation or internal fixation and traction. There are often other injuries associated with a pelvic fracture so the type of surgery involved must be thoroughly planned. Rehabilitation Pelvic fractures that are treatable without surgery are treated with bed rest. Once the fracture has healed enough, rehabilitation can be started with first standing upright with the help of a physical therapist, followed by starting to walk using a walker and eventually progressing to a cane. Prognosis Mortality rates in people with pelvic fractures are between 10 and 16 percent. However, death is typically due to associated trauma affecting other organs, such as the brain. Death rates due to complications directly related to pelvic fractures, such as bleeding, are relatively low. Epidemiology About 10 percent of people that seek treatment at a level 1 trauma center after a blunt force injury have a pelvic fracture. Motorcycle injuries are the most common cause of pelvic fractures, followed by injuries to pedestrians caused by motor vehicles, large falls (over 15 feet), and motor vehicle crashes. See also Bulbar urethral necrosis Coopernail sign References External links Wheeless Textbook of Orthopaedics: Pelvic fractures
Injury of axillary nerve	Injury of axillary nerve (axillary neuropathy) is a condition that can be associated with a surgical neck of the humerus fracture. It can also be associated with a dislocated shoulder or with traction injury to the nerve, which may be caused by over-aggressive stretching or blunt trauma that does not result in fracture or dislocation. One form of this injury is referred to as axillary nerve palsy. Injury most commonly occurs proximal to the quadrangular space.Injury in this nerve causes paralysis (as always) to the muscles innervated by it, most importantly deltoid muscle. This muscle is the main abductor of the shoulder joint from 18 to 90 degrees (from 0 to 18 by supraspinatus). Injury can result in a reduction in shoulder abduction. So a test can be applied to a patient with injury of axillary nerve by trying to abduct the injured shoulder against resistance.The pain from axillary neuropathy is usually dull and aching rather than sharp, and increases with increasing range of motion. Many people notice only mild pain but considerable weakness when they try to use the affected shoulder. References == External links ==
Acromion	In human anatomy, the acromion (from Greek: akros, "highest", ōmos, "shoulder", plural: acromia) is a bony process on the scapula (shoulder blade). Together with the coracoid process it extends laterally over the shoulder joint. The acromion is a continuation of the scapular spine, and hooks over anteriorly. It articulates with the clavicle (collar bone) to form the acromioclavicular joint. Structure The acromion forms the summit of the shoulder, and is a large, somewhat triangular or oblong process, flattened from behind forward, projecting at first lateralward, and then curving forward and upward, so as to overhang the glenoid fossa. It starts from the base of acromion which marks its projecting point emerging from the spine of scapula. Surfaces Its superior surface, directed upward, backward, and lateralward, is convex, rough, and gives attachment to some fibers of the deltoideus, and in the rest of its extent is subcutaneous. Its inferior surface is smooth and concave. Borders Its lateral border is thick and irregular, and presents three or four tubercles for the tendinous origins of the deltoid. Its medial border, shorter than the lateral, is concave, gives attachment to a portion of the trapezius, and presents about its center a small oval surface for articulation with the acromial end of the clavicle. Variation There are three morphologically distinct types of acromia and a correlation between these morphologies and rotator cuff tear: Os acromiale The acromion has four ossification centers called (from tip to base) pre-acromion, meso-acromion, meta-acromion, and basi-acromion. In most cases, the first three fuse at 15–18 years, whereas the base part fuses to the scapular spine at 12 years. However, in between 1% and 15% of cases, this osseous union fails and the acromion remains separate as an accessory bone. This condition is referred to as os acromiale, but rarely causes pain. Earlier estimates of its prevalence were as low as 1.4%, and this higher estimate was made by Sammarco in the year 2000, based on radiographic and anatomical studies.Four types of os acromiale can be distinguished: A non-union between the meso- and meta-acromia, the most common or typical os acromiale A non-union between the pre- and meso-acromia A non-union between the pre- and meso-acromia; and between the meso- and meta-acromia, atypical A non-union between the pre- and meso-acromia; between the pre- and meso-acromia; and between the meta- and basi-acromiaThis feature was common in skeletons recovered from the Mary Rose shipwreck: it is thought that in those men, much archery practice from childhood on with the mediaeval war bow (which needs a pull three times as strong as the modern standard Olympic bow) pulled at the acromion so much that it prevented bony fusion of the acromion with the scapula. Although historically regarded as an incidental finding, the os acromiale may occasionally produce symptoms from subacromial impingement or instability at the site of non-union. In people with symptoms of os acromiale, dynamic ultrasound sometimes shows hypermobility in the area during shoulder movement, or graded compression with the probe. In other animals The acromion process of bats (Mammalia: Chiroptera) is particularly elongated compared to that of humans. Turtles have an acromion that forms the anterior part of the triradiate pectoral girdle (together with the coracoid and scapula). In this highly specialized endoskeletal structure, the scapula is a dorsal (directed upwards) process attached to the first rib; the coracoid is a posteroventral (directed backward and down) process; and the acromion is a medioventral (directed inwards and down) process (also known as the prescapular process) located at the base of the scapula. This had led to some controversy regarding the evolutionary origin of turtles, because in both pareiasaurs and non-mammalian therapsids the acromion is located at the dorsal tip of the scapula. In modern turtles, the acromion projects ventrally and articulates with the plastron (the flat lower part of the shell), but it evolved in a common ancestor of pareiasaurs and turtles long before the plastron. In these primitive ancestors, the acromion projected forward to form a strong and flexible articulation between the shoulder girdle and the clavicle. Notwithstanding these changes, the acromion of turtles retains its original function, to support the shoulder girdle and increase stride length. Additional images Notes This article incorporates text in the public domain from page 203 of the 20th edition of Grays Anatomy (1918) Habermeyer, Peter; Magosch, Petra; Lichtenberg, Sven (2006). Classifications and Scores of the Shoulder. Heidelberg: Springer. ISBN 978-3-540-24350-2. Lee, Michael S. Y. (January 22, 1996). "The Homologies and Early Evolution of the Shoulder Girdle in Turtles". Proc. R. Soc. Lond. B. 263 (1366): 111–117. doi:10.1098/rspb.1996.0018. S2CID 84529868. Rieppel, Olivier; Reisz, Robert R. (1999). "The Origin and Early Evolution of Turtles". Annual Review of Ecology and Systematics. 30: 1–22. doi:10.1146/annurev.ecolsys.30.1.1. Archived from the original (PDF) on 2018-12-26. Retrieved 2020-06-08. Warner, Jon J.P.; Beim, Gloria M.; Higgins, Laurence (September 1998). "The Treatment of Symptomatic Os Acromiale". The Journal of Bone and Joint Surgery. 80 (9): 1320–6. doi:10.2106/00004623-199809000-00011. PMID 9759817. == External links ==
Brachymetacarpia	Brachymetacarpia is a medical condition in which the metacarpals of the hands are shortened, the foot equivalent to this condition is brachymetatarsia. This condition is one of the causes of brachydactyly.
Hypergonadism	Hypergonadism is a condition where there is a hyperfunction of the gonads. It can manifest as precocious puberty, and is caused by abnormally high levels of testosterone or estrogen, crucial hormones for sexual development. In some cases, it may be caused by a tumor, which can be malignant, but is more commonly benign. Anabolic steroids may also be a major cause of high androgen and estrogen functional activity. Other possible causes include head injuries and brain inflammatory diseases. Hypergonadism may contribute to symptoms such as precocious puberty and abnormal facial hair growth in females. Symptoms Men and women exhibit different symptoms for hypergonadism. A few of the symptoms that men can experience are increased sex drive, early balding, excessive muscle mass, and acne. Women can have symptoms such as, increased growth of facial hair, deepened voice, coarse body hair, and an irregular menstrual cycle. See also Hypergonadotropic hypergonadism Hyperandrogenism and hyperestrogenism Hypothalamus, pituitary gland, and HPG axis GnRH and gonadotropins (FSH and LH) Hypogonadism (hypoandrogenism and hypoestrogenism) == References ==
Sebaceoma	Sebaceoma (also known as a "sebaceous epithelioma") is a cutaneous condition that appears as a yellow or orange papule.: 662 See also Sebaceous carcinoma Sebaceous adenoma Skin lesion == References ==
Riddoch syndrome	The Riddoch syndrome is a term coined by Zeki and Ffytche (1998) in a paper published in Brain. The term acknowledges the work of George Riddoch who was the first to describe a condition in which a form of visual impairment, caused by lesions in the occipital lobe, leaves the sufferer blind but able to distinguish visual stimuli with specific characteristics when these appear in the patients blind field. The most common stimuli that can be perceived consciously are the presence and direction of fast moving objects (moving at a speed in excess of 10 degrees per second); in his work these moving objects were described as "vague and shadowy". Riddoch concluded from his observations that "movement may be recognized as a special visual perception".Riddochs description was dismissed by Sir Gordon Holmes in a 1918 paper in which he wrote that" The condition described by Riddoch should not be spoken of as a dissociation of the elements of visual sensation" because "occipital lesions do not produce true dissociations of function with intact retinal sensibility". The idea of a separate representation of visual motion was further dismissed by H.L. Teuber and, in general, such an idea was not accepted until physiological studies in the monkey demonstrated the existence of a cortical area lying outside the primary visual cortex (area V1) in which almost all cells were selective for directional motion. With that new knowledge, a new study of patient GY, who had been used extensively to demonstrate the phenomenon of Blindsight (that is to say the ability to discriminate correctly visual stimuli presented to the blind field without conscious awareness) led to interesting findings. The re-examination showed that, when presented with fast-moving, high contrast, visual stimuli in his blind field, he could discriminate their presence and direction of motion consciously, This, in turn, led to a re-classification of blindsight into Type 1 and Type 2 the former adhering to the previous definition of blindsight while the latter acknowledging the fact that the experience of such subjects can be conscious even if much degraded. Only moving objects in the scotoma are visible, static ones being invisible to the patient. The moving objects are not perceived to have color or detail. The subject may only have awareness of the movement without visual perception of it (gnosanopsia), or the general shape of a moving object may be perceivable as a shadow like outline. The syndrome is named after George Riddoch who had been a temporary officer in the Royal Army Medical Corps and examined soldiers who were blinded by gunshot wounds to their brains.At least one patient was able to use a rocking chair—putting non-moving surroundings in relative motion to her head—to improve her motion perception. She eventually was able to do the same with movement of her head. See also Blindsight – Visual response in some blind people Visual agnosia == References ==
Magnesium deficiency	Magnesium deficiency is an electrolyte disturbance in which there is a low level of magnesium in the body. It can result in multiple symptoms. Symptoms include tremor, poor coordination, muscle spasms, loss of appetite, personality changes, and nystagmus. Complications may include seizures or cardiac arrest such as from torsade de pointes. Those with low magnesium often have low potassium.Causes include low dietary intake, alcoholism, diarrhea, increased urinary loss, poor absorption from the intestines, and diabetes mellitus. A number of medications may also cause low magnesium, including proton pump inhibitors (PPIs) and furosemide. The diagnosis is typically based on finding low blood magnesium levels (hypomagnesemia). Normal magnesium levels are between 0.6 and 1.1 mmol/L (1.46–2.68 mg/dL) with levels less than 0.6 mmol/L (1.46 mg/dL) defining hypomagnesemia. Specific electrocardiogram (ECG) changes may be seen.Treatment is with magnesium either by mouth or intravenously. For those with severe symptoms, intravenous magnesium sulfate may be used. Associated low potassium or low calcium should also be treated. The condition is relatively common among people in hospitals. Signs and symptoms Deficiency of magnesium can cause tiredness, generalized weakness, muscle cramps, abnormal heart rhythms, increased irritability of the nervous system with tremors, paresthesias, palpitations, low potassium levels in the blood, hypoparathyroidism which might result in low calcium levels in the blood, chondrocalcinosis, spasticity and tetany, migraines, epileptic seizures, basal ganglia calcifications and in extreme and prolonged cases coma, intellectual disability or death. Magnesium plays an important role in carbohydrate metabolism and its deficiency may worsen insulin resistance, a condition that often precedes diabetes, or may be a consequence of insulin resistance.People being treated on an intensive care unit (ICU) who have a low magnesium level may have a higher risk of requiring mechanical ventilation, and death. Causes Magnesium deficiency may result from gastrointestinal or kidney causes. Gastrointestinal causes include low dietary intake of magnesium, reduced gastrointestinal absorption or increased gastrointestinal loss due to rapid gastrointestinal transits. Kidney causes involve increased excretion of magnesium. Poor dietary intake of magnesium has become an increasingly important factor – many people consume diets high in refined foods such as white bread and polished rice which have been stripped of magnesium-rich plant fiber.Magnesium deficiency is not uncommon in hospitalized patients. Up to 12% of all people admitted to hospital, and as high as 60–65% of people in an intensive care unit, have hypomagnesemia.About 57% of the US population does not meet the US RDA for dietary intake of magnesium. The kidneys are very efficient at maintaining body levels; however, if the diet is deficient, or certain medications such as diuretics or proton pump inhibitors are used, or in chronic alcoholism, levels may drop. Low levels of magnesium in blood may be due to not enough magnesium in the diet, the intestines not absorbing enough magnesium, or the kidneys excreting too much magnesium. Deficiencies may be due to the following conditions: Medications Loop and thiazide diuretic use (the most common cause of hypomagnesemia) Antibiotics (i.e. aminoglycoside, amphotericin, pentamidine, gentamicin, tobramycin, viomycin) block resorption in the loop of Henle. 30% of patients using these antibiotics have hypomagnesemia. Long term, high dosage use of proton-pump inhibitors such as omeprazole Other drugs Digitalis, displaces magnesium into the cell. Digitalis causes an increased intracellular concentration of sodium, which in turn increases intracellular calcium by passively increasing the action of the sodium-calcium exchanger in the sarcolemma. The increased intracellular calcium gives a positive inotropic effect. Adrenergics, displace magnesium into the cell Cisplatin, stimulates kidney excretion Ciclosporin, stimulates kidney excretion Mycophenolate mofetil Genetics Gitelman-like diseases, which include the syndromes caused by genetic mutations in SLC12A3, CLNCKB, BSND, KCNJ10, FXYD2, HNF1B or PCBD1. In these diseases, the hypomagnesemia is accompanied by other defects in electrolyte handling such as hypocalciuria and hypokalemia. The genes involved in this group of diseases all encode proteins that are involved in reabsorbing electrolytes (including magnesium) in the distal convoluted tubule of the kidney. Hypercalciuric hypomagnesemic syndromes, which encompass the syndromes caused by mutations in CLDN16, CLDN19, CASR or CLCNKB. In these diseases, reabsorption of divalent cations (such as magnesium and calcium) in the thick ascending limb of Henles loop of the kidney is impaired. This results in loss of magnesium and calcium in the urine. Mitochondriopathies, such as caused by mutations in SARS2, MT-TI or as seen with Kearns-Sayre syndrome. Other genetic causes of hypomagnesemia, such as mutations in TRPM6, CNNM2, EGF, EGFR, KCNA1 or FAM111A. Many of the proteins encoded by these genes play a role in the transcellular absorption of magnesium in the distal convoluted tubule. Metabolic abnormalities Insufficient selenium, vitamin D or sunlight exposure, or vitamin B6. Gastrointestinal causes: the distal digestive tract secretes high levels of magnesium. Therefore, secretory diarrhea can cause hypomagnesemia. Thus, Crohns disease, ulcerative colitis, Whipples disease and celiac sprue can all cause hypomagnesemia. Postobstructive diuresis, diuretic phase of acute tubular necrosis (ATN) and kidney transplant. Other Acute myocardial infarction: within the first 48 hours after a heart attack, 80% of patients have hypomagnesemia. This could be the result of an intracellular shift because of an increase in catecholamines. Malabsorption Acute pancreatitis Fluoride poisoning Massive transfusion (MT) is a lifesaving treatment of hemorrhagic shock, but can be associated with significant complications. Pathophysiology Magnesium is a co-factor in over 300 functions in the body regulating many kinds of biochemical reactions. It is involved in protein synthesis, muscle and nerve functioning, bone development, energy production, the maintenance of normal heart rhythm, and the regulation of glucose and blood pressure, among other important roles. Low magnesium intake over time can increase the risk of illnesses, including high blood pressure and heart disease, diabetes mellitus type 2, osteoporosis, and migraines.There is a direct effect on sodium (Na), potassium (K), and calcium (Ca) channels. Magnesium has several effects: Potassium Potassium channel efflux is inhibited by magnesium. Thus hypomagnesemia results in an increased excretion of potassium in kidney, resulting in a hypokalaemia. This condition is believed to occur secondary to the decreased normal physiologic magnesium inhibition of the ROMK channels in the apical tubular membrane.In this light, hypomagnesemia is frequently the cause of hypokalaemic patients failing to respond to potassium supplementation. Thus, clinicians should ensure that both magnesium and potassium is replaced when deficient. Patients with diabetic ketoacidosis should have their magnesium levels monitored to ensure that the serum loss of potassium, which is driven intracellularly by insulin administration, is not exacerbated by additional urinary losses. Calcium Release of calcium from the sarcoplasmic reticulum is inhibited by magnesium. Thus hypomagnesemia results in an increased intracellular calcium level. This inhibits the release of parathyroid hormone, which can result in hypoparathyroidism and hypocalcemia. Furthermore, it makes skeletal and muscle receptors less sensitive to parathyroid hormone. Arrhythmia Magnesium is needed for the adequate function of the Na+/K+-ATPase pumps in cardiac myocytes, the muscles cells of the heart. A lack of magnesium inhibits reuptake of potassium, causing a decrease in intracellular potassium. This decrease in intracellular potassium results in a tachycardia. Pre-eclampsia Magnesium has an indirect antithrombotic effect upon platelets and endothelial function. Magnesium increases prostaglandins, decreases thromboxane, and decreases angiotensin II, microvascular leakage, and vasospasm through its function similar to calcium channel blockers. Convulsions are the result of cerebral vasospasm. The vasodilatatory effect of magnesium seems to be the major mechanism. Asthma Magnesium exerts a bronchodilatatory effect, probably by antagonizing calcium-mediated bronchoconstriction. Neurological effects reducing electrical excitation modulating release of acetylcholine antagonising N-methyl-D-aspartate (NMDA) glutamate receptors, an excitatory neurotransmitter of the central nervous system and thus providing neuroprotection from excitoxicity. Diabetes mellitus Magnesium deficiency is frequently observed in people with type 2 diabetes mellitus, with an estimated prevalence ranging between 11.0 and 47.7%. Magnesium deficiency is strongly associated with high glucose and insulin resistance, which indicate that it is common in poorly controlled diabetes. Patients with type 2 diabetes and a magnesium deficiency have a higher risk of heart failure, atrial fibrillation and microvascular complications. Oral magnesium supplements has been demonstrated to improve insulin sensitivity and lipid profile. However, their effect on cardiovascular risk in diabetes are to be determined. Homeostasis Magnesium is abundant in nature. It can be found in green vegetables, chlorophyll (chloroplasts), cocoa derivatives, nuts, wheat, seafood, and meat. It is absorbed primarily in the duodenum of the small intestine. The rectum and sigmoid colon can absorb magnesium. Forty percent of dietary magnesium is absorbed. Hypomagnesemia stimulates and hypermagnesemia inhibits this absorption.The body contains 21–28 grams of magnesium (0.864–1.152 mol). Of this, 53% is located in bone, 19% in non-muscular tissue, and 1% in extracellular fluid. For this reason, blood levels of magnesium are not an adequate means of establishing the total amount of available magnesium.The majority of serum magnesium is bound to chelators, including proteins and citrate. Roughly 33% is bound to proteins, and 5–10% is not bound. This "free" magnesium is essential in regulating intracellular magnesium. Normal plasma Mg is 1.7–2.3 mg/dL (0.69–0.94 mmol/L). The kidneys regulate the serum magnesium. About 2400 mg of magnesium passes through the kidneys daily, of which 5% (120 mg) is excreted through urine. The loop of Henle is the major site for magnesium homeostasis, and 60% is reabsorbed. Magnesium homeostasis comprises three systems: kidney, small intestine, and bone. In the acute phase of magnesium deficiency there is an increase in absorption in the distal small intestine and tubular resorption in the kidneys. When this condition persists, serum magnesium drops and is corrected with magnesium from bone tissue. The level of intracellular magnesium is controlled through the reservoir in bone tissue. Diagnosis Magnesium deficiency is not easy to directly measure. Typically the diagnosis is based on finding low blood magnesium levels (hypomagnesemia). Specifically by finding a plasma magnesium concentration of less than 0.6 mmol/L (1.46 mg/dL). Severe disease generally has a level of less than 0.50 mmol/L (1.25 mg/dL).Magnesium deficiency (or depletion) refers to low total body levels of magnesium which is usually determined by finding low blood levels (hypomagnesemia). Hypomagnesemia refers only to blood levels of magnesium. Either of magnesium deficiency and hypomagnesemia can be present without the other. Electrocardiogram The electrocardiogram (ECG) change may show a tachycardia with a prolonged QT interval. Other changes may include prolonged PR interval, ST segment depression, flipped T waves, and long QRS duration. Treatments Treatment of hypomagnesemia depends on the degree of deficiency and the clinical effects. Replacement by mouth is appropriate for people with mild symptoms, while intravenous replacement is recommended for people with severe effects.Numerous oral magnesium preparations are available. In two trials of magnesium oxide, one of the most common forms in magnesium dietary supplements because of its high magnesium content per weight, was less bioavailable than magnesium citrate, chloride, lactate or aspartate. Magnesium citrate has been reported as more bioavailable than oxide or amino-acid chelate forms.Intravenous magnesium sulfate (MgSO4) can be given in response to heart arrhythmias to correct for hypokalemia, preventing pre-eclampsia, and has been suggested as having a potential use in asthma. Food Food sources of magnesium include leafy green vegetables, beans, nuts, and seeds. Epidemiology The condition is relatively common among people in hospital. History Magnesium deficiency in humans was first described in the medical literature in 1934. Plants Magnesium deficiency is a detrimental plant disorder that occurs most often in strongly acidic, light, sandy soils, where magnesium can be easily leached away. Magnesium is an essential macronutrient constituting 0.2-0.4% of plants dry matter and is necessary for normal plant growth. Excess potassium, generally due to fertilizers, further aggravates the stress from magnesium deficiency, as does aluminium toxicity.Magnesium has an important role in photosynthesis because it forms the central atom of chlorophyll. Therefore, without sufficient amounts of magnesium, plants begin to degrade the chlorophyll in the old leaves. This causes the main symptom of magnesium deficiency, interveinal chlorosis, or yellowing between leaf veins, which stay green, giving the leaves a marbled appearance. Due to magnesiums mobile nature, the plant will first break down chlorophyll in older leaves and transport the Mg to younger leaves which have greater photosynthetic needs. Therefore, the first sign of magnesium deficiency is the chlorosis of old leaves which progresses to the young leaves as the deficiency progresses. Magnesium also acts as an activator for many critical enzymes, including ribulosebisphosphate carboxylase (RuBisCO) and phosphoenolpyruvate carboxylase (PEPC), both essential enzymes in carbon fixation. Thus low amounts of Mg lead to a decrease in photosynthetic and enzymatic activity within the plants. Magnesium is also crucial in stabilizing ribosome structures, hence, a lack of magnesium causes depolymerization of ribosomes leading to premature aging of the plant. After prolonged magnesium deficiency, necrosis and dropping of older leaves occurs. Plants deficient in magnesium also produce smaller, woodier fruits. Magnesium deficiency in plants may be confused with zinc or chlorine deficiencies, viruses, or natural aging, since all have similar symptoms. Adding Epsom salts (as a solution of 25 grams per liter or 4 oz per gal) or crushed dolomitic limestone to the soil can rectify magnesium deficiencies. An organic treatment is to apply compost mulch, which can prevent leaching during excessive rainfall and provide plants with sufficient amounts of nutrients, including magnesium. See also Magnesium in biology Hypermagnesemia References External links Magnesium
Folliculitis	Folliculitis is the infection and inflammation of one or more hair follicles. The condition may occur anywhere on hair-covered skin. The rash may appear as pimples that come to white tips on the face, chest, back, arms, legs, buttocks, or head.Although acne can often involve superficial infection and inflammation of some hair follicles, the condition of those follicles is usually not called folliculitis, as that term is usually reserved for the separate set of disease entities comprising infected and inflamed hair follicles with causes other than acne. Signs and symptoms Rash (reddened skin area) Itching skin Pimples or pustules located around a hair or follicle; may be confused with chicken pox May crust over Typically occur on neck, armpit, or groin May present as genital lesions Spreading from leg to arm to body through improper treatment with antibiotics Complications This condition can develop into a more severe skin condition, such as cellulitis or abscess. Causes Most carbuncles, boils, and other cases of folliculitis are infected with Staphylococcus aureus.Folliculitis starts with the introduction of a skin pathogen to a hair follicle. Hair follicles can also be damaged by friction from clothing, an insect bite, blockage of the follicle, shaving, or braids that are very tight and close to the scalp. The damaged follicles are then infected by Staphylococcus spp. Folliculitis can affect people of all ages.Iron-deficiency anemia is sometimes associated with chronic cases. Bacterial Staphylococcus aureus folliculitis Hot-tub folliculitis is caused by the bacterium Pseudomonas aeruginosa. The folliculitis usually occurs after sitting in a hot tub that was not properly cleaned before use. Symptoms are found around the body parts that sit in the hot tub - the legs, hips, chest, buttocks, and surrounding areas. Symptoms are amplified around regions that were covered by wet clothing, such as bathing suits. Sycosis vulgaris, sycosis barbae, or barbers itch is a staphylococcal infection of the hair follicles in the bearded area of the face, usually the upper lip. Shaving aggravates the condition. Gram-negative folliculitis may appear after prolonged acne treatment with antibiotics. Fungal Tinea barbae is similar to barbers itch, but the infection is caused by the fungus T. rubrum. Malassezia folliculitis, formerly known as Pityrosporum folliculitis, is caused by yeasts (part of the fungus kingdom) of the genus Malassezia Mites Demodex folliculitis is usually caused by an overgrowth of Demodex folliculorum a mite that lives in human hair follicles. Although most people with D. folliculorurm have no symptoms, the mite can reproduce excessively, particularly in people with oily scalps. Viral Herpetic folliculitis is rarer, but may occur when herpes simplex virus infection spreads to nearby hair follicles appearing in groups or clusters, mostly around the mouth. Noninfectious Pseudofolliculitis barbae is a disorder occurring when hair curves back into the skin and causes inflammation. Eosinophilic folliculitis may appear in persons with impaired immune systems. Folliculitis decalvans or tufted folliculitis usually affects the scalp. Several hairs arise from the same hair follicle. Scarring and permanent hair loss may follow. The cause is unknown. Folliculitis keloidalis scarring on the nape of the neck is most common among males with curly hair. Oil folliculitis is inflammation of hair follicles due to exposure to various oils, and typically occurs on forearms or thighs. It is common in refinery workers, road workers, mechanics, and sheep shearers. Even makeup may cause it. Malignancy may also be represented by recalcitrant cases. Treatment Most simple cases resolve on their own, but first-line treatments are typically topical medications. Topical antiseptic treatment is adequate for most cases. Topical antibiotics, such as mupirocin or neomycin/polymyxin B/bacitracin ointment may be prescribed. Oral antibiotics may also be used. Some patients may benefit from systemic narrow-spectrum penicillinase-resistant penicillins (such as dicloxacillin in the US or flucloxacillin in UK). Fungal folliculitis may require an oral antifungal such as fluconazole. Topical antifungals such as econazole nitrate may also be effective.Folliculitis may recur even after symptoms have gone away. See also Ingrown hair Keratosis References External links Folliculitis Treatments Malassezia (Pityrosporum) Folliculitis Treatment & Management
Urtica dioica	Urtica dioica, often known as common nettle, burn nettle, stinging nettle (although not all plants of this species sting) or nettle leaf, or just a nettle or stinger, is a herbaceous perennial flowering plant in the family Urticaceae. Originally native to Europe, much of temperate Asia and western North Africa, it is now found worldwide, including New Zealand and North America. The species is divided into six subspecies, five of which have many hollow stinging hairs called trichomes on the leaves and stems, which act like hypodermic needles, injecting histamine and other chemicals that produce a stinging sensation upon contact ("contact urticaria", a form of contact dermatitis).The plant has a long history of use as a source for traditional medicine, food, tea, and textile raw material in ancient (such as Saxon) and modern societies. Description Urtica dioica is a dioecious, herbaceous, perennial plant, 3 to 7 feet (0.9 to 2 metres) tall in the summer and dying down to the ground in winter. It has widely spreading rhizomes and stolons, which are bright yellow, as are the roots. The soft, green leaves are 1 to 6 inches (30 to 200 mm) long and are borne oppositely on an erect, wiry, green stem. The leaves have a strongly serrated margin, a cordate base, and an acuminate tip with a terminal leaf tooth longer than adjacent laterals. It bears small, greenish or brownish, numerous flowers in dense axillary inflorescences. The leaves and stems are very hairy with non-stinging hairs, and in most subspecies, also bear many stinging hairs (trichomes or spicules), whose tips come off when touched, transforming the hair into a needle that can inject several chemicals causing a painful sting or paresthesia, giving the species its common names: stinging nettle, burn-nettle, burn-weed, or burn-hazel. Taxonomy The taxonomy of Urtica species has been confused, and older sources are likely to use a variety of systematic names for these plants. Formerly, more species were recognised than are now accepted. However, at least six clear subspecies of U. dioica are described, some formerly classified as separate species: U. dioica subsp. dioica (European stinging nettle), from Europe, Asia, and northern Africa, has stinging hairs. U. dioica subsp. galeopsifolia (fen nettle or stingless nettle), from Europe, does not have stinging hairs. U. dioica subsp. afghanica, from southwestern and central Asia, sometimes has stinging hairs or is sometimes hairless. U. dioica subsp. gansuensis, from eastern Asia (China), has stinging hairs. U. dioica subsp. gracilis (Ait.) Selander (American stinging nettle), from North America, has stinging hairs and is monoecious. U. dioica subsp. holosericea (Nutt.) Thorne (hoary stinging nettle), from North America, has stinging hairs and is monoecious.Other species names formerly accepted as distinct by some authors but now regarded as synonyms of one or other subspecies include U. breweri, U. californica, U. cardiophylla, U. lyalli, U. major, U. procera, U. serra, U. strigosissima, U. trachycarpa, and U. viridis. Etymology Urtica is derived from a Latin word meaning sting.Dioica (δίοικος) is derived from Greek, meaning of two houses (having separate staminate and pistillate plants; dioecious). Distribution and habitat U. dioica is considered to be native to Europe, much of temperate Asia and western North Africa. It is abundant in northern Europe and much of Asia, usually found in the countryside. It is less widespread in southern Europe and north Africa, where it is restricted by its need for moist soil, but is still common. It has been introduced to many other parts of the world. In North America, it is widely distributed in Canada and the United States, where it is found in every province and state except for Hawaii, and also can be found in northernmost Mexico. It grows in abundance in the Pacific Northwest, especially in places where annual rainfall is high. The European subspecies has been introduced into Australia, North America and South America.In Europe, nettles have a strong association with human habitation and buildings. The presence of nettles may indicate the site of a long-abandoned building, and can also indicate soil fertility. Human and animal waste may be responsible for elevated levels of phosphate and nitrogen in the soil, providing an ideal environment for nettles. Ecology Nettles are the larval food plant for several species of butterflies, such as the peacock butterfly, comma (Polygonia c-album), and the small tortoiseshell. It is also eaten by the larvae of some moths including angle shades, buff ermine, dot moth, the flame, the gothic, grey chi, grey pug, lesser broad-bordered yellow underwing, mouse moth, setaceous Hebrew character, and small angle shades. The roots are sometimes eaten by the larva of the ghost moth (Hepialus humuli). It is a known host to the pathogenic fungus Phoma herbarum.Stinging nettle is particularly found as an understory plant in wetter environments, but it is also found in meadows. Although nutritious, it is not widely eaten by either wildlife or livestock, presumably because of the sting. It spreads by abundant seeds and also by rhizomes, and is often able to survive and re-establish quickly after fire. Cultivation Field Sowing and planting Three cultivation techniques can be used for the stinging nettle: 1) direct sowing, 2) growing seedlings in nurseries with subsequent transplantation and 3) vegetative propagation via stolons or head cuttings. Direct sowing: The seedbed should have a loose and fine structure, but should be reconsolidated using a packer roller imminently prior to sowing. Sowing time can be either in autumn or in spring. Seed density should be 6 kilograms/hectare with row spacing of 30 cm (12 in) and 42–50 cm in autumn and spring, respectively. The disadvantage of direct sowing is that it usually leads to incomplete plant coverage. This drawback can be mitigated by covering the seedbed with a transparent perforated foil in order to improve seed germination. Further, weed control can be problematic as the stinging nettle has a slow seedling development time. Growing seedlings: For this technique pre-germinated seeds are sown between mid-/end-February and beginning of April and grown in nurseries. Seedlings are grown in tuffs with 3–5 plants/tuff and a seed density of 1.2–1.6 kg/1000 tuffs. A fastened germination is achieved by alternating high temperature during daytime (30 °C for 8 h) and lower temperature during nighttime (20 °C for 16 h). Before transplanting, the seedlings should be fertilized and acclimated to cold temperatures. Transplantation should start around Mid-April with row spacing of 42–50 cm (17–20 in) and plant spacing within rows of 25–30 cm. Vegetative propagation: Stolons (with several buds) of 10 cm should be planted from mid-April in a depth of 5–7 cm (2–2+3⁄4 in). Head cuttings are grown in nurseries starting between mid-May and mid-June. Growing tips with two leaf pairs are cut from the mother plant and treated with root-growth inducing hormones. Transplantation can be delayed in comparison to the growing seedling technique. Greenhouse The stinging nettle can also be grown in controlled-environment agriculture systems, such as soil-less medium cultivations or aeroponics, which may achieve higher yields, standardize quality, and reduce harvesting costs and contamination. Sting and treatment Urtica dioica produces its inflammatory effect on skin (stinging, burning sensation often called "contact urticaria") both by impaling the skin via spicules – causing mechanical irritation – and by biochemical irritants, such as histamine, serotonin, and acetylcholine, among other chemicals. Anti-itch drugs, usually in the form of creams containing antihistamines or hydrocortisone, may provide relief from nettle dermatitis. The term, contact urticaria, has a wider use in dermatology, involving dermatitis caused by various skin irritants and pathogens.Docks, especially the broad-leaf dock (Rumex obtusifolius) often grow in similar environments to stinging nettles and are regarded as a folk remedy to counteract the sting of a nettle, although there is no evidence of any chemical effect. It may be that the act of rubbing a dock leaf against a nettle sting acts as a distracting counterstimulation, or that belief in the docks effect provides a placebo effect. Uses Culinary U. dioica has a flavour similar to spinach when cooked. Young plants were harvested by Native Americans and used as a cooked plant in spring when other food plants were scarce. Soaking stinging nettles in water or cooking removes the stinging chemicals from the plant, which allows them to be handled and eaten without injury. After the stinging nettle enters its flowering and seed-setting stages, the leaves develop gritty particles called cystoliths, which can irritate the kidneys and urinary tract.: 106–107 Cystoliths are made of calcium carbonate, and will not dissolve when boiled. Leaves harvested post-flowering must have their cystoliths broken down by acid, as in the fermentation process. In its peak season, nettle contains up to 25% protein, dry weight, which is high for a leafy green vegetable. The leaves are also dried and may then be used to make a herbal tea, as can also be done with the nettles flowers. Nettles can be used in a variety of recipes, such as polenta, pesto, and purée. Nettle soup is a common use of the plant, particularly in Northern and Eastern Europe. Nettles are sometimes used in cheesemaking, such as for Cornish Yarg and as a flavouring in varieties of Gouda.Nettles are used in Montenegro, Serbia and Bosnia and Hercegovina as part of the dough filling for the börek pastry. The top baby leaves are selected and simmered, and then mixed with other ingredients such as herbs and rice, before being used as a filling between dough layers. Similarly, in Greece the tender leaves are often used, after simmering, as a filling for hortopita, which is similar to spanakopita, but with wild greens rather than spinach for filling.Young nettles can also be used to make an alcoholic drink. Competitive eating In the UK, an annual World Nettle Eating Championship draws thousands of people to Dorset, where competitors attempt to eat as much of the raw plant as possible. Competitors are given 60 cm (24 in) stalks of the plant, from which they strip the leaves and eat them. Whoever strips and eats the most stinging nettle leaves in a fixed time is the winner. The competition dates back to 1986, when two neighbouring farmers attempted to settle a dispute about which had the worst infestation of nettles, and one of them said, "Ill eat any nettle of yours thats longer than mine." Traditional medicine As Old English stiðe, nettle is one of the nine plants invoked in the pagan Anglo-Saxon Nine Herbs Charm, recorded in 10th century traditional medicine. Nettle was believed to be a galactagogue – a substance that promotes lactation. Urtication, or flogging with nettles is the process of deliberately applying stinging nettles to the skin to provoke inflammation. An agent thus used was considered to be a rubefacient (something that causes redness), used as a folk remedy for treating rheumatism. Chastisement In indigenous justice systems in Ecuador, urtication was used as punishment for severe crimes in 2010. The sentenced perpetrator of a crime was flogged with stinging nettle, in public, naked, whilst being showered with freezing cold water. Textiles and fibre Nettle stems contain a bast fibre that has been traditionally used for the same purposes as linen and is produced by a similar retting process. Unlike cotton, nettles grow easily without pesticides. The fibres are coarser, however.Historically, nettles have been used to make clothing for almost 3,000 years, as ancient nettle textiles from the Bronze Age have been found in Denmark. It is widely believed that German Army uniforms were almost all made from nettle during World War I due to a potential shortage of cotton, although there is little evidence to support this. More recently, companies in Austria, Germany, and Italy have started to produce commercial nettle textiles.The fibre content in nettle shows a high variability and reaches from below 1% to 17%. Under middle-European conditions, stems yield typically between 45 and 55 dt / ha (decitons per hectare), which is comparable to flax stem yield. Due to the variable fibre content, the fibre yields vary between 0.2 and 7 dt / ha, but the yields are normally in the range between 2 and 4 dt / ha. Fibre varieties are normally cloning varieties and therefore planted from vegetative propagated plantlets. Direct seeding is possible, but leads to great heterogeneity in maturity.Nettles may be used as a dye-stuff, producing yellow from the roots, or yellowish green from the leaves. Feed Nutrient contents Fresh leaves contain approximately 82.4% water, 17.6% dry matter, 5.5% protein, 0.7 to 3.3% fat, and 7.1% carbohydrates. Mature leaves contain about 40% α- linolenic acid, a valuable omega-3 acid. For exact fatty acid contents see Table 1. Seeds contain much more fatty acid than leaves. Minerals (Ca, K, Mg, P, Si, S, Cl) and trace elements (Ti, 80 ppm, Mn, Cu, Fe) contents depend mostly on the soil and the season.Carotenoids can be found primarily in the leaves, where different forms of lutein, xanthophyll and carotene are present (Table 2). Some carotenes are precursors of vitamin A (retinol), their retinol equivalents RE or retinol activity equivalents per g dry weight are 1.33 for mature leaves and 0.9 for young leaves. Nettle contains much less carotenes and retinol than carrots, which contain 8.35 RE per g fresh weight. Depending on the batch and the leave and stem content, nettle contains only traces of zeaxanthin or between 20–60 mg/kg of dry matter. Nettle contains ascorbic acid (vitamin C), riboflavin (vitamin B2), pantothenic acid, vitamin K1 and tocopherols (vitamin E). The highest vitamin contents can be found in the leaves. Poultry: Egg yolk colouring in laying hens In laying hens, nettle can be used as an egg yolk colorant instead of artificial pigments or other natural pigments (derived from marigold for yellow). Nettle has high carotenoid contents, especially lutein, β-carotene and zeaxanthin, of which lutein and zeaxanthin act as yellow pigments. Feeding as little as 6.25 g dry nettle per kg feed is as effective as the synthetic pigments to colour the egg yolk. Feeding nettle has no detrimental effect on the performance of the laying hens or on the general quality of eggs. Ruminants Ruminants avoid fresh stinging nettles; however, if the nettles are wilted or dry, voluntary intake can be high. Use in agriculture / horticulture In the European Union and United Kingdom, nettle extract can be used as a insecticide, fungicide, and acaricide under Basic Substance regulations. As an insecticide nettle extract can be used for the control of codling moth, diamondback moth, and spider mites. As a fungicide, it can be used for the control of Pythium root rot, powdery mildew, early blight, late blight, Septoria blight, Alternaria leaf spot, and grey mould. Gardening Nettles have a number of other uses in the vegetable garden, including the potential for encouraging beneficial insects. Since nettles prefer to grow in phosphorus-rich and nitrogen rich soils that have recently been disturbed (and thus aerated), the growth of nettles is an indicator that an area has high fertility (especially phosphate and nitrate), and thus is an indicator to gardeners as to the quality of the soil.Nettles contain nitrogenous compounds, so are used as a compost activator or can be used to make a liquid fertilizer, which although low in phosphate, is useful in supplying magnesium, sulphur, and iron. They are also one of the few plants that can tolerate, and flourish in, soils rich in poultry droppings. The stinging nettle is the red admiral caterpillars primary host plant and can attract migrating red admiral butterflies to a garden. U. dioica can be a troubling weed, and mowing can increase plant density. Regular and persistent tilling will greatly reduce its numbers, and the use of herbicides such as 2,4-D and glyphosate are effective control measures. Culture In Great Britain and Ireland, U. dioica and the annual nettle Urtica urens are the only common stinging plants and have found a place in several figures of speech in the English language. Shakespeares Hotspur urges that "out of this nettle, danger, we pluck this flower, safety" (Henry IV, Part 1, Act II Scene 3). The figure of speech "to grasp the nettle" probably originated from Aesops fable "The Boy and the Nettle". In Seán OCaseys Juno and the Paycock, one of the characters quotes Aesop "Gently touch a nettle and itll sting you for your pains/Grasp it as a lad of mettle and soft as silk remains". The metaphor may refer to the fact that if a nettle plant is grasped firmly rather than brushed against, it does not sting so readily, because the hairs are crushed down flat and do not penetrate the skin so easily.In the German language, the idiom sich in die Nesseln setzen, or to sit in nettles, means to get into trouble. In Hungarian, the idiom csalánba nem üt a mennykő, the lightning bolt does not strike into nettles, alludes to the belief that bad people escape trouble or the devil looks after his own. The same idiom exists in the Serbian language – неће гром у коприве. In Dutch, a netelige situatie means a predicament. In French, the idiom faut pas pousser mémé dans les orties (do not push granny into the nettles) means that we should be careful not to abuse a situation. The name urticaria for hives comes from the Latin name of nettle (Urtica, from urere, to burn). The English word nettled, meaning irritated or angry, is derived from nettle.There is a common idea in Great Britain that the nettle was introduced by the Romans. The idea was mentioned by William Camden in his book Britannia of 1586. However, in 2011, an early Bronze Age burial cist on Whitehorse Hill, Dartmoor, Devon was excavated. The cist dated from between 1730 and 1600 BC. It contained various high value beads as well as fragments of a sash made from nettle fibre. It is possible that the sash was traded from mainland Europe, but perhaps more probable that it was locally made. See also Nettles in folklore References Further reading Elliott, C. (1997). "Rash Encounters". Horticulture. 94: 30. Schofield, Janice J. (1998). Nettles ISBN 0-585-10500-6 Thiselton-Dyer, T. F., (1889). The Folk-Lore of Plants. Glawe, G. A. (2006). Sex ratio variation and sex determination in Urtica diocia. ISBN 90-6464-026-2 External links "Urtica dioica L." Germplasm Resources Information Network (GRIN). Agricultural Research Service (ARS), United States Department of Agriculture (USDA). Flora of China: Urtica dioica
Ornithine aminotransferase deficiency	Ornithine aminotransferase deficiency (also known as gyrate atrophy of the choroid and retina) is an inborn error of ornithine metabolism, caused by decreased activity of the enzyme ornithine aminotransferase. Biochemically, it can be detected by elevated levels of ornithine in the blood. Clinically, it presents initially with poor night vision, which slowly progresses to total blindness. It is believed to be inherited in an autosomal recessive manner. Approximately 200 known cases have been reported in the literature. The incidence is highest in Finland, estimated at 1:50,000.Research suggests there can be some adverse effect on muscles and also the brain. The cause of this is somewhat unclear but may relate to very low levels of creatine often found in this population. Treatment may include vitamin B6, lysine or dramatic dietary change to minimise arginine from patients diet. Research has indicated that these treatments may be somewhat effective in lowering ornithine blood concentration levels in some patients, either in combination or individually. Vitamin B6 has been found to be very effective in a small proportion of patients. Presentation Quite often, the presenting symptom of ornithine aminotransferase (OAT) deficiency is myopia which progresses to night blindness. The onset of myopia is often in early childhood. Ophthalmological findings in affected individuals include constricted visual fields, posterior subcapsular cataracts (can begin in late teens), elevated dark adaptation thresholds and decreased or absent electroretinographic responses. Symptoms of OAT deficiency are progressive, and between the ages of 45 and 65, most affected individuals are almost completely blind.In some cases, affected individuals will present in the neonatal period with disease that closely mimics a classic urea cycle defect, such as ornithine transcarbamylase deficiency, as the block in ornithine metabolism leads to secondary dysfunction of the urea cycle. These individuals present with hyperammonemia, poor feeding, failure to thrive and increased excretion of orotic acid. Genetics OAT deficiency is inherited in an autosomal recessive manner, meaning an affected individual must inherit a mutated allele from both parents. The enzyme, ornithine aminotransferase is coded for by the gene OAT, located at 10q26. OAT deficiency has an increased incidence in Finland, and this population has a common mutation accounting for more than 85% of mutant alleles in this population. It has not been described in any other populations. Diagnosis Upon clinical suspicion, diagnostic testing will often consist of measurement of amino acid concentrations in plasma, in search of a significantly elevated ornithine concentration. Measurement of urine amino acid concentrations is sometimes necessary, particularly in neonatal onset cases to identify the presence or absence of homocitrulline for ruling out ornithine translocase deficiency (hyperornithinemia, hyperammonemia, homocitrullinuria syndrome, HHH syndrome). Ornithine concentrations can be an unreliable indicator in the newborn period, thus newborn screening may not detect this condition, even if ornithine is included in the screening panel. Enzyme assays to measure the activity of ornithine aminotransferase can be performed from fibroblasts or lymphoblasts for confirmation or during the neonatal period when the results of biochemical testing is unclear. Molecular genetic testing is also an option. Treatment To reduce the levels of ornithine in the blood, a diet restricted in arginine has been used. Some research has shown that when diet or other treatment is initiated early in life, the outcome can be improved. References == External links ==
Valsalva retinopathy	Valsalva retinopathy is a form of retinopathy due to retinal bleeding secondary to rupture of retinal vessels caused by intrathoracic or intra-abdominal pressure due to physical activities. It can occur in any person irrespective of age, gender, race or health status. Pathophysiology Valsalva retinopathy is a form of sub-retinal, sub-hyaloid or sub-internal limiting membrane hemorrhage occur due to rupture of retinal vessels caused by a strenuous physical activity. Physical exertion like weight lifting and aerobic exercise, coughing, sneezing, straining at stool, vomiting, sexual intercourse, pregnancy, asthma, blowing up balloons, blowing musical instruments, cardiopulmonary resuscitation or compression injuries may cause sudden increase in intrathoracic or intra-abdominal pressure may lead to rupture of superficial retinal blood vessels. A sudden increase in venous pressure due to intrathoracic or intra-abdominal pressure cause the small perifoveal capillaries of retina to rupture, leading to premacular hemorrhage of varying intensity. Signs and symptoms The main symptom of valsalva retinopathy is painless sudden loss of vision. Sudden-onset floaters and central or paracentral visual field defects and nausea resulting from increased intraocular pressure are other symptoms. Diagnosis Patients may have a history of sudden vision loss after a strenuous physical activity. Physical examination and eye examination is needed for diagnosis of valsalava retinopathy. OCT scanning can be used to identify the location of the bleeding. Complications One of the main complications of valsalva retinopathy is vitreous hemorrhage. Epidemiology As of 2022, there is currently no specific age, gender or racial preference noted for this retinopathy in the medical literature. Treatment Depending on the location and extent of the bleeding, valsalva retinopathy usually resolves within weeks to months, without any complications. Patients are instructed to avoid anticoagulant drugs and physical activities which cause increase in intrathoracic or intra-abdominal pressure. For a speedy recovery, sometimes Nd:YAG laser or argon laser membranotomy may be advised. History Valsalva retinopathy was first described in 1972 by American ophthalmologist Thomas D. Duane. == References ==
Nelsons syndrome	Nelsons syndrome is a disorder that occurs in about one in four patients who have had both adrenal glands removed to treat Cushings disease. In patients with pre-existing adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, loss of adrenal feedback following bilateral adrenalectomy can trigger the rapid growth of the tumor, leading to visual symptoms (e.g. bitemporal hemianopsia) and hyperpigmentation. The severity of the disease is dependent upon the effect of ACTH release on the skin, pituitary hormone loss from mass compression, as well as invasion into surrounding structures around the pituitary gland.The first case of Nelsons syndrome was reported in 1958 by Dr. Don Nelson. Within the past ten to twenty years, improvements have been made with identification and care for patients with Cushings disease. Techniques such as pituitary radiation therapy, ACTH assay, transsphenoidal pituitary surgery, higher resolution MRIs, and sampling of the inferior petrosal sinus have allowed physicians to pursue routes for Cushings syndrome therapy prior to consideration of bilateral adrenalectomy.Nelsons syndrome is also referred to as post adrenalectomy syndrome, a possible result of adrenalectomy performed for Cushings disease. Symptoms and signs The common symptoms include: hyper-pigmentation of the skin visual disturbances headaches abnormally high levels of beta-MSH and ACTH abnormal enlargements of the pituitary gland, interruption of menstrual cycles in women Cause Common causes include bilateral adrenalectomy for the treatment of Cushings disease, and hypopituitarism. The onset of the disease can occur up to 24 years after a bilateral adrenalectomy has been performed, with an average of up to 15 years after. A preventative measure that can be utilized is prophylactic radiotherapy when a bilateral adrenalectomy is being performed in order to prevent Nelsons syndrome from manifesting. Screening can also be done with the help of an MRI in order to visualize the pituitary for tumors. If tumors are not present then an MRI should be performed at intervals. Hyper-pigmentation and fasting ACTH levels within plasma above 154 pmol/L are predictive of Nelsons syndrome after an adrenalectomy. Risk factors include being younger in age and pregnancy. Mechanism After a bilateral adrenalectomy is performed cortisol levels are no longer normal. This increases CRH production because it is not suppressed within the hypothalamus anymore. The increased CRH levels promote the growth of the tumor. Mutations with genes and with the glucocorticoid receptor can affect the tumor as well. Furthermore, differences between Nelson syndrome and Cushings disease have been studied. Particularly Nelsons syndrome differs from Cushings disease due to the following: secretions from the tumors, replacement of glucocorticoids, and injury to the hypothalamus due to radiation therapy utilized on the patient. The pathophysiology of Nelsons syndrome is not understood very well. Corticotrophinomas are generated from corticotroph cells. Expression of functional CRH and vasopressin V3 receptors increase in number. Additionally, there are two isoforms of glucocorticoid receptors. Heterozygosity loss in the glucocorticoid receptor can occur in the tumors present from Nelsons syndrome. Overall, not all patients that have had a total bilateral adrenalectomy develop Nelsons syndrome, which makes the mechanism harder to understand for such a rare disease. It is not clear whether the adrenalectomy or reduced cortisol secretion causes aggressive tumor growth. Diagnosis Common diagnostic techniques include: MRIs CAT scans blood samples.Blood samples are assessed for the absence or presence of aldosterone and cortisol. Physical examinations are also useful in patients in order to examine vision, skin pigmentation, how the body replaces steroids, and the cranial nerves. Recent advancements in high-resolution MRIs allow for adenomas to be detected during the early stages of Nelson syndrome. Physical examination including height, weight, vital signs, blood pressure, eye examination, thyroid examination, abdominal examination, neurological examination, skin examination and pubertal staging needs to be assessed. Through blood pressure and pulse readings can indicate hypothyroidism and adrenal insufficiency. Hyper-pigmentation, hyporeflexia, and loss of vision can also indicate Nelsons syndrome when assessed together. Specifically for a child who might have Nelsons syndrome, the patient should be questioned about the symptoms of the disease, and well as symptoms of other diseases to narrow down which disease the patient presents with. The patient should be questioned about how often and to what degree headaches, visual disturbances, and symptoms associated with pituitary malfunction occur. Additionally, adrenal steroid replacement should be assessed. Treatment Common treatments for Nelsons syndrome include radiation or surgical procedure. Radiation allows for the limitation of the growth of the pituitary gland and the adenomas. If the adenomas start to affect the surrounding structures of the brain, then a micro-surgical technique can be adapted in order to remove the adenomas in a transsphenoidal (bone at base of the skull) process. Death may result with development of a locally aggressive pituitary tumor. However, does not commonly occur with pituitary diseases. In the rare case, ACTH-secreting tumors can become malignant. Morbidity from the disease can occur due to pituitary tissue compression or replacement, and compression of structures that surround the pituitary fossa. The tumor can also compress the optic apparatus, disturb cerebrospinal fluid flow, meningitis, and testicular enlargement in rare cases. Research Through multiple advancements within the medical field, caregivers have been able to stray away from utilizing bilateral adrenalectomy as the treatment for Cushings disease. This has decreased the risk of patients presenting with Nelsons syndrome. Alternative treatments for Nelsons syndrome have been discovered. The most utilized technique for Nelsons syndrome has been transsphenoidal surgery. In addition, pharmacotherapy, radiotherapy, and radiosurgery have been utilized accompanying a surgical procedure. Pharmacological drugs can also be given accompanying a transsphenoidal surgery including the following: pasireotide, temozolomide and octreotide. Within rats/mice, rosiglitazone has been an effective measure, however this has not been discovered in humans yet. References == External links ==
Retinal dysplasia	Retinal dysplasia is an eye disease affecting the retina of animals and, less commonly, humans. It is usually a nonprogressive disease and can be caused by viral infections, drugs, vitamin A deficiency, or genetic defects. Retinal dysplasia is characterized by folds or rosettes (round clumps) of the retinal tissue. Retinal dysplasia in dogs Most cases of retinal dysplasia in dogs are hereditary. It can involve one or both retinas. Retinal dysplasia can be focal, multifocal, geographic, or accompanied by retinal detachment. Focal and multifocal retinal dysplasia appears as streaks and dots in the central retina. Geographic retinal dysplasia appears as an irregular or horseshoe-shaped area of mixed hyper or hyporeflectivity in the central retina. Retinal detachment occurs with complete retinal dysplasia, and is accompanied by blindness in that eye. Cataracts or glaucoma can also occur secondary to retinal dysplasia. Other causes of retinal dysplasia in dogs include infection with canine adenovirus or canine herpesvirus, or radiation of the eye in newborns. Commonly affected breeds Bedlington Terrier - complete retinal dysplasia. Sealyham Terrier - complete retinal dysplasia. Rottweiler - focal or multifocal. English Springer Spaniel - focal, multifocal, or geographic. American Cocker Spaniel - focal or multifocal. Beagle - focal or multifocal. Cavalier King Charles Spaniel - retinal folds, geographic, or retinal detachment. Labrador Retriever - focal, multifocal, geographic, or complete retinal dysplasia. It can also be seen in combination with a congenital skeletal disorder. Australian Shepherd - retinal dysplasia occurs with other eye disorders, such as an oval pupil, microcornea (small cornea), cataracts, and retinal detachment. Retinal dysplasia in other animals Cats - Retinal dysplasia occurs in utero or in newborns infected with feline leukemia virus or feline panleukopenia, which cause necrosis and disorganization of the retina. It appears as folds and rosettes. Cattle - Retinal dysplasia occurs in utero through infection with bovine viral diarrhea. It is also inherited in Shorthorns and Herefords. Both forms often cause retinal detachment. Sheep - Retinal dysplasia occurs by in utero infection with bluetongue disease. Horses - Retinal dysplasia is bilateral, not inherited, and appears as multifocal or geographic disease. It is usually accompanied by other eye problems. Chickens See also Progressive retinal atrophy == References ==
5α-Reductase 2 deficiency	5α-Reductase 2 deficiency (5αR2D) is an autosomal recessive condition caused by a mutation in SRD5A2, a gene encoding the enzyme 5α-reductase type 2 (5αR2). The condition is rare, affects only genetic males, and has a broad spectrum of presentations, most apparent in the genitalia where a male is born with an underdeveloped penis that might develop to various extents in puberty and hence be raised as female up to a certain age. 5αR2 is expressed in specific tissues and catalyzes the transformation of testosterone (T) to 5α-dihydrotestosterone (DHT). DHT plays a key role in the process of sexual differentiation in the external genitalia and prostate during development of the male fetus. 5αR2D is a result of impaired 5αR2 activity resulting in decreased DHT levels. This defect results in a spectrum of phenotypes including overt genital ambiguity, female appearing genitalia, hypospadias, and isolated micropenis. Affected males still develop typical masculine features at puberty (deep voice, facial hair, muscle bulk) since most aspects of pubertal virilization are driven by testosterone, not DHT. Management of this condition in the context of sex assignment is a challenging and controversial area. Diagnostic availability, local laws, parental anxiety all play roles in treatment decisions. The investigation of 5αR2D as a disease has played a key role in the biochemical characterization of the SRD5A2 gene, the 5αR2 enzyme, and DHT in male sexual differentiation. Presentation Mutations in the SRD5A2 gene can result in a 46,XY disorder of sex development (46,XY DSD) called 5α-reductase 2 deficiency (5αR2D). The mutations are inherited in an autosomal recessive pattern can be either homozygous or, less frequently, compound heterozygous loss-of-function. Affected males exhibit a broad spectrum of presentation including atypical genitalia (ranging from female appearing to undervirilized male), hypospadias, and isolated micropenis. The internal reproductive structures (vasa deferentia, seminal vesicles, epididymides and ejaculatory ducts) are normal but testes are usually undescended and prostate hypoplasia is common. Males with the same mutations in SRD5A2 can have different phenotypes suggesting additional factors that are involved in clinical presentation. Females with the same mutations in SRD5A2 as affected males (as seen in siblings) are unaffected and have normal female phenotypes and reproductive function.Virilization of genitalia with voice deepening, development of muscle mass occur at puberty in affected males and height is not impaired. Gynecomastia is uncommon and bone density is normal in contrast to 46,XY DSD from other causes such as partial androgen insensitivity syndrome and 17β-hydroxysteroid dehydrogenase 3 deficiency. Hair on the face and body is reduced and male pattern baldness does not occur. Mechanism 5α-Reductase type 2 (5αR2) is an enzyme, encoded by the SRD5A2 gene, that is expressed in specific tissues in the male body from fetal development to adulthood. The enzyme catalyzes the transformation of testosterone (T) to 5α-dihydrotestosterone (DHT) intracellularly. DHT is the most potent ligand to the androgen receptor (AR). Upon binding, the DHT-AR complex translocates from cytoplasm to the nucleus and activates the androgen receptor-regulated genes involved in processes that include male sexual differentiation.Some mutations in 5αR2 impair the synthesis of DHT resulting in 5αR2D. In the male fetus, T mediates Wolffian ductal differentiation while DHT mediates external genital and prostate differentiation. The fact that women with the same 5αR2 mutations as affected male siblings have normal female phenotypes and normal reproductive function supports the notion that 5αR2 does not play an important role in female biology. Most aspects of virilization in male puberty are driven by testosterone, which is why most affected males undergo virilization at that time.Though 5αR2D only affects a small number of people, study of this disorder revealed fundamental aspects of 5α-reductases (including cloning of the underlying genes), androgen action, the process of sexual differentiation, and the factors that influence normal sexual behavior. Genetics Two of three isozymes of 5αR can catalyze the transformation of T to DHT, but it is only 5αR2D that causes 46XY, DSD. 5αR2 is encoded by the gene SRD5A2 which is located on the short arm of chromosome 2 and contains five exons and four introns. 5αR2 consists of 254 amino acid residues with reported mutations at 67 of them with multiple different mutations at some residues.The first known mutation SRD5A2 was almost a complete deletion which was discovered from analysis of affected males in Papua New Guinean tribe. The majority of SRD5A2 mutations are missense mutations but small deletions, splice junction mutations, and gross deletions were also observed. Mutations result in a spectrum of activity effects ranging from destabilizing 5αR2 to complete loss of activity.SRD5A2 mutations are inherited in an autosomal recessive pattern. Homozygous defects are more common than compound heterozygous ones. A phenotype-genotype correlation is not known to exist for many of the most common mutations, and affected males with the same 5αR2 mutations have variable phenotypes suggesting other interacting genetic factors that determine phenotype. Diagnosis Diagnosis is usually made between birth and puberty. Pseudovaginal perineoscrotal hypospadias presenting with female appearing genitalia and pubertal virilization is the classical syndrome attributed to 5αR2D, but modern diagnostic methods can diagnose the deficiency shortly after birth and recognize the broad spectrum of presentation.The initial diagnosis of 46,XY DSD is indicated by overt genital abnormality. The objective clinical evaluation of dysmorphic features to diagnose 46,XY DSD for apparent female genitalia include: enlarged clitoris, posterior labial fusion, and inguinal/labial mass. For apparent male genitalia: nonpalpable testes, micropenis, isolated perineal hypospadias, or mild hypospadias with undescended testis. Family history and prenatal history are also taken into account in evaluation. Karyotyping and SRY gene analysis on samples from peripheral leukocytes will exclude sex chromosome abnormalities. With the determination of an XY karyotype and normal SRY, the differential diagnosis of 46,XY DSD is made with endocrinological measurements of T/DHT ratios (which indicate 5αR2 activity) and precise anatomical imaging since 5αR2D can be difficult to distinguish from other causes of 46,XY DSD (e.g., partial androgen insensitivity syndrome and 17β- hydroxysteroid dehydrogenase type 3 enzyme deficiencies).The measurement of the serum DHT concentration is challenging since the concentrations are low and DHT has a high level of cross-reactivity. A high level of assay specificity is required to measure concentrations of DHT since serum T levels are generally 10 fold higher than DHT in young males. Endocrinological tests for T/DHT ratios can be difficult to interpret since the normal ratio level varies according to age and severity of 5αR2 activity impairment. Affected young males of at least pubertal age with normal serum T levels demonstrate elevated T/DHT levels (normal T, lower than normal DHT). Stimulation with human chorionic gonadotropin (hCG) (alternatively, testosterone enanthate) is required in prepubertal children (with stimulation and samples taken over several days) to increase serum testosterone levels for measurement. Interpreting T/DHT ratios in male newborns is especially challenging due to neonatal testosterone surge and higher than normal 5a-reductase type 1 activity. SRD5A2 gene analysis is recommended for diagnosis in newborns. Broadly, 5αR2D is diagnosed with T/DHT ratios greater than 18 while ratios greater than 30 have been observed in severely affected individuals. 5αR2D can also be indicated by low ratios of 5α- to 5ß- reduced steroids, as measured in urine measured via gas chromatography–mass spectrometry.Ultrasonography is the primary means for assessing internal reproductive organs for diagnosis while genitography and voiding cystourethrography are used to resolve structures such as urethral and vaginal tracts. The use of pelvic MRI for diagnostic imaging for 5αR2D remains controversial. Management One of the most clinically challenging and controversial topics with 46,XY DSD is the practice of "sex assignment" or "sex of rearing". This is especially so in 5αR2D, since most affected individuals have undervirilized genitalia at birth but virilize to varying degrees at puberty. Historically most 5αR2D individuals have been "raised as females", but later reports show that over half of patients who underwent virilizing puberty adopted a male gender identity thus challenging historical practices.The goal of sex assignment/of rearing is to facilitate the greatest likelihood of a concordant gender identity in the patients adulthood. The factors that contribute to gender identity are complex and not easy to report but some factors that contribute include sex chromosomes, androgen exposure, psychosocial development, cultural expectations, family dynamics and social situation.Female sex of rearing in 5αR2D individuals involves surgical procedures such as childhood gonadectomy (to prevent virilization at puberty) and vaginoplasty. Life-long hormonal treatments as also required for the development and maintenance of female secondary sex characteristics. Male sex of rearing avoids lifelong hormonal treatments and allow for the potential of fertility. Cryptorchidism and hypospadias must be addressed to prevent damage to the seminiferous tubules that are essential for spermatogenesis and fertility. Diagnosis in infancy is essential before any gender assignment or surgical intervention since patients should be considered males at birth.The intersection of the childs well-being, parental wishes, recommendations of the associated medical team and local laws makes decision making challenging in these cases. The necessity and ethics around consent and deception involved in administering such interventions has been seriously questioned. Fertility Spontaneous fertility in 5αR2D affected males is usually not possible (though has been observed) due to semen abnormalities that include reduced sperm counts, high semen viscosity and, in some cases, lack of primary spermatocytes. This supports the notion that DHT has an important role in spermatocyte differentiation. The broad spectrum of presentation is consistent with highly varying sperm counts among affected males. Testicular function may also be impaired by incomplete descent as well as the genetic mutation itself.Assisted reproduction methods involving sperm extraction and concentration for intrauterine insemination, intracytoplasmic sperm injection, and in vitro fertilization have all demonstrated successful outcomes. Epidemiology 5αR2D is a rare condition, but has a worldwide distribution. A 2020 study identified 434 cases of 5αR2D across 44 countries including Turkey (23%), China (17%), Italy (9%), and Brazil (7%). The same study also found that genitalia virilization influenced sex assignment while gender change was influenced by cultural aspects across the countries. Molecular diagnosis resulted in favoring male sex assignment in affected newborns.Many SRD5A2 mutations come from areas with high coefficients of inbreeding, including the Dominican Republic (where people with the condition are called güevedoces – "testes at twelve"), and Papua New Guinea (where it is known as kwolu-aatmwol – suggesting a persons transformation "into a male thing"), and Turkey.In the Dominican Republic, güevedoces are regarded as a third gender and experience ambivalent gender socialisation. In adulthood, they most commonly self-identify as men, but are not necessarily completely treated as such by society. In the cases in Papua New Guinea, it has been said that the "girl" is shunned when he begins his natural transformation into a male body and socially assumes a male gender role. History An autosomal recessive disorder of sex development, described as pseudovaginal perineoscrotal hypospadias (PPSH), was discovered in males in 1961. The main feature of this syndrome was female appearing external genitalia with the presence of bilateral testes and male urogenital tracts in which the ejaculatory ducts terminate in a blind-ending vagina. This disorder was consistent with 5αR2D as the underlying cause as observed in animal models. 5αR2D was confirmed as the cause in humans in 1974, when studies of 24 participants in the Dominican Republic and 2 in Dallas Texas, USA. One of the cases in Dallas began to virilze at puberty and underwent surgery to remove testes and "repair" the apparent clitoromegaly. During surgery, a normal male urogenital tract was observed as well as other features consistent with PPSH. DHT was almost undetectable in cultured fibroblasts from foreskin, epididymis and the presumed "labia majora" whereas in normal males DHT is detected, suggesting impaired DHT formation. Similar conclusions were obtained for participants in a family in the Dominican Republic study in whom high serum concentration ratios of T to DHT and low concentrations of urinary 5a-reduced androgens were observed. This disorder is now known to be due to homozygous or compound heterozygous loss-of-function mutations of the SRD5A2 gene. Society and culture Sport In April 2014, the BMJ reported that four elite women athletes with 5-ARD were subjected to sterilization and "partial clitoridectomies" in order to compete in sport. The authors noted that "partial clitoridectomy" was "not medically indicated, does not relate to real or perceived athletic advantage," relating to elevated androgen levels. The athletes were all from developing countries where lifetime access to hormone replacement may prove elusive. Intersex advocates regard this intervention as "a clearly coercive process". Popular culture In the Nip/Tuck season three episode "Quentin Costa", it is revealed that Quentin Costa had 5-ARD.Jeffrey Eugenides Pulitzer Prize-winning 2002 novel Middlesex is about a young man with 5-ARD. The character was originally born Calliope and raised as a girl, but upon realizing his genetic sex, he transitions into Cal. Notable people Caster Semenya See also Intersex Disorders of sexual development, pseudohermaphroditism, and ambiguous genitalia Inborn errors of steroid metabolism 5α-Reductase (I, II) Androgen (testosterone and dihydrotestosterone) Ambiguous genitalia Intersex surgery Androgen insensitivity syndrome Congenital adrenal hyperplasia References External links OMIM article 5-Alpha-Reductase Deficiency at eMedicine
Björnstad syndrome	Björnstad syndrome is an autosomal recessive congenital condition involving pili torti, sensorineural deafness, and hair abnormalities. It was first characterized in 1965, in Oslo, by prof. Roar Theodor Bjørnstad after he observed an association between pili torti and hearing loss. The condition is extremely rare, with less than 50 cases documented in medical literature worldwide.Björnstad syndrome is caused by mutations of the BCS1L gene. The protein product of this gene is BCS1L, which plays an important role in oxidative phosphorylation. Mutated BCS1L increases production of reactive oxygen species, which may be the molecular cause of pili torti and hearing loss, both of which are associated with Björnstad syndrome. Pili torti is recognized in early childhood and is characterized by twisted hair shafts and brittle hair. The hearing loss usually becomes evident very early in life as well, often in the first year. Signs and symptoms The two major symptoms of Björnstad syndrome are pili torti and sensorineural hearing impairment. These two symptoms typically appear before the age of 2 and are present in 80-99% of individuals with Björnstad syndrome. Approximately 5-29% of individuals also experience intellectual disabilities and hypogonadism. Cases showing lack of hair pigmentation and anhidrosis have also been documented.Pili torti is a hair abnormality characterized by twisted hair shafts. In Björnstad syndrome patients, the hair usually appears dry, fragile, coarse, and is easily broken. In some patients, hair abnormalities only affect hair on the head, although cases affecting eyebrows, eyelashes, and hair on other parts of the body have been documented. Weakening of the hair associated with pili torti also causes alopecia in approximately 80% of patients.The severity of hearing loss associated with Björnstad syndrome varies. Some individuals are unable to hear sounds at certain frequencies, while others are completely deaf. Their hearing loss is caused by tissue damage of the inner ear. Genetics Björnstad syndrome is caused by a mutation in the BCS1L gene (position 2pq35) and is inherited in an autosomal recessive pattern. BCS1L is a protein that adds Rieske Fe/S to complex III during oxidative phosphorylation of cellular respiration. Mutations of BCS1L gene prevents the protein product from aiding in complex III formation, which reduces oxidative phosphorylation and increases the production of reactive oxygen species.Two missense mutations linked to Björnstad syndrome have been documented, but several other variants are suspected to be pathogenic. The clinical severity of different BCS1L mutations may be caused by the varying production of reactive oxygen species. The symptoms of Björnstad syndrome may be attributed to a particular sensitivity of inner ear and hair tissues to reactive oxygen species, but more research is needed. Mutations of the BCS1L gene may also result in GRACILE syndrome, which is an inherited lethal metabolic disease. Diagnosis Roar Theodor Björnstad first noticed a correlation between pilli torti and hearing loss in 1965, and subsequently diagnosed eight patients with Björnstad syndrome. Out of these eight patients with pili torti, five experienced sensorineural deafness. Björnstad presented his diagnosis and observations at a medical conference in Copenhagen.Björnstad syndrome is diagnosed by observation of twisted hair, known as pili torti, which can be observed as early as birth. To confirm presence of pili torti, the hair shafts of an individual are examined under an electron microscope. Any infants with confirmed pili torti should undergo a series of auditory tests to evaluate potential sensorineural deafness. Finally, a diagnosis of Björnstad syndrome can be confirmed by genetic testing for mutations in the BCS1L gene. Epidemiology Björnstad syndrome is extremely rare, with less than 50 documented cases worldwide. In 2013, five individuals from a consanguineous Pakistani family were diagnosed with Björnstad syndrome. They each experienced a varying degree of progressive hearing loss as well as hair loss on the scalp. The males with Björnstad syndrome also experienced shorter stature.Given its autosomal recessive inheritance pattern, Björnstad syndrome should theoretically affect males and females in equal numbers. However, more females than males have been diagnosed with Björnstad syndrome in medical literature. See also GRACILE syndrome Mitochondrial complex III deficiency References == External links ==
Herpetic gingivostomatitis	Gingivostomatitis is a combination of gingivitis and stomatitis, or an inflammation of the oral mucosa and gingiva. Herpetic gingivostomatitis is often the initial presentation during the first ("primary") herpes simplex infection. It is of greater severity than herpes labialis (cold sores) which is often the subsequent presentations. Primary herpetic gingivostomatitis is the most common viral infection of the mouth.Primary herpetic gingivostomatitis (PHGS) represents the clinically apparent pattern of primary herpes simplex virus (HSV) infection, since the vast majority of other primary infections are symptomless. PHGS is caused predominantly by HSV-1 and affects mainly children. Prodromal symptoms, such as fever, anorexia, irritability, malaise and headache, may occur in advance of disease. The disease presents as numerous pin-head vesicles, which rupture rapidly to form painful irregular ulcerations covered by yellow–grey membranes. Sub-mandibular lymphadenitis, halitosis and refusal to drink are usual concomitant findings. Signs and symptoms The symptoms can be mild or severe and may include: Not able to chew or swallow Sores on the inside of the cheeks or gums Fever General discomfort, uneasiness, or ill feeling Very sore mouth with no desire to eat Halitosis (bad breath) Causes Herpetic gingivostomatitis is an infection caused by the herpes simplex virus (HSV). The HSV is a double-stranded DNA virus categorised into two types; HSV-1 and HSV-2. HSV-1 is predominantly responsible for oral, facial and ocular infections whereas HSV-2 is responsible for most genital and cutaneous lower herpetic lesions. Both HSV-1, and HSV-2 can be the cause of herpetic gingivostomatitis, although HSV-1 is the source of infection in around 90% of cases.Herpetic gingivostomatitis infections can present as acute or recurrent. Acute infection refers to the first invasion of the virus, and recurrent is when reactivation of the latent virus occurs. Acute herpetic gingivostomatitis primarily occurs in children, particularly of those under the age of six years old.On external surfaces the virus is short lived, however it is extremely contagious. Most people acquire the virus via direct contact, it can enter the body by disrupting the integrity of skin, mucous membranes or enter via infected secretions such as saliva. The virus replicates once it has penetrated the epithelial cell, then it travels to the corresponding nerve ganglion (i.e. trigeminal ganglion) via sensory nerves endings. At the nerve ganglion the virus enters a latent phase and remains dormant until it is reactivated. Reactivation can be spontaneous or stimulated by a number of factors such as: reinfection by direct effect of stimuli, immunosuppression, ultraviolet light, febrile illnesses and stress. Risk factors Age: Primary herpetic gingivostomatitis is common in children from 6 months to 5 years old. This virus is also common in young adults aged around 20–25.Immune system: The prevalence and severity of the disease is dependent on the hosts immune response and the virulence of the virus. Environment: As this virus is very contagious it has the potential to spread quickly in enclosed environments e.g. nurseries and orphanages.Epidemiology: Those living in developing countries are at a higher risk of HSV-1 infection. It has been reported that around a 1/3rd of children living in developing countries are HSV-1 positive by 5 years old and 70-80% of the population are infected by the age of adolescence. In developed countries only 20% of children are infected at the age of 5 and there is no significant increase in disease prevalence until 20–40 years old where the percentage of infected individuals ranges from 40-60% Socio-economic status: Those with a lower income have a higher risk of HSV-1 infection at a younger age.Race: Studies have demonstrated that in the USA 35% of African Americans by the age of 5 have presented with the disease whereas only 18% of White Americans are affected. Pathophysiology Herpetic gingivostomatitis originates from a primary infection of HSV-1. The series of events that take place during this infection include replication of the herpes simplex virus, cell lysis and finally, destruction of the mucosal tissue.HSV-1 can very easily enter and replicate within epidermal and dermal cells through skin or mucosal surfaces which have abrasions. This results in numerous small vesicles or blisters of up to 1-2mm on the oral mucosa, erosions on the lips, eventual hemorrhagic crusting and even ulceration, covered by a yellowish-grey pseudomembrane, surrounded by an erythematous halo.As the virus continues to replicate and incolulate in great amounts, it can enter autonomic or sensory ganglia, where it travels within axons to reach ganglionic nerve bodies. HSV-1 most commonly infects the trigeminal ganglia, where it remains latent. If reactivated, it presents as herpes labialis, also known as cold sores. Diagnosis Histopathology The histological appearance of a herpetic infection on the mucosa includes degeneration of stratified squamous epithelial cells, the loss of intercellular connections and inflammatory infiltrate around the capillaries of the dermis layer. An intact herpetic vesicle presents as an intraepithelial blister histologically. This vesicle is caused by rupture and distension of the virally epithelial cells by intracellular oedema and coalescence of disrupted cells.Rupturing of the infected cells cause a great number of viral particles to be released, rendering them the ability to affect adjacent epithelial cells and even the sensory axons of the trigeminal nerve. Histologically, these infected cells have an eosinophilic cytoplasm and large, pale vesicular nuclei, appearing swollen under the microscope. The cytoplasms of the infected cells fuse, collectively forming giant cells with many nuclei. The balloon cells and multi-nucleated giant cells can often be identified in smears taken from an intact vesicle or from one which has been recently ruptured.The lamina propria shows a variable inflammatory infiltrate, the density of which depends on the stage and severity of the disease, and inflammatory cells also extend into the epithelium.Cowdry type A bodies are intranuclear inclusion bodies visible under light microscopy. They show electron dense glycoproteins and viral capsids. Both Cowdry type A bodies can both be found in varicella zoster and herpetic gingivostomatitis, making it impossible to distinguish between both eosinophilic bodies. One way to distinguish between the herpes virus (and hence herpetic gingivostomatitis) and varicella virus is by direct immunohistochemistry using fluorescent antibodies. Differential diagnosis Diagnosis of HG is very much clinically based. Therefore, it is imperative to rule out other diseases that present similarly, bearing in mind the past medical history of the patient. Some differential diagnoses to bear in mind when considering herpetic gingivostomatitis are: Teething in infants: A study mentioned that "primary tooth eruption begins at about the time that infants are losing maternal antibody protection against the herpes virus. Also, reports on teething difficulties have recorded symptoms which are remarkably consistent with primary oral herpetic infection such as fever, irritability, sleeplessness, and difficulty with eating." Another study highlighted that "younger infants with higher residual levels of antibodies would experience milder infections and these would be more likely to go unrecognized or be dismissed as teething difficulty." Herpangina: It is a disease that is caused by the Coxackie A virus rather than a herpes virus. In herpangina, ulcers are usually isolated to the soft palate and anterior pillar of the mouth. In herpetic gingivostomatitis, lesions can be found in these locations, but they are almost always accompanied by ulcerations on the gums, lips, tongue or buccal mucosa and/or by hyperemia, hypertrophy or hemorrhage of the gums. Hand Foot and Mouth Disease: Similar to herpangina, hand foot and mouth disease occurs predominantly in children. It is caused by Coxsackie A and B virus, and lesions or blisters are found bilaterally on the hands, feet and mouth of the patient. Oral candidiasis: Also known as thrush, herpetic gingivostomatitis can often be differentiated from these microorganism/bacterial causing white plaques on the palate, buccal mucosa, tongue, oropharynx etc. Apthous stomatitis: They are commonly known as apthous ulcers, and are characterized by grey membranes and peripheral erythema. Lesions/ulcers for herpetic gingivostomatitis may also be found on the palate and keratinzied gingivae hence aphthous ulcers can be ruled out. Stevens–Johnson syndrome: Stevens–Johnson syndrome is characterized by early symptoms of malaise and fever, and shortly after that erythema, purpura and plaques on the skin, which often progresses to epidermal necrosis and sloughing in extreme cases. Infectious mononucleosis - Infectious Mononucleosis presents with a high fever and lymphadenopathy, which is may or may not be presented in the symptoms of herpetic gingivostomatitis. However, upon closer oral examination, ulceration, petechiae and occasional gingivostomatitis may be spotted. Behcets syndrome - It is an inflammatory disorder in which the presenting symptoms are recurrent aphthous ulcers, and severe cases may result in the patient having genital lesions, gastro-intestinal problems, and even arthritis. Varicella - Small ulcers on the back of the oral cavity and vesicular lesions on the scalp and trunk are common for Varicella. It is ruled out as the location of the infections are unilateral, unlike herpetic gingivostomatitis which is bilateral. Treatment The aim of treatment is mostly supportive such as pain control, duration of symptoms, viral shedding and in some cases, preventing outbreak. Antibiotics are rarely prescribed to treat bacterial superinfection of oral lesions. Antiviral drugs are used to treat herpetic gingivostomatitis such as aciclovir, valaciclovir, famciclovir, and in resistance cases foscarnet can be used. Treatment does not prevent recurrence. Most individuals who are immunocompetent will fully recover from recurrent herpes labialis in 7 to 14 days. However treatment with antipyretics, oral anaesthetics and analgesics is often needed. In severe cases of herpetic gingivostomatitis, mouth rinses are useful in relieving oral discomfort. These contain topical anaesthetic agents such as lidocaine and diphenhydramine as well as coating agents such as magnesium-containing antacids. In order to prevent dehydration, oral fluid intake is encouraged. Other treatment options include good oral hygiene and gentle debridement of the mouth. A number of precautions can be taken to reduce the risk of infection of HSV including; Avoid saliva exchange with those with active HSV Avoid direct contact with active lesions (if contact occurred, ensure area is washed adequately) Those with recurrent HSV can apply sunscreen lip balm as ultraviolet light is a stimulus for the infection Epidemiology See also Acute necrotizing ulcerative gingivitis References External links Underlying Causes at wrongdiagnosis.com CDC Case Definition: Mercury (Elemental)
Segmental odontomaxillary dysplasia	Segmental odontomaxillary dysplasia is a painless, unilateral enlargement of the upper jaw. The cause is unknown, and the disease affects the jaws, teeth, and adjacent soft tissue. The premolars may be congenitally missing, and the primary teeth (baby teeth) may be smaller than usual. It is a relatively recent discovery. Description It is a rare developmental disorder that affects maxilla, also known as the upper jaw in most vertebrates. The disorder is often diagnosed in early childhood. Since its original description as hemimaxillofacial dysplasia by doctors in 1987, less than 40 cases have been reported in the English literature. Epidiomology All cases reported appear to represent sporadic occurrence. There is no specific inheritance pattern. The male-to-female ratio of affected is 1.8:1 and is often diagnosed before the age of 9. The disorder affects the right and left sides of the maxilla almost equally. References Kahn, Michael A. Basic Oral and Maxillofacial Pathology. Volume 1. 2001.
Tuberculoma	A tuberculoma is a clinical manifestation of tuberculosis which conglomerates tubercles into a firm lump, and so can mimic cancer tumors of many types in medical imaging studies. Since these are evolutions of primary complex, the tuberculomas may contain within caseum or calcifications. With the passage of time Mycobacterium tuberculosis can transform into crystals of calcium. These can affect any organ such as the brain, intestine, ovaries, breast, lungs, esophagus, liver, pancreas, bones, and many others. As the histologic and clinical indications, as well as tumor markers such as the CA-125, are similar, it is often difficult to differentiate tuberculoma from cancer. For these reasons, tuberculosis should always be considered in the differential diagnosis of cancer.Tuberculoma is commonly treated through the HRZE drug combination (Isoniazid, Rifampin, Pyrazinamide, Ethambutol) followed by maintenance therapy. == References ==
Hypoplasminogenemia	Hypoplasminogenemia, also known as plasminogen deficiency type 1, is a genetic disorder characterized by a lack of the protein plasminogen, which is responsible for the ability of the body to break down fibrin clots. Plasminogen deficiency leads to an accumulation of fibrin, causing the development of growths (lesions) that can impair normal tissue and organ function and may lead to blindness when these lesions affect the eyes.It is caused by mutations in the PLG gene. Treatment Plasminogen, human-tvmh (Ryplazim) was approved for medical use in the United States in June 2021. It is the first therapy for hypoplasminogenemia approved by the U.S. Food and Drug Administration (FDA). References External links Congenital plasminogen deficiency MeSH, National Library of Medicine
Progressive bulbar palsy	Progressive bulbar palsy (PBP) is a medical condition. It belongs to a group of disorders known as motor neuron diseases. PBP is a disease that attacks the nerves supplying the bulbar muscles. These disorders are characterized by the degeneration of motor neurons in the cerebral cortex, spinal cord, brain stem, and pyramidal tracts. This specifically involves the glossopharyngeal nerve (IX), vagus nerve (X), and hypoglossal nerve (XII).This disorder should not be confused with pseudobulbar palsy or progressive spinal muscular atrophy. The term infantile progressive bulbar palsy is used to describe progressive bulbar palsy in children. The ICD-11 lists progressive bulbar palsy as a variant of amyotrophic lateral sclerosis (ALS). Signs and symptoms Prognosis for PBP patients is poor. Progressive bulbar palsy symptoms can include progressive difficulty with talking and swallowing. Patients can also exhibit reduced gag reflexes, weak palatal movements, fasciculations, and weak movement of the facial muscles and tongue. In advanced cases of PBP, patients may be unable to protrude their tongue or manipulate food in their mouth.Patients with early cases of PBP have difficulty with pronunciations, particularly lateral consonants (linguals) and velars, and may show problems with drooling saliva. If the corticobulbar tract is affected a pseudobulbar affect with emotional changes may occur. Because PBP patients have such difficulty swallowing, food and saliva can be inhaled into the lungs. This can cause gagging and choking, and it increases the risk of pneumonia. Death, which is often from pneumonia, usually occurs 1 to 3 years after the start of the disorder.About twenty-five percent of patients with PBP eventually develop the widespread symptoms common to ALS. Cause The cause of PBP is unknown. One form of PBP is found to occur within patients that have a CuZn-superoxide dismutase (SOD1) mutation. Progressive bulbar palsy patients that have this mutation are classified with FALS patients, Familial ALS (FALS) accounts for about 5%-10% of all ALS cases and is caused by genetic factors. Within these, about 20–25% are linked to the SOD1 mutation. It is not currently known if and how the decreased SOD1 activity contributes to Progressive Bulbar Palsy or FALS, and studies are being done in patients and transgenic mice to help further understand the impact of this gene on the disease.A case study was done on a 42-year-old woman who complained of muscle weakness 10 months prior to admission in the hospital. Upon neurological examination, the patient showed muscle atrophy, fasciculation in all limbs and decreased deep tendon reflexes. The patient’s older brother, father, and paternal uncle had previously all died of ALS or an ALS type syndrome. The patient developed progressive bulbar palsy, became dependent on a respirator, and had two episodes of cardiac arrest. The patient died from pneumonia two years after the onset of the disease. After studying the patient, it was found that the patient had a two base pair deletion in the 126th codon in exon 5 of the SOD1 gene. This mutation produced a frameshift mutation, which led to a stop codon at position 131. SOD1 activity was decreased by about 30%. The patient’s histological examination showed severe reduction in lower motor neurons. Upon further study, this case proved to be important because it demonstrated that SOD1 mutations might not effect steady neuropathological changes, and that environmental and genetic factors might affect the phenotype of the SOD1 mutations. Treatment PBP is aggressive and relentless, and there were no treatments for the disease as of 2005. However, early detection of PBP is the optimal scenario in which doctors can map out a plan for management of the disease. This typically involves symptomatic treatments that are frequently used in many lower motor disorders. History The disease was first recognized by the French neurologist Guillaume Duchenne in 1860 and termed, “labioglossolaryngeal paralysis”. In 1859, Wachsmuth changed the name to progressive bulbar palsy. In 1869, Charcot studied the involvement of the corticospinal tracts and with Joffroy, who noted the loss of the bulbar motor nuclei, discovered the similarities to amyotrophic lateral sclerosis (ALS). It was observed that a distinction from ALS was fatigue that predominated in muscles innervated by lower cranial nerve nuclei, rather than the upper motor neurons. See also Amyotrophic lateral sclerosis Motor neuron disease References Bibliography Lapiedra RC, Moreno Lopez LA, and Esparza Gomez GC. Progressive bulbar palsy: a case report diagnosed by lingual symptoms. J Oral Pathol Med. 31: 277-279. (2002) Hughes TAT and Wiles CM. Neurogenic dysphagia: the role of the neurologist. J Neurol Neurosurg Psychiatry. 64:569-572. (1998) Motor Neuron Disorders: Peripheral Nervous System Disorders. Merck Manual Professional section 16, chapter 223f. Merck Online Medical Library www.merck.com. (2005) Collins, Joseph. Progressive Bulbar Palsy. ‘’The Treatment of Diseases of the Nervous System: A Manual for Practitioners’’. W. Wood and Company. (1900) Swash M, and Desai J. Motor Neuron Disease: Classification and nomenclature. ALS and Other Motor Neuron Disorders. 1:105-112. (2000) Kadekawa J et al. A clinicopathological study of a patient with familial amyotrophic lateral sclerosis associated with a two base pair deletion in the copper/zinc superoxide dismutase (SOD1) gene. Act Neuropathol. 94:617-622. (1997) Campbell, William W. The Cranial Nerves. DeJong’s The Neurologic Examination. Lippincott Williams and Wilkins. (2005) JW Fawcett, AE Rosser & SB Dunnett. Motor Neuron Disease (or ‘amyotrophic lateral sclerosis’, ALS). ‘’Brain Damage, Brain Repair.’’ Oxford University Press. (2000) External links 06-095b. at Merck Manual of Diagnosis and Therapy Home Edition
Effects of cannabis	The effects of cannabis are caused by chemical compounds in the cannabis plant, including 113 different cannabinoids such as tetrahydrocannabinol (THC) and 120 terpenes, which allow its drug to have various psychological and physiological effects on the human body. Different plants of the genus Cannabis contain different and often unpredictable concentrations of THC and other cannabinoids and hundreds of other molecules that have a pharmacological effect, so that the final net effect cannot reliably be foreseen. Acute effects while under the influence can sometimes include euphoria. Although some assert that cannabidiol (CBD), another cannabinoid found in cannabis in varying amounts, may alleviate the adverse effects of THC that some users experience, little is known about CBD effects on humans. Cannabinoid receptor antagonists have previously been tested as antidotes for cannabis intoxication with success, reducing or eliminating the physiological and psychological effects of intoxication. Some of these products are currently in development as cannabis antidotes. In the United States, medical cannabis research is limited by federal restrictions. Smoking any substance could possibly carry similar risks as smoking tobacco due to carcinogens in all smoke, and the ultimate conclusions on these factors are disputed.Cannabis use disorder is defined as a medical diagnosis in the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Chemistry Cannabinoids and cannabinoid receptors The most prevalent psychoactive substances in cannabis are cannabinoids, particularly THC. Some varieties, having undergone careful selection and growing techniques, can yield as much as 34% THC. Another psychoactive cannabinoid present in Cannabis sativa is tetrahydrocannabivarin (THCV), but it is only found in small amounts and is a cannabinoid antagonist.There are similar compounds in cannabis that do not exhibit psychoactive response but are obligatory for functionality: cannabidiol (CBD), an isomer of THC; cannabivarin (CBV), an analog of cannabinol (CBN) with a different side chain, cannabidivarin (CBDV), an analog of CBD with a different side chain, and cannabinolic acid. CBD is believed to regulate the metabolism of THC by inactivating cytochrome P450 enzymes that metabolize drugs; one such mechanism is via generation of carbon monoxide (a pharmacologically active neurotransmitter) by upon metabolism of CBD. THC is converted rapidly to 11-hydroxy-THC, which is also pharmacologically active, so the euphoria outlasts measurable THC levels in blood. Biochemical mechanisms in the brain Cannabinoids usually contain a 1,1-di-methyl-pyran ring, a variedly derivatized aromatic ring and a variedly unsaturated cyclohexyl ring and their immediate chemical precursors, constituting a family of about 60 bi-cyclic and tri-cyclic compounds. Like most other neurological processes, the effects of cannabis on the brain follow the standard protocol of signal transduction, the electrochemical system of sending signals through neurons for a biological response. It is now understood that cannabinoid receptors appear in similar forms in most vertebrates and invertebrates and have a long evolutionary history of 500 million years. The binding of cannabinoids to cannabinoid receptors decrease adenylyl cyclase activity, inhibit calcium N channels, and disinhibit K+A channels. There are at least two types of cannabinoid receptors (CB1 and CB2). Sustainability in the body Most cannabinoids are lipophilic (fat soluble) compounds that are easily stored in fat, thus yielding a long elimination half-life relative to other recreational drugs. The THC molecule, and related compounds, are usually detectable in drug tests from 3 days up to 10 days according to Redwood Laboratories. Long-term users can produce positive tests for two to three months after ceasing cannabis use (see drug test). Toxicities When cannabis is smoked, blood levels of THC peak rapidly after a few minutes and then decline, although the psychotropic effects persist for longer. Edible forms of cannabis often contain several hundred milligrams of THC, much more than the 32mg of a typical cannabis cigarette. The rise of edible cannabis products has been responsible for a large increase of poisoning of children and young people: in American states which have legalized cannabis, emergency room admissions of such cases have typically doubled. Symptoms in children can include lethargy, sedation and seizure.Cannabis is suspected of being a potential contributory factor or direct cause of sudden death, due to the strain it can place on the cardiovascular system, or because of cannabinoid hyperemesis syndrome. Related to cannabinoids THC, the principal psychoactive constituent of the cannabis plant, has an extremely low toxicity and the amount that can enter the body through the consumption of cannabis plants poses no threat of death. In dogs, the minimum lethal dose of THC is over 3000 mg/kg. Edible forms of cannabis often contain several hundred milligrams of THC per dose, much more than the 32mg of a typical cannabis cigarette According to the Merck Index, the LD50 of THC (the dose which causes the death of 50% of individuals) is 1270 mg/kg for male rats and 730 mg/kg for female rats from oral consumption in sesame oil, and 42 mg/kg for rats from inhalation.It is important though to note that cannabinoids and other molecules present in cannabis can alter the metabolism of other drugs, especially due to competition for clearing metabolic pathways such as cytochromes CYP450, thus leading to drug toxicities by medications that the person consuming cannabis may be taking. Related to smoking A 2007 study found that while tobacco and cannabis smoke are quite similar, cannabis smoke contained higher amounts of ammonia, hydrogen cyanide, and nitrogen oxides, but lower levels of carcinogenic polycyclic aromatic hydrocarbons (PAHs). This study found that directly inhaled cannabis smoke contained as much as 20 times as much ammonia and 5 times as much hydrogen cyanide as tobacco smoke and compared the properties of both mainstream and sidestream (smoke emitted from a smouldering joint or cone) smoke. Mainstream cannabis smoke was found to contain higher concentrations of selected polycyclic aromatic hydrocarbons (PAHs) than sidestream tobacco smoke. However, other studies have found much lower disparities in ammonia and hydrogen cyanide between cannabis and tobacco, and that some other constituents (such as polonium-210, lead, arsenic, nicotine, and tobacco-specific nitrosamines) are either lower or non-existent in cannabis smoke. A 2021 longitudinal study conducted among populations of HIV-positive and HIV-negative adults found that smoke-related carcinogenic toxicants and biomarkers detected in tobacco smokers were also detected in exclusive marijuana smokers, including carbon monoxide (CO), polycyclic aromatic hydrocarbons (PAHs), aldehydes (such as acrolein), acrylonitrile and acrylamide metabolites, but exposures are lower compared with tobacco or dual smokers. Increased levels of acrolein exposure by tobacco smoking but not exclusive marijuana smoking were detected both in HIV-positive and HIV-negative adults, and contribute to increased diagnoses of cardiovascular diseases and respiratory diseases among tobacco smokers.Cannabis smoke contains thousands of organic and inorganic chemical compounds. This tar is chemically similar to that found in tobacco smoke or cigars. Over fifty known carcinogens have been identified in cannabis smoke. These include nitrosamines, reactive aldehydes, and polycylic hydrocarbons, including benz[a]pyrene. Marijuana smoke was listed as a cancer agent in California in 2009. A study by the British Lung Foundation published in 2012 identifies cannabis smoke as a carcinogen and also finds awareness of the danger is low compared with the high awareness of the dangers of smoking tobacco particularly among younger users. Other observations include possible increased risk from each cigarette; lack of research on the effect of cannabis smoke alone; low rate of addiction compared to tobacco; and episodic nature of cannabis use compared to steady frequent smoking of tobacco. Professor David Nutt, a UK drug expert, points out that the study cited by the British Lung Foundation has been accused of both "false reasoning" and "incorrect methodology". Further, he notes that other studies have failed to connect cannabis with lung cancer, and accuses the BLF of "scaremongering over cannabis". Short-term effects When smoked, the short-term effects of cannabis manifest within seconds and are fully apparent within a few minutes, typically lasting for 1–3 hours, varying by the person and the strain of cannabis. After oral ingestion of cannabis, the onset of effect is delayed relative to smoking, taking 30 minutes to 2 hours, but the duration is prolonged due to continued slow absorption. The duration of noticeable effects has been observed to diminish after prolonged, repeated use and the development of increased tolerance to cannabinoids. Psychological effects The psychoactive effects of cannabis, known as a "high", are subjective and vary among persons and the method of use. When THC enters the blood stream and reaches the brain, it binds to cannabinoid receptors. The endogenous ligand of these receptors is anandamide, the effects of which THC emulates. This agonism of the cannabinoid receptors results in changes in the levels of various neurotransmitters, especially dopamine and norepinephrine; neurotransmitters which are closely associated with the acute effects of cannabis ingestion, such as euphoria and anxiety. Some effects may include a general alteration of conscious perception, euphoria, feelings of well-being, relaxation or stress reduction, increased appreciation of the arts, including humor and music (especially discerning its various components/instruments), joviality, metacognition and introspection, enhanced recollection (episodic memory), increased sensuality, increased awareness of sensation, increased libido, and creativity. Abstract or philosophical thinking, disruption of linear memory and paranoia or anxiety are also typical. Anxiety is the most commonly reported negative side effect of smoking marijuana. Between 20 and 30 percent of recreational users experience intense anxiety and/or panic attacks after smoking cannabis; however, some report anxiety only after not smoking cannabis for a prolonged period of time. Inexperience and use in an unfamiliar environment are major contributing factors to this anxiety. Cannabidiol (CBD), another cannabinoid found in cannabis in varying amounts, has been shown to ameliorate the adverse effects of THC, including anxiety, that some consumers experience.Cannabis produces many other subjective effects, including an increased enjoyment of food taste and aroma, and marked distortions in the perception of time (where experiencing a "rush" of ideas can create the subjective impression of much time passing). At higher doses, effects can include altered body image, auditory and/or visual illusions, pseudohallucinations, and ataxia from selective impairment of polysynaptic reflexes. In some cases, cannabis can lead to acute psychosis and dissociative states such as depersonalization and derealization.Furthermore, even in those with no family history of psychosis, the administration of pure THC in clinical settings has been demonstrated to elicit transient psychotic symptoms. Any episode of acute psychosis that accompanies cannabis use usually abates after six hours, but in rare instances, heavy users may find the symptoms continuing for many days. If the episode is accompanied by aggression or sedation, physical restraint may be necessary.While psychoactive drugs are typically categorized as stimulants, depressants, or hallucinogens, cannabis exhibits a mix of all of these effects, perhaps leaning more towards hallucinogenic or psychedelic properties, though with other effects quite pronounced. THC is considered the primary active component of the cannabis plant. Scientific studies have suggested that other cannabinoids like CBD may also play a significant role in its psychoactive effects. Somatic effects Some of the short-term physical effects of cannabis use include increased heart rate, dry mouth, reddening of the eyes (congestion of the conjunctival blood vessels), a reduction in intra-ocular pressure, muscle relaxation and a sensation of cold or hot hands and feet and / or flushed face.Electroencephalography or EEG shows somewhat more persistent alpha waves of slightly lower frequency than usual. Cannabinoids produce a "marked depression of motor activity" via activation of neuronal cannabinoid receptors belonging to the CB1 subtype. Duration Peak levels of cannabis-associated intoxication occur approximately 20 minutes after smoking it and last for several hours. Smoked The total short-term duration of cannabis use when smoked depends on the potency, method of smoking – e.g. whether pure or in conjunction with tobacco – and how much is smoked. Peak levels of intoxication typically last an average of three to four hours. Oral When taken orally (in the form of capsules, food, or drink), the psychoactive effects take longer to manifest and generally last longer, typically lasting for an average of four to six hours after consumption. Oral ingestion use eliminates the need to inhale toxic combustion products created by smoking and therefore negates the risk of respiratory harm associated with cannabis smoking. Effects on driving While several studies have shown increased risk associated with cannabis use by drivers, other studies have not found increased risk. Cannabis usage has been shown in some studies to have a negative effect on driving ability. The British Medical Journal indicated that "drivers who consume cannabis within three hours of driving are nearly twice as likely to cause a vehicle collision as those who are not under the influence of drugs or alcohol".In Cannabis and driving: a review of the literature and commentary, the United Kingdoms Department for Transport reviewed data on cannabis and driving, finding although impaired, "subjects under cannabis treatment appear to perceive that they are indeed impaired. Where they can compensate, they do". In a review of driving simulator studies, researchers note that "even in those who learn to compensate for a drugs impairing effects, substantial impairment in performance can still be observed under conditions of general task performance (i.e. when no contingencies are present to maintain compensated performance)."A 2012 meta-analysis found that acute cannabis use increased the risk of an automobile crash. An extensive 2013 review of 66 studies regarding crash risk and drug use found that cannabis was associated with minor, but not statistically significant increased odds of injury or fatal accident.In the largest and most precisely controlled study of its kind carried out by the U.S. Department of Transportations National Highway Traffic Safety Administration, it was found that other "studies that measure the presence of THC in the drivers blood or oral fluid, rather than relying on self-report tend to have much lower (or no) elevated crash risk estimates. Likewise better controlled studies have found lower (or no) elevated crash risk estimates". The study found that "after adjusting for age, gender, race and alcohol use, drivers who tested positive for marijuana were no more likely to crash than those who had not used any drugs or alcohol prior to driving".A 2018 study indicated that the number of fatal crashes involving marijuana after the recreational marijuana legalization or decriminalization increased in Colorado, Washington, and Massachusetts. Cardiovascular effects Short-term (one to two hours) effects on the cardiovascular system can include increased heart rate, dilation of blood vessels, and fluctuations in blood pressure. There are medical reports of occasional heart attacks or myocardial infarction, stroke and other cardiovascular side effects. Marijuanas cardiovascular effects are not associated with serious health problems for most young, healthy users. Researchers reported in the International Journal of Cardiology, "Marijuana use by older people, particularly those with some degree of coronary artery or cerebrovascular disease, poses greater risks due to the resulting increase in catecholamines, cardiac workload, and carboxyhemoglobin levels, and concurrent episodes of profound postural hypotension. Indeed, marijuana may be a much more common cause of myocardial infarction than is generally recognized. In day-to-day practice, a history of marijuana use is often not sought by many practitioners, and even when sought, the patients response is not always truthful".A 2013 analysis of 3,886 myocardial infarction survivors over an 18-year period showed "no statistically significant association between marijuana use and mortality".A 2008 study by the National Institutes of Health Biomedical Research Centre in Baltimore found that heavy, chronic smoking of marijuana (138 joints per week) changed blood proteins associated with heart disease and stroke.A 2000 study by researchers at Bostons Beth Israel Deaconess Medical Center, Massachusetts General Hospital and Harvard School of Public Health found that a middle age persons risk of heart attack rises nearly fivefold in the first hour after smoking marijuana, "roughly the same risk seen within an hour of sexual activity".Cannabis arteritis is a very rare peripheral vascular disease similar to Buergers disease. There were about 50 confirmed cases from 1960 to 2008, all of which occurred in Europe. Combination with other drugs A confounding factor in cannabis research is the prevalent usage of other recreational drugs, especially alcohol and nicotine. Such complications demonstrate the need for studies on cannabis that have stronger controls, and investigations into alleged symptoms of cannabis use that may also be caused by tobacco. Some critics question whether agencies doing the research make an honest effort to present an accurate, unbiased summary of the evidence, or whether they "cherry-pick" their data to please funding sources which may include the tobacco industry or governments dependent on cigarette tax revenue; others caution that the raw data, and not the final conclusions, are what should be examined.The Australian National Household Survey of 2001 showed that cannabis in Australia is rarely used without other drugs. 95% of cannabis users also drank alcohol; 26% took amphetamines; 19% took ecstasy and only 2.7% reported not having used any other drug with cannabis. While research has been undertaken on the combined effects of alcohol and cannabis on performing certain tasks, little research has been conducted on the reasons why this combination is so popular. Evidence from a controlled experimental study undertaken by Lukas and Orozco suggests that alcohol causes THC to be absorbed more rapidly into the blood plasma of the user. Data from the Australian National Survey of Mental Health and Wellbeing found that three-quarters of recent cannabis users reported using alcohol when cannabis was not available, this suggests that the two are substitutes. Memory and learning Studies on cannabis and memory are hindered by small sample sizes, confounding drug use, and other factors. The strongest evidence regarding cannabis and memory focuses on its temporary negative effects on short-term and working memory.In a 2001 study looking at neuropsychological performance in long-term cannabis users, researchers found "some cognitive deficits appear detectable at least 7 days after heavy cannabis use but appear reversible and related to recent cannabis exposure rather than irreversible and related to cumulative lifetime use". On his studies regarding cannabis use, lead researcher and Harvard professor Harrison Pope said he found marijuana is not dangerous over the long term, but there are short-term effects. From neuropsychological tests, Pope found that chronic cannabis users showed difficulties, with verbal memory in particular, for "at least a week or two" after they stopped smoking. Within 28 days, memory problems vanished and the subjects "were no longer distinguishable from the comparison group". Researchers from the University of California, San Diego School of Medicine failed to show substantial, systemic neurological effects from long-term recreational use of cannabis. Their findings were published in the July 2003 issue of the Journal of the International Neuropsychological Society. The research team, headed by Dr Igor Grant, found that cannabis use did affect perception, but did not cause permanent brain damage. Researchers looked at data from 15 previously published controlled studies involving 704 long-term cannabis users and 484 nonusers. The results showed long-term cannabis use was only marginally harmful on the memory and learning. Other functions such as reaction time, attention, language, reasoning ability, perceptual and motor skills were unaffected. The observed effects on memory and learning, they said, showed long-term cannabis use caused "selective memory defects", but that the impact was "of a very small magnitude". A study at Johns Hopkins University School of Medicine showed that very heavy use of marijuana is associated with decrements in neurocognitive performance even after 28 days of abstinence. Appetite The feeling of increased appetite following the use of cannabis has been documented for hundreds of years, and is known colloquially as "the munchies" in the English-speaking world. Clinical studies and survey data have found that cannabis increases food enjoyment and interest in food. A 2015 study suggests that cannabis triggers uncharacteristic behaviour in POMC neurons, which are usually associated with decreasing hunger.Endogenous cannabinoids ("endocannabinoids") were discovered in cows milk and soft cheeses. Endocannabinoids are also found in human breast milk. It is widely accepted that the neonatal survival of many species "is largely dependent upon their suckling behavior, or appetite for breast milk" and recent research has identified the endogenous cannabinoid system to be the first neural system to display complete control over milk ingestion and neonatal survival. It is possible that "cannabinoid receptors in our body interact with the cannabinoids in milk to stimulate a suckling response in newborns so as to prevent growth failure". Pathogens and microtoxins Most microorganisms found in cannabis only affect plants and not humans, but some microorganisms, especially those that proliferate when the herb is not correctly dried and stored, can be harmful to humans. Some users may store marijuana in an airtight bag or jar in a refrigerator to prevent fungal and bacterial growth. Fungi The fungi Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Aspergillus parasiticus, Aspergillus tamarii, Aspergillus sulphureus, Aspergillus repens, Mucor hiemalis (not a human pathogen), Penicillium chrysogenum, Penicillium italicum and Rhizopus nigricans have been found in moldy cannabis. Aspergillus mold species can infect the lungs via smoking or handling of infected cannabis and cause opportunistic and sometimes deadly aspergillosis. Some of the microorganisms found create aflatoxins, which are toxic and carcinogenic. Researchers suggest that moldy cannabis should thus be discarded to avoid these serious risks.Mold is also found in smoke from mold-infected cannabis, and the lungs and nasal passages are a major means of contracting fungal infections. Levitz and Diamond (1991) suggested baking marijuana in home ovens at 150 °C [302 °F], for five minutes before smoking. Oven treatment killed conidia of A. fumigatus, A. flavus and A. niger, and did not degrade the active component of marijuana, tetrahydrocannabinol (THC)." Bacteria Cannabis contaminated with Salmonella muenchen was positively correlated with dozens of cases of salmonellosis in 1981. "Thermophilic actinomycetes" were also found in cannabis. Long-term effects Exposure to marijuana may have biologically based physical, mental, behavioral, and social health consequences and is "associated with diseases of the liver (particularly with co-existing hepatitis C), lungs, heart, eyesight, and vasculature" according to a 2013 literature review by Gordon and colleagues. The association with these diseases has only been reported in cases where people have smoked cannabis. The authors cautioned that "evidence is needed, and further research should be considered, to prove causal associations of marijuana with many physical health conditions".Cannabis use disorder is defined in the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as a condition requiring treatment. Several drugs have been investigated in an attempt to ameliorate the symptoms of stopping cannabis use. Such drugs include bupropion, divalproex, nefazodone, lofexidine, and dronabinol. Of these, dronabinol (a trade name for THC) has proven the most effective. The drugs buspirone and rimonabant have shown some success in helping maintain cannabis abstinence.There is evidence that long-term use of cannabis increases the risk of psychosis, regardless of confounding factors, and particularly for people who have genetic risk factors. A 2019 meta-analysis found that 34% of people with cannabis-induced psychosis transitioned to schizophrenia. This was found to be comparatively higher than hallucinogens (26%) and amphetamines (22%).Long-term cannabis users are at risk for developing cannabinoid hyperemesis syndrome (CHS), characterized by recurrent bouts of intense vomiting. The mechanism behind CHS is poorly understood and is contrary to the antiemetic properties of cannabis and cannabinoids. Of those who went to the emergency department (ED) with recurrent vomiting in one institution in the United States from 2005 to 2010, about 6% had the condition. Effects in pregnancy Cannabis consumption in pregnancy might be associated with restrictions in growth of the fetus, miscarriage, and cognitive deficits in offspring based on animal studies, although there is limited evidence for this in humans at this time. A 2012 systematic review found although it was difficult to draw firm conclusions, there was some evidence that prenatal exposure to cannabis was associated with "deficits in language, attention, areas of cognitive performance, and delinquent behavior in adolescence". A report prepared for the Australian National Council on Drugs concluded cannabis and other cannabinoids are contraindicated in pregnancy as it may interact with the endocannabinoid system. Effects in pediatrics Children can become exposed to cannabis, typically through accidental exposure which can lead to very high doses, especially in the case of edibles. Unlike in adults, these levels of exposure can lead to major complications in children. These complications include encephalopathy, hypotension, respiratory depression severe enough to require ventilation, somnolence, coma, and there have been case reports of death. Pediatric exposure to edibles is of increasing concern because these products are typically sweets (gummies, cookies, etc.), and their prevalence is increasing as cannabis is legalized or decriminalized in many territories. See also Cannabis smoking Psychoactive drug References Further reading National Academies of Sciences, Engineering, and Medicine (2017). The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. National Academies of Sciences, Engineering, and Medicine. Washington, DC: The National Academies Press. doi:10.17226/24625. ISBN 978-0-309-45304-2. PMID 28182367.{{cite book}}: CS1 maint: multiple names: authors list (link)
Trichoadenoma	A trichoadenoma is a cutaneous condition characterized by a solitary, rapidly growing skin lesion ranging from 3 to 15mm in diameter.: 675 See also Dilated pore Pilar sheath acanthoma Skin lesion List of cutaneous conditions References == External links ==
Uremia	Uremia is the term for high levels of urea in the blood. Urea is one of the primary components of urine. It can be defined as an excess of amino acid and protein metabolism end products, such as urea and creatinine, in the blood that would be normally excreted in the urine. Uremic syndrome can be defined as the terminal clinical manifestation of kidney failure (also called renal failure). It is the signs, symptoms and results from laboratory tests which result from inadequate excretory, regulatory, and endocrine function of the kidneys. Both uremia and uremic syndrome have been used interchangeably to denote a very high plasma urea concentration that is the result of renal failure. The former denotation will be used for the rest of the article. Azotemia is a similar, less severe condition with high levels of urea, where the abnormality can be measured chemically but is not yet so severe as to produce symptoms. Uremia describes the pathological and symptomatic manifestations of severe azotemia.There is no specific time for the onset of uremia for people with progressive loss of kidney function. People with kidney function below 50% (i.e. a glomerular filtration rate [GFR] between 50 and 60 mL/min) and over 30 years of age may have uremia to a degree. This means an estimated 8 million people in the United States with a GFR of less than 60 mL/min have uremic symptoms. The symptoms, such as fatigue, can be very vague, making the diagnosis of impaired kidney function difficult. Treatment can be by dialysis or a kidney transplant, though some patients choose to pursue symptom control and conservative care instead. Signs and symptoms Classical signs of uremia are: progressive weakness and easy fatigue, loss of appetite due to nausea and vomiting, muscle atrophy, tremors, abnormal mental function, frequent shallow respiration, and metabolic acidosis. Without intervention via dialysis or kidney transplant, uremia due to renal failure will progress and cause stupor, coma, and death. Because uremia is mostly a consequence of kidney failure, its signs and symptoms often occur concomitantly with other signs and symptoms of kidney failure. Glomerular filtration rate (GFR) measures the amount of plasma in millilitres being filtered through the kidneys each minute. As the GFR decreases, the prognosis worsens. Some of the effects can be reversed, albeit temporarily, with dialysis. Residual syndrome People on dialysis acquire what is known as "residual syndrome". Residual syndrome is a non-life-threatening disease which is displayed as toxic effects causing many of the same signs and symptoms that uremia displays. There are several hypotheses why residual syndrome is present. They are: the accumulation of large molecular weight solutes that are poorly dialyzed (e.g. β2-microglobulin); the accumulation of protein-bound small molecular weight solutes that are poorly dialyzed (e.g. p-cresyl sulfate and indoxyl sulfate); the accumulation of dialyzable solutes that are incompletely removed (e.g. sequestered solutes like phosphate in cells or insufficient elimination of other more toxic solutes); indirect phenomena such as carbamylation of proteins, tissue calcification, or a toxic effect of hormone imbalance (e.g. parathyroid hormone) and; the toxic effects of dialysis itself (e.g. removal of unknown important vitamins or minerals). Dialysis increases life span but patients may have more limited function. They have physical limitations which include impairment of balance, walking speed, and sensory functions. They also have cognitive impairments such as impairment in attention, memory, and performance of higher-order tasks. Patients have been maintained longer than three decades on dialysis, but average mortality rates and hospitalizations are high. Also, patient rehabilitation and quality of life is poor. Causes Conditions causing increased blood urea fall into three different categories: prerenal, renal, and postrenal.Prerenal azotemia can be caused by decreased blood flow through the kidneys (e.g. low blood pressure, congestive heart failure, shock, bleeding, dehydration) or by increased production of urea in the liver via a high protein diet or increased protein catabolism (e.g. stress, fever, major illness, corticosteroid therapy, or gastrointestinal bleeding).Renal causes can be attributed to decreased kidney function. These include acute and chronic kidney failure, acute and chronic glomerulonephritis, tubular necrosis, and other kidney diseases.Postrenal causes can be due to decreased elimination of urea. These could be due to urinary outflow obstruction such as by calculi, tumours of the bladder or prostate, or a severe infection. Diagnosis A detailed and accurate history and physical examination will help determine if uremia is acute or chronic. In the cases of acute uremia, causes may be identified and eliminated, leading to a higher chance for recovery of normal kidney function, if treated correctly. Blood tests Primary tests performed for the diagnosis of uremia are basic metabolic panel with serum calcium and phosphorus to evaluate the GFR, blood urea nitrogen and creatinine as well as serum potassium, phosphate, calcium and sodium levels. Principal abnormality is very low GFR (<30 mL/min). Uremia will demonstrate elevation of both urea and creatinine, likely elevated potassium, high phosphate and normal or slightly high sodium, as well as likely depressed calcium levels. As a basic work up a physician will also evaluate for anemia, and thyroid and parathyroid functions. Chronic anemia may be an ominous sign of established renal failure. The thyroid and parathyroid panels will help work up any symptoms of fatigue, as well as determine calcium abnormalities as they relate to uremia versus longstanding or unrelated illness of calcium metabolism. Urine tests A 24-hour urine collection for determination of creatinine clearance may be an alternative, although not a very accurate test due to the collection procedure. Another laboratory test that should be considered is urinalysis with microscopic examination for the presence of protein, casts, blood and pH. Radioisotope tests The most trusted test for determining GFR is iothalamate clearance. However, it may be cost-prohibitive and time-consuming. Clinical laboratories generally calculate the GFR with the modification of diet in renal disease (MDRD) formula or the Cockcroft-Gault formula. Other In addition, coagulation studies may indicate prolonged bleeding time with otherwise normal values. Mechanism Uremia results in many different compounds being retained by the body. With the failure of the kidneys, these compounds can build up to dangerous levels. There are more than 90 different compounds that have been identified. Some of these compounds can be toxic to the body. Uremic toxins Uremic toxins are any biologically active compounds that are retained due to kidney impairment. Many uremic salts can also be uremic toxins.Urea was one of the first metabolites identified. Its removal is directly related to patient survival but its effect on the body is not yet clear. Still, it is not certain that the symptoms currently associated with uremia are actually caused by excess urea, as one study showed that uremic symptoms were relieved by initiation of dialysis, even when urea was added to the dialysate to maintain the blood urea nitrogen level at approximately 90 mg per deciliter (that is, approximately 32 mmol per liter). Urea could be the precursor of more toxic molecules but it is more likely that damage done to the body is from a combination of different compounds which may act as enzyme inhibitors or derange membrane transport. Indoxyl sulfate is one of the better characterized uremic toxins. Indoxyl sulfate has been shown to aggravate vascular inflammation in atherosclerosis by modulating macrophage behavior. Biochemical characteristics Many regulatory functions of the body are affected. Regulation of body fluids, salt retention, acid and nitrogenous metabolite excretion are all impaired and can fluctuate widely. Body fluid regulation is impaired due to a failure to excrete fluids, or due to fluid loss from vomiting or diarrhea. Regulation of salt is impaired when salt intake is low or the vascular volume is inadequate. Acid excretion and nitrogenous metabolite excretion are impaired with the loss of kidney function. History Urea was crystallized and identified between 1797 and 1808. Urea was hypothesized to be the source of urinary ammonia during this time and was confirmed in 1817. It was hypothesized that excess urea may lead to specific disorders. Later in 1821, it was confirmed that the body did produce urea and that it was excreted by the kidneys. In 1827, urea was first synthesized in the lab, confirming the composition of urea and making it the first biological substance synthesized. In 1856, urea was produced in vitro via oxidation of proteins. It was in 1827 that Henri Dutrochet seeded the idea of dialysis with the discovery of separating smaller molecules from larger molecules through a semipermeable membrane. It was in 1829 and 1831 when convincing proof was obtained that in certain patients, blood urea was elevated. They also suggested that harm may be caused by this. Later research suggested that major neurological disorders like coma and convulsions did not correlate with physical findings which included generalized edema of the brain. This suggested that uremia was a form of blood poisoning. In 1851, E.T. Frerich described clinical uremic syndrome and suggested that a toxicity was the mechanism of its cause. It was in 1856 that J. Picard developed a sensitive method to reproducibly measure blood urea. He was able to detect a 40% decrease of urea concentration between the renal artery and the renal vein. This work solidified the fact that renal failure coincided with an increase in blood urea. It was J. Picard with E.T. Frerichs work that made the term uremia popular. Oral manifestations Oral symptoms of uremia can be found in up to 90% of renal patients. The patients may present with ammonia-like taste and smell in mouth, stomatitis, gingivitis, decreased salivary flow, xerostomia and parotitis.One of the early symptoms of renal failure is uremic fetor. It is an ammonia odour in the mouth caused by the high concentration of urea in the saliva which subsequently breaks down to ammonia. As the blood urea nitrogen (BUN) level increases, patient might develop uremic stomatitis. Uremic stomatitis appears as a pseudo membrane or the frank ulcerations with redness and a pultaceous coat in the mouth. These lesions could be related to high BUN level >150 mg/dl and disappear spontaneously when the BUN level is reduced with medical treatment. It is believed to be caused by loss of tissue resistance and failure to withstand traumatic influences. Besides that, the patient may develop a rare manifestation which is uremic frost. It is a white plaque found on the skin or in the mouth, it is caused by residual urea crystals left on the epithelial surface after perspiration and saliva evaporation or as a result of reduced salivary flow. Xerostomia is a common oral finding, it results from a combination of direct involvement of salivary glands, chemical inflammation, dehydration and mouth breathing. It may be due to restricted fluid intake, adverse effect of drug therapy or low salivary rate. Salivary swelling can be seen sometimes.In patients with renal disease, pallor of the oral mucosa can sometimes be noticed due to anaemia caused by reduction of erythropoietin. Uraemia can lead to alteration of platelet aggregation. This situation, combined with the use of heparin and other anticoagulants in haemodialysis, causes the patients to become predisposed to ecchymosis, petechiae, and haemorrhages in the oral cavity. It can also lead to mucositis and glossitis which can bring about pain and inflammation of the tongue and oral mucosa. In addition, patients might also experience altered taste sensations, dysgeusia, and be predisposed to bacterial and candidiasis infections. Candidiasis is more frequent in renal transplant patients because of generalized immunosuppression.In children with renal disease, enamel hypoplasia of the primary and permanent dentition has been observed. The abnormalities of dental development correlate with the age at which metabolic disturbances occur. For example, enamel hypoplasia in the form of white or brown discoloration of primary teeth is commonly seen in young children with early-onset renal disease. Poor oral hygiene, a carbohydrate-rich diet, disease-related debilitation, hypoplastic enamel, low salivary flow rate and long-term medication contribute to increased risk of caries formation. However, the patients usually have low caries activity, particularly in children. This is due to the presence of highly buffered and alkaline saliva caused by the high concentration of urea nitrogen and phosphate in saliva. The salivary pH will usually be above the critical pH level for demineralization of the enamel to occur and this helps to prevent the formation of caries. Besides that, pulpal narrowing and calcifications is a frequent finding in patients with renal disease. For patients who are on dialysis, the nausea and vomiting resulting from dialysis treatment may lead to severe tooth erosion. Dental considerations When treating patients with renal insufficiency, a dentist should collect a complete medical history, with particular attention to ESRD-related illnesses, drugs with prescribed dosages, blood parameters, timing, and type of dialysis performed. These aspects can be directly discussed with the nephrologist when necessary. Any alterations in drugs or other aspects of treatment must be previously agreed upon by the nephrologist.Dental examination for such patients consists of a non-invasive complete assessment of dental, periodontal, and mucosal tissues, with radiographs to aid with the diagnostic process. All potential foci of infection should be intercepted; these include periodontal and endodontic lesions, residual roots, partially erupted and malpositioned third molars, peri-implantitis, and mucosal lesions. When periodontitis is suspected, a periodontal chart should be recorded. Orthodontic appliances can be maintained if they do not interfere with oral hygiene.Uremia is commonly seen in patients who undergo dialysis due to renal insufficiency. For hemodialysis patients, it is important to determine the treatment schedule. Dental treatment should be started on the day after hemodialysis due to several reasons: there is no accumulation of uremic toxins in the blood, and circulating heparin is absent. Treatment should not commence on the same day as hemodialysis as patients usually feel unwell and their blood is heparinized, which might cause excessive bleeding. For patients undergoing peritoneal dialysis, there are no contraindications to dental treatment except in cases of acute peritoneal infections, where elective procedure should be deferred.Special care should be taken when positioning the patient, avoiding compression of the arm with the vascular access for hemodialysis. Any injections or blood pressure measurement should not be performed on an arm with an arteriovenous (AV) fistula. If the AV site is located on a leg, the patient should avoid sitting for lengthy periods, as venous drainage may be obstructed. During long dental procedures, the dentist should allow patients with AV sites on their legs to take a brief walk or stand for a while every hour.Hemostatic aids should be instituted in cases of excessive bleeding, which is commonly seen in uremia and renal failure. To manage postoperative bleeding, primary closure techniques and local hemostatic agents should be used routinely. To reduce bleeding during and after a procedure, tranexamic acid, both as a rinse or administered orally, can be used.Patients undergoing dialysis are exposed to numerous transfusions and renal failure-related immunosuppression; thus, they are at greater risks of infection by human immunodeficiency virus (HIV) and hepatitis types B and C. It is important to adopt infection control measures to avoid cross-contamination in the dental clinic and prevent risk of exposure to dental personnel.A majority of medications are eliminated from the body at least partially by the kidney. Due to renal failure, the plasma half-lives of drugs normally excreted in urine will be prolonged, leading to increased toxicity. Many drugs which are normally safely administered cannot be given to patients with reduced renal function. Besides, some drugs can be given, but the dosage must be reduced. However, in patients undergoing dialysis, reduced plasma half-lives of drugs will be observed. Antibiotics of the aminoglycoside and tetracycline families need to be avoided due to their nephrotoxicities. The antibiotics of choice are penicillins, clindamycin, and cephalosporins, which can be administered at normal doses even if the therapeutic range will be extended. For analgesics, paracetamol is the option of choice for cases of episodic pain. Aspirin is characterized by an anti-platelet activity and thus its use should be avoided in uremic patients. The challenge in pharmacotherapy for patients with renal disease is to maintain a medications therapeutic level within a narrow range in order to avoid subtherapeutic dosing and toxicity. Notes References External links Uremia, WebMD.com
Hereditary motor and sensory neuropathy	Hereditary motor and sensory neuropathies (HMSN) is a name sometimes given to a group of different neuropathies which are all characterized by their impact upon both afferent and efferent neural communication. HMSN are characterised by atypical neural development and degradation of neural tissue. The two common forms of HMSN are either hypertrophic demyelinated nerves or complete atrophy of neural tissue. Hypertrophic condition causes neural stiffness and a demyelination of nerves in the peripheral nervous system, and atrophy causes the breakdown of axons and neural cell bodies. In these disorders, a patient experiences progressive muscle atrophy and sensory neuropathy of the extremities.The term "hereditary motor and sensory neuropathy" was used mostly historically to denote the more common forms Charcot–Marie–Tooth disease (CMT). With the identification of a wide number of genetically and phenotypically distinct forms of CMT, the term HMSN is now used less frequently. Symptoms and signs Neuropathy disorders usually have onset in childhood or young adulthood. Motor symptoms seem to be more predominant than sensory symptoms. Symptoms of these disorders include: fatigue, pain, lack of balance, lack of feeling, lack of reflexes, and lack of sight and hearing, which result from muscle atrophy. Patients can also have high arched feet, hammer toes, foot drop, foot deformities, and scoliosis. These symptoms are a result of severe muscular weakness and atrophy. In patients with demyelinating neuropathy, symptoms are due to slow nerve conduction velocities; however people with axonal degradation have average-to-normal nerve conduction velocities. Causes All hereditary motor and sensory neuropathies are inherited. Chromosomes 17 and 1 seem to be the most common chromosomes with mutations. The disease can be inherited in an autosomal dominant, autosomal recessive or X-linked manner. Diagnosis Patients with hereditary motor and sensory neuropathies are diagnosed through a physical evaluation that looks for muscle atrophy, weakness, and sensory responses. In addition to this, electromyography and motor nerve conduction tests can help clinicians decide what type of motor and sensory neuropathy it is and how severe the disease is. Final confirmation can come through genetic testing. Classification Charcot–Marie–Tooth disease was first described in 1886 by Jean-Martin Charcot, Pierre Marie, and independently Howard Henry Tooth. In the 1950s, further classification occurred and separated patients into two distinct groups. Group one was characterized by slow nerve conduction velocities and demyelinating neuropathy. Group two was characterized by mostly normal nerve conduction velocities and degeneration of axons. In 1968, HMSN were classified again into seven groups: Treatment There is currently no known pharmacological treatment to hereditary motor and sensory neuropathy. However, the majority of people with these diseases are able to walk and be self-sufficient. Some methods of relief for the disease include physical therapy, stretching, braces, and sometimes orthopedic surgery. Since foot disorders are common with neuropathy, precautions must be taken to strengthen these muscles and use preventative care and physical therapy to prevent injury and deformities. Prognosis Hereditary motor and sensory neuropathy are relatively common and are often inherited with other neuromuscular conditions, and these comorbidities cause an accelerated progression of the disease.Most forms of HMSN affect males earlier and more severely than females, but others show no predilection to either sex. HMSN affects all ethnic groups, with the most common forms having no racial predilection, but other recessively inherited forms tending to impact specific ethnic groups. Onset of HMSN is most common in early childhood, with clinical effects occurring before the age of 10, but some symptoms are lifelong and progress slowly. Therefore, these symptoms do not appear until later in life. See also Hereditary motor and sensory neuropathy with proximal dominance Charcot–Marie–Tooth disease Hereditary motor neuropathies Hereditary sensory and autonomic neuropathies Spinal muscular atrophies References Further reading Reilly MM (October 2000). "Classification of the hereditary motor and sensory neuropathies". Curr. Opin. Neurol. 13 (5): 561–4. doi:10.1097/00019052-200010000-00009. PMID 11073363. S2CID 43241647. == External links ==
Osteoma cutis	Osteoma cutis is a cutaneous condition characterized by the presence of bone within the skin in the absence of a preexisting or associated lesion.: 529 See also Calcinosis cutis Skin lesion List of cutaneous conditions References == External links ==
Otospondylomegaepiphyseal dysplasia	Otospondylomegaepiphyseal dysplasia (OSMED) is an autosomal recessive disorder of bone growth that results in skeletal abnormalities, severe hearing loss, and distinctive facial features. The name of the condition indicates that it affects hearing (oto-) and the bones of the spine (spondylo-), and enlarges the ends of bones (megaepiphyses). The features of OSMED are similar to those of another skeletal disorder, Weissenbacher-Zweymüller syndrome. Otospondylomegaepiphyseal dysplasia is a subtype of collagenopathy, types II and XI. Pathophysiology Mutations in the COL11A2 gene cause otospondylomegaepiphyseal dysplasia. The protein made by the COL11A2 gene is involved in the production of type XI collagen. This type of collagen is important for the normal development of bone and other connective tissues. Mutations in the COL11A2 gene lead to a loss of function of this type of collagen, resulting in the signs and symptoms of OSMED. OSMED is inherited in an autosomal recessive pattern, which means the defective gene is located on an autosome, and two copies of the defective gene - one from each parent - must be inherited for a person to be affected by the disorder. The parents of a child with an autosomal recessive disorder are usually not affected but are carriers of one copy of the altered gene. A recessive pattern of inheritance makes OSMED unique among the type II and type XI collagenopathies. Diagnosis The distinctive characteristics of OSMED include severe bone and joint problems and very severe hearing loss. This disorder affects the epiphyses, the parts of the bone where growth occurs. People with the condition are often shorter than average because the bones in their arms and legs are unusually short. Other skeletal signs include enlarged joints, short hands and fingers, and flat bones of the spine (vertebrae). People with the disorder often experience back and joint pain, limited joint movement, and arthritis that begins early in life. Severe high-tone hearing loss is common. Typical facial features include protruding eyes; a sunken nasal bridge; an upturned nose with a large, rounded tip; and a small lower jaw. Some affected infants are born with an opening in the roof of the mouth, which is called a cleft palate. Treatment Treatment is symptomatic only, involving closure of the cleft palate, audiometry and adapted management of the hearing loss, and treatment of the joint pain. Epidemiology The frequency of this disorder is unknown, but it is very rare. Only a few families with the condition have been reported. References Melkoniemi M, Brunner HG, Manouvrier S, Hennekam R, Superti-Furga A, Kaariainen H, Pauli RM, van Essen T, Warman ML, Bonaventure J, Miny P, Ala-Kokko L (2000). "Autosomal recessive disorder otospondylomegaepiphyseal dysplasia is associated with loss-of-function mutations in the COL11A2 gene". Am J Hum Genet. 66 (2): 368–77. doi:10.1086/302750. PMC 1288089. PMID 10677296. van Steensel MA, Buma P, de Waal Malefijt MC, van den Hoogen FH, Brunner HG (1997). "Oto- spondylo-megaepiphyseal dysplasia (OSMED): clinical description of three patients homozygous for a missense mutation in the COL11A2 gene" (PDF). Am J Med Genet. 70 (3): 315–23. doi:10.1002/(SICI)1096-8628(19970613)70:3<315::AID-AJMG19>3.0.CO;2-O. hdl:2066/24596. PMID 9188673. External links This article incorporates public domain text from The U.S. National Library of Medicine
Brainstem death	Brainstem death is a clinical syndrome defined by the absence of reflexes with pathways through the brainstem – the "stalk" of the brain, which connects the spinal cord to the mid-brain, cerebellum and cerebral hemispheres – in a deeply comatose, ventilator-dependent patient. Identification of this state carries a very grave prognosis for survival; cessation of heartbeat often occurs within a few days, although it may continue for weeks if intensive support is maintained.In the United Kingdom, death can be certified on the basis of a formal diagnosis of brainstem death, so long as this is done in accordance with a procedure established in "A Code of Practice for the Diagnosis and Confirmation of Death", published in 2008 by the Academy of Medical Royal Colleges. The premise of this is that a person is dead when consciousness and the ability to breathe are permanently lost, regardless of continuing life in the body and parts of the brain, and that death of the brainstem alone is sufficient to produce this state.This concept of brainstem death is also accepted as grounds for pronouncing death for legal purposes in India and Trinidad & Tobago. Elsewhere in the world, the concept upon which the certification of death on neurological grounds is based is that of permanent cessation of all function in all parts of the brain – whole brain death – with which the British concept should not be confused. The United States Presidents Council on Bioethics made it clear, for example, in its White Paper of December 2008, that the British concept and clinical criteria are not considered sufficient for the diagnosis of death in the United States. Evolution of diagnostic criteria The United Kingdom (UK) criteria were first published by the Conference of Medical Royal Colleges (with advice from the Transplant Advisory Panel) in 1976, as prognostic guidelines. They were drafted in response to a perceived need for guidance in the management of deeply comatose patients with severe brain damage who were being kept alive by mechanical ventilators but showing no signs of recovery. The Conference sought "to establish diagnostic criteria of such rigour that on their fulfilment the mechanical ventilator can be switched off, in the secure knowledge that there is no possible chance of recovery". The published criteria – negative responses to bedside tests of some reflexes with pathways through the brainstem and a specified challenge to the brainstem respiratory centre, with caveats about exclusion of endocrine influences, metabolic factors and drug effects – were held to be "sufficient to distinguish between those patients who retain the functional capacity to have a chance of even partial recovery and those where no such possibility exists". Recognition of that state required the withdrawal of further artificial support so that death is allowed to occur, thus "sparing relatives from the further emotional trauma of sterile hope".In 1979, the Conference of Medical Royal Colleges promulgated its conclusion that identification of the state defined by those same criteria – then thought sufficient for a diagnosis of brain death – "means that the patient is dead". Death certification on those criteria has continued in the United Kingdom (where there is no statutory legal definition of death) since that time, particularly for organ transplantation purposes, although the conceptual basis for that use has changed. In 1995, after a review by a Working Group of the Royal College of Physicians of London, the Conference of Medical Royal Colleges formally adopted the "more correct" term for the syndrome, "brainstem death" – championed by Pallis in a set of 1982 articles in the British Medical Journal – and advanced a new definition of human death as the basis for equating this syndrome with the death of the person. The suggested new definition of death was the "irreversible loss of the capacity for consciousness, combined with irreversible loss of the capacity to breathe". It was stated that the irreversible cessation of brainstem function will produce this state and "therefore brainstem death is equivalent to the death of the individual". Diagnosis In the UK, the formal rules for the diagnosis of brainstem death have undergone only minor modifications since they were first published in 1976. The most recent revision of the UKs Department of Health Code of Practice governing use of that procedure for the diagnosis of death reaffirms the preconditions for its consideration. These are: There should be no doubt that the patients condition – deeply comatose, unresponsive and requiring artificial ventilation – is due to irreversible brain damage of known cause. There should be no evidence that this state is due to depressant drugs. Primary hypothermia as the cause of unconsciousness must have been excluded, and Potentially reversible circulatory, metabolic and endocrine disturbances likewise. Potentially reversible causes of apnoea (dependence on the ventilator), such as muscle relaxants and cervical cord injury, must be excluded.With these pre-conditions satisfied, the definitive criteria are: Fixed pupils which do not respond to sharp changes in the intensity of incident light. No corneal reflex. Absent oculovestibular reflexes – no eye movements following the slow injection of at least 50ml of ice-cold water into each ear in turn (the caloric reflex test). No response to supraorbital pressure. No cough reflex to bronchial stimulation or gagging response to pharyngeal stimulation. No observed respiratory effort in response to disconnection of the ventilator for long enough (typically 5 minutes) to ensure elevation of the arterial partial pressure of carbon dioxide to at least 6.0 kPa (6.5 kPa in patients with chronic carbon dioxide retention). Adequate oxygenation is ensured by pre-oxygenation and diffusion oxygenation during the disconnection (so the brainstem respiratory centre is not challenged by the ultimate, anoxic, drive stimulus). This test – the apnoea test – is dangerous, and may prove lethal.Two doctors, of specified status and experience, are required to act together to diagnose death on these criteria and the tests must be repeated after "a short period of time ... to allow return of the patients arterial blood gases and baseline parameters to the pre-test state". These criteria for the diagnosis of death are not applicable to infants below the age of two months. Prognosis and management With due regard for the cause of the coma, and the rapidity of its onset, testing for the purpose of diagnosing death on brainstem death grounds may be delayed beyond the stage where brainstem reflexes may be absent only temporarily – because the cerebral blood flow is inadequate to support synaptic function, although there is still sufficient blood flow to keep brain cells alive and capable of recovery. There has recently been renewed interest in the possibility of neuronal protection during this phase by use of moderate hypothermia and by correction of the neuroendocrine abnormalities commonly seen in this early stage.Published studies of patients meeting the criteria for brainstem death or whole brain death – the American standard which includes brainstem death diagnosed by similar means – record that even if ventilation is continued after diagnosis, the heart stops beating within only a few hours or days. However, there have been some very long-term survivals and it is noteworthy that expert management can maintain the bodily functions of pregnant brain dead women for long enough to bring them to term. Criticism The diagnostic criteria were originally published for the purpose of identifying a clinical state associated with a fatal prognosis (see above). The change of use, in the UK, to criteria for the diagnosis of death itself was protested immediately. The initial basis for the change of use was the claim that satisfaction of the criteria sufficed for the diagnosis of the death of the brain as a whole, despite the persistence of demonstrable activity in parts of the brain. In 1995, that claim was abandoned and the diagnosis of death (acceptable for legal purposes in the UK in the context of organ procurement for transplantation) by the specified testing of brainstem functions was based on a new definition of death – the permanent loss of the capacity for consciousness and spontaneous breathing. There are doubts that this concept is generally understood and accepted and that the specified testing is stringent enough to determine that state. It is, however, associated with substantial risk of exacerbating the brain damage and even causing the death of the apparently dying patient so tested (see "the apnoea test" above). This raises ethical problems which seem not to have been addressed. It has been argued that sound scientific support is lacking for the claim that the specified purely bedside tests have the power to diagnose true and total death of the brainstem, the necessary condition for the assumption of permanent loss of the intrinsically untestable consciousness-arousal function of those elements of the reticular formation which lie within the brainstem (there are elements also within the higher brain). Knowledge of this arousal system is based upon the findings from animal experiments as illuminated by pathological studies in humans. The current neurological consensus is that the arousal of consciousness depends upon reticular components which reside in the midbrain, diencephalon and pons. It is said that the midbrain reticular formation may be viewed as a driving centre for the higher structures, loss of which produces a state in which the cortex appears, on the basis of electroencephalographic (EEG) studies, to be awaiting the command or ability to function. The role of diencephalic (higher brain) involvement is stated to be uncertain and we are reminded that the arousal system is best regarded as a physiological rather than a precise anatomical entity. There should, perhaps, also be a caveat about possible arousal mechanisms involving the first and second cranial nerves (serving sight and smell) which are not tested when diagnosing brainstem death but which were described in cats in 1935 and 1938. In humans, light flashes have been observed to disturb the sleep-like EEG activity persisting after the loss of all brainstem reflexes and of spontaneous respiration.There is also concern about the permanence of consciousness loss, based on studies in cats, dogs and monkeys which recovered consciousness days or weeks after being rendered comatose by brainstem ablation and on human studies of brainstem stroke syndrome raising thoughts about the "plasticity" of the nervous system. Other theories of consciousness place more stress on the thalamocortical system. Perhaps the most objective statement to be made is that consciousness is not currently understood. That being so, proper caution must be exercised in accepting a diagnosis of its permanent loss before all cerebral blood flow has permanently ceased. The ability to breathe spontaneously depends upon functioning elements in the medulla – the respiratory centre. In the UK, establishing a neurological diagnosis of death involves challenging this centre with the strong stimulus offered by an unusually high concentration of carbon dioxide in the arterial blood, but it is not challenged by the more powerful drive stimulus provided by anoxia – although the effect of that ultimate stimulus is sometimes seen after final disconnection of the ventilator in the form of agonal gasps. No testing of testable brain stem functions such as oesophageal and cardiovascular regulation is specified in the UK Code of Practice for the diagnosis of death on neurological grounds. There is published evidence strongly suggestive of the persistence of brainstem blood pressure control in organ donors. A small minority of medical practitioners working in the UK have argued that neither requirement of the UK Health Departments Code of Practice basis for the equation of brainstem death with death is satisfied by its current diagnostic protocol and that in terms of its ability to diagnose de facto brainstem death it falls far short. Most of these criticisms overlook the fact that in practice brainstem death testing would not be conducted in isolation. In most cases this is only performed after running a series of CT and MRI scans to look at brain and brainstem health. References External links Great Ormond Street Hospital for Children
Hermaphrodite	In reproductive biology, a hermaphrodite () is an organism that has both kinds of reproductive organs and can produce both gametes associated with male and female sexes.Many taxonomic groups of animals (mostly invertebrates) do not have separate sexes. In these groups, hermaphroditism is a normal condition, enabling a form of sexual reproduction in which either partner can act as the female or male. For example, the great majority of tunicates, pulmonate molluscs, opisthobranch, earthworms, and slugs are hermaphrodites. Hermaphroditism is also found in some fish species and to a lesser degree in other vertebrates. Most plants are also hermaphrodites. Animal species having different sexes, male and female, are called gonochoric, which is the opposite of hermaphrodite.There are also species where hermaphrodites exist alongside males (called androdioecy) or alongside females (called gynodioecy), or all three exist in the same species (called trioecy); these three systems are sometimes called mixed breeding systems. In plants there are cases where male flowers and hermaphrodite flowers occur on the same plant (andromonoecy) or female flowers and hermaphrodite flowers on the same plant (gynomonoecy).The term hermaphrodite is commonly used for abnormal cases of dioecious animal species but according to geneticist Michael Majerus this definition should be distinguished from the scientific definition.In recent years the term hermaphrodite applied to humans has fallen out of favor since there have been no identified cases of a human reproducing as both male and female, with some biologists saying hermaphroditism does not occur in humans. Intersex activists have preferred the word intersex, since the word hermaphrodite is considered to be stigmatizing, as well as "scientifically specious and clinically problematic."There are no hermaphroditic species among mammals or birds. According to David B. Rivers there is controversy around hermaphroditism in insects with some experts believing it does not occur. Hermaphroditism is said to occur in one or two insect species.A rough estimate of the number of hermaphroditic animal species is 65,000. The percentage of animal species that are hermaphroditic is about 5% in all animal species, or 33% excluding insects. (Although the current estimated total number of animal species is about 7.7 million, the study, which estimated the number, 65,000, used an estimated total number of animal species, 1,211,577 from "Classification phylogénétique du vivant (Vol. 2)" - Lecointre and Le Guyader (2001)). Most hermaphroditic species exhibit some degree of self-fertilization. The distribution of self-fertilization rates among animals is similar to that of plants, suggesting that similar pressures are operating to direct the evolution of selfing in animals and plants. Etymology The term derives from the Latin: hermaphroditus, from Ancient Greek: ἑρμαφρόδιτος, romanized: hermaphroditos, which derives from Hermaphroditus (Ἑρμαφρόδιτος), the son of Hermes and Aphrodite in Greek mythology. According to Ovid, he fused with the nymph Salmacis resulting in one individual possessing physical traits of male and female sexes; according to the earlier Diodorus Siculus, he was born with a physical body combining male and female sexes. The word hermaphrodite entered the English lexicon as early as the late fourteenth century. Alexander ab Alexandro stated, using the term hermaphrodite, that the people who bore the sexes of both man and woman were regarded by the Athenians and the Romans as monsters, and thrown into the sea at Athens and into the Tiber at Rome. Animals Sequential hermaphrodites Sequential hermaphrodites (dichogamy) occur in species in which the individual is born as one sex, but can later change into the opposite sex. This contrasts simultaneous hermaphrodites, in which an individual may possess fully functional male and female genitalia. Sequential hermaphroditism is common in fish (particularly teleost fish) and many gastropods (such as the common slipper shell), and some flowering plants. Sequential hermaphrodites can only change sex once. Sequential hermaphroditism can best be understood in terms of behavioral ecology and evolutionary life history theory, as described in the size-advantage mode first proposed by Michael T. Ghiselin which states that if an individual of a certain sex could significantly increase its reproductive success after reaching a certain size, it would be to their advantage to switch to that sex. Sequential hermaphrodites can be divided into three broad categories: Protandry: Where an organism is born as a male, and then changes sex to a female.Example: The clownfish (genus Amphiprion) are colorful reef fish found living in symbiosis with sea anemones. Generally one anemone contains a harem, consisting of a large female, a smaller reproductive male, and even smaller non-reproductive males. If the female is removed, the reproductive male will change sex and the largest of the non-reproductive males will mature and become reproductive. It has been shown that fishing pressure can change when the switch from male to female occurs, since fishermen usually prefer to catch the larger fish. The populations are generally changing sex at a smaller size, due to natural selection. Protogyny: Where the organism is born as a female, and then changes sex to a male.Example: Wrasses (Family Labridae) are a group of reef fish in which protogyny is common. Wrasses also have an uncommon life history strategy, which is termed diandry (literally, two males). In these species, two male morphs exists: an initial phase male and a terminal phase male. Initial phase males do not look like males and spawn in groups with females. They are not territorial. They are, perhaps, female mimics (which is why they are found swimming in group with females). Terminal phase males are territorial and have a distinctively bright coloration. Individuals are born as males or females, but if they are born males, they are not born as terminal phase males. Females and initial phase males can become terminal phase males. Usually, the most dominant female or initial phase male replaces any terminal phase male when those males die or abandon the group. Bidirectional sex changers: Where an organism has female and male reproductive organs, but act as either female or male during different stages in life.Example: Lythrypnus dalli (Family Lythrypnus) are a group of coral reef fish in which bidirectional sex change occurs. Once a social hierarchy is established a fish changes sex according to its social status, regardless of the initial sex, based on a simple principle: if the fish expresses subordinate behavior then it changes its sex to female, and if the fish expresses dominant or not subordinate behavior then the fish changes its sex to male.Dichogamy can have both conservation-related implications for humans, as mentioned above, as well as economic implications. For instance, groupers are favoured fish for eating in many Asian countries and are often aquacultured. Since the adults take several years to change from female to male, the broodstock are extremely valuable individuals. Simultaneous hermaphrodites A simultaneous (or synchronous) hermaphrodite (or homogamous) is an adult organism that has both male and female sexual organs at the same time. Simultaneous hermaphrodites can be regarded as both sexes present in the same individual. Self-fertilization often occurs. Reproductive system of gastropods: Pulmonate land snails and land slugs are perhaps the best-known kind of simultaneous hermaphrodite, and are the most widespread of terrestrial animals possessing this sexual polymorphism. Sexual material is exchanged between both animals via spermatophore, which can then be stored in the spermatheca. After exchange of spermatozoa, both animals will lay fertilized eggs after a period of gestation; then the eggs will proceed to hatch after a development period. Snails typically reproduce from early spring through late autumn. Banana slugs are another example of a hermaphroditic gastropod. Mating with a partner is more desirable biologically, as the genetic material of the resultant offspring is varied, but if mating with a partner is not possible, self-fertilization is practiced. The male sexual organ of an adult banana slug is quite large in proportion to its size, as well as compared to the female organ. It is possible for banana slugs, while mating, to become stuck together. If a substantial amount of wiggling fails to separate them, the male organ will be bitten off (using the slugs radula), see apophallation. If a banana slug has lost its male sexual organ, it can still mate as a female, making its hermaphroditic quality a valuable adaptation. The species of colourful sea slugs Goniobranchus reticulatus is hermaphroditic, with both male and female organs active at the same time during copulation. After mating, the external portion of the penis detaches, but is able to regrow within 24 hours. Hamlets, unlike other fish, seem quite at ease mating in front of divers, allowing observations in the wild to occur readily. They do not practice self-fertilization, but when they find a mate, the pair takes turns between which one acts as the male and which acts as the female through multiple matings, usually over the course of several nights. Earthworms are another example of a simultaneous hermaphrodite. Although they possess ovaries and testes, they have a protective mechanism against self-fertilization. Sexual reproduction occurs when two worms meet and exchange gametes, copulating on damp nights during warm seasons. Fertilized eggs are protected by a cocoon, which is buried on or near the surface of the ground. The free-living hermaphroditic nematode Caenorhabditis elegans reproduces primarily by self-fertilization, but infrequent out-crossing events occur at a rate of approximately 1%. The mangrove killifish (Kryptolebias marmoratus) is a species of fish that lives along the east coast of North, Central and South America. These fish are simultaneous hermaphrodites. K. marmoratus produces eggs and sperm by meiosis and routinely reproduces by self-fertilization. Each individual hermaphrodite normally fertilizes itself when an egg and sperm produced by an internal organ unite inside the fishs body. This species is also regarded as the only known vertebrate species that can reproduce by self fertilization. Pseudohermaphroditism When spotted hyenas were first scientifically observed by explorers, they were thought to be hermaphrodites. Early observations of spotted hyenas in the wild led researchers to believe that all spotted hyenas, male and female, were born with what appeared to be a penis. The apparent penis in female spotted hyenas is in fact an enlarged clitoris, which contains an external birth canal. It can be difficult to determine the sex of wild spotted hyenas until sexual maturity, when they may become pregnant. When a female spotted hyena gives birth, they pass the cub through the cervix internally, but then pass it out through the elongated clitoris. Plants Hermaphrodite is used in botany to describe, for example, a flower that has both staminate (male, pollen-producing) and carpellate (female, ovule-producing) parts. Monoecy Flowering plant species with separate male and female flowers on the same individual are called monoecious. Monoecious plants are often referred to as hermaphroditic because they produce both male and female gametes. However, the individual flowers are not hermaphroditic because they are only one sex. Monoecy only occurs in about 7% of angiosperm species. Conifers are almost all monoecious, but 65% of gymnosperm species are dioecious. Some plants can change their sex throughout their lifetime. This process is called Sequential hermaphroditism. Andromonecy In andromonecious species, the plants produce perfect (hermaphrodite) flowers and separate staminate flowers that function as male but are sterile as female. Andromonecy occurs in about 4000 species of flowering plants (2% of flowering plants). Use regarding humans Historically, the term hermaphrodite was used in law to refer to people whose sex was in doubt. The 12th-century Decretum Gratiani states that "Whether an hermaphrodite may witness a testament, depends on which sex prevails" ("Hermafroditus an ad testamentum adhiberi possit, qualitas sexus incalescentis ostendit."). Similarly, the 17th-century English jurist and judge Edward Coke (Lord Coke), wrote in his Institutes of the Lawes of England on laws of succession stating, "Every heire is either a male, a female, or an hermaphrodite, that is both male and female. And an hermaphrodite (which is also called Androgynus) shall be heire, either as male or female, according to that kind of sexe which doth prevaile."During the Victorian era, medical authors attempted to ascertain whether or not humans could be hermaphrodites, adopting a precise biological definition to the term. From that period until the early 21st century, intersex individuals were termed true hermaphrodites if their gonadal tissue contained both testicular and ovarian tissue, or pseudohermaphrodites if their external appearance (phenotype) differed from sex expected from internal gonads. This language has fallen out of favor due to misconceptions and pejorative connotations associated with the terms, and also a shift to nomenclature based on genetics. The term intersex describes a wide variety of combinations of what are considered male and female biological characteristics. Intersex biology may include, for example, ambiguous-looking external genitalia, karyotypes that include mixed XX and XY chromosome pairs (46XX/46XY, 46XX/47XXY or 45X/XY mosaic). Clinically, medicine currently describes intersex people as having disorders of sex development, a term vigorously contested. This is particularly because of a relationship between medical terminology and medical intervention.Intersex civil society organizations, and many human rights institutions, have criticized medical interventions designed to make intersex bodies more typically male or female. In some cases, intersex traits are caused by unusual levels of sex hormones, which may be the result of an atypical set of sex chromosomes. One possible pathophysiological explanation of intersex in humans is a parthenogenetic division of a haploid ovum into two haploid ova. Upon fertilization of the two ova by two sperm cells (one carrying an X chromosome and the other carrying a Y chromosome), the two fertilized ova are then fused together resulting in a person having dual genitalial, gonadal (ovotestes) and genetic sex. Another common cause of being intersex is the crossing over of the testis-determining factor (SRY) from the Y chromosome to the X chromosome during meiosis. The SRY is then activated in only certain areas, causing development of testes in some areas by beginning a series of events starting with the upregulation of the transcription factor (SOX9), and in other areas not being active (causing the growth of ovarian tissues). Thus, testicular and ovarian tissues will both be present in the same individual.Fetuses before sexual differentiation are sometimes described as female by doctors explaining the process. This is not technically true. Before this stage, humans are simply undifferentiated and possess a paramesonephric duct, a mesonephric duct, and a genital tubercle. Evolution The evolution of anisogamy may have contributed to the evolution of simultaneous hermaphroditism and sequential hermaphroditism but, as of 2016 it remains unclear if the evolution of anisogamy first led to hermaphroditism or gonochorism.: 213 It is possible that hermaphroditism evolved from gonochorism, or vice versa. Most studies on its evolution focus on plants, and its evolution in animals is unclear as of December 2017.Simultaneous hermaphroditism that exclusively reproduces through self-fertilization has evolved many times in plants and animals, but it might not last long evolutionarily.: 14 In animals Joan Roughgarden and Priya Iyer argued that the last common ancestor for animals was hermaphroditic and that transitions from hermaphroditism to gonochorism were more numerous than the reverse. However, their argument was based on paraphyletic Spiralia, assignments of sexual modes for the phylum level than the species level, and methods exclusively based on maximum parsimony.Hermaphroditism is polyphyletic in invertebrates where it evolved from gonochorism: 97 and gonochorism is also ancestral to hermaphroditic fishes. According to Nelson Çabej simultaneous hermaphroditism in animals most likely evolved due to a limited number of mating partners. In plants It is widely accepted that the first vascular plants were outcrossing hermaphrodites. In flowering plants, hermaphroditism is ancestral to dioecy. Flowers in angiosperms evolved to attract insects as vectors for pollination.Hermaphroditism in plants may promote self fertilization in pioneer populations. However, plants have evolved multiple different mechanisms to avoid self-fertilization in hermaphrodites, including sequential hermaphroditism, molecular recognition systems and mechanical or morphological mechanisms such as heterostyly.: 73, 74 See also Asexual reproduction Trioecy Androgyny Gonochorism Gynandromorph Self-pollination Self-fertilization Futanari Non-binary gender References Further reading External links Britannica Online Encyclopedia: hermaphroditism (biology) Current Biology – Gender trading in a hermaphrodite The Evolution of Self-Fertile Hermaphroditism: The Fog Is Clearing "Born True Hermaphrodite – Pictorial Profile", about Lynn Edward Harris
Oslers node	Oslers nodes are painful, red, raised lesions found on the hands and feet. They are associated with a number of conditions, including infective endocarditis, and are caused by immune complex deposition. Their presence is one definition of Oslers sign. Causes Oslers nodes result from the deposition of immune complexes. The resulting inflammatory response leads to swelling, redness, and pain that characterize these lesions. The nodes are commonly indicative of subacute bacterial endocarditis. 10–25% of endocarditis patients will have Oslers nodes. Other signs of endocarditis include Roths spots and Janeway lesions. The latter, which also occur on the palms and soles, can be differentiated from Oslers nodes because they are non-tender.Oslers nodes can also be seen in Systemic lupus erythematosus Marantic endocarditis Disseminated gonococcal infection Distal to infected arterial catheter Etymology Oslers nodes are named after Sir William Osler who described them in the early twentieth century. He described them as "ephemeral spots of a painful nodular erythema, chiefly in the skin of the hands and feet." == References ==
Mitral stenosis	Mitral stenosis is a valvular heart disease characterized by the narrowing of the opening of the mitral valve of the heart. It is almost always caused by rheumatic valvular heart disease. Normally, the mitral valve is about 5 cm2 during diastole. Any decrease in area below 2 cm2 causes mitral stenosis. Early diagnosis of mitral stenosis in pregnancy is very important as the heart cannot tolerate increased cardiac output demand as in the case of exercise and pregnancy. Atrial fibrillation is a common complication of resulting left atrial enlargement, which can lead to systemic thromboembolic complications like stroke. Signs and symptoms Signs and symptoms of mitral stenosis include the following: Heart failure symptoms, such as dyspnea on exertion, orthopnea and paroxysmal nocturnal dyspnea (PND) Palpitations Chest pain Hemoptysis Thromboembolism in later stages when the left atrial volume is increased (i.e., dilation). The latter leads to increase risk of atrial fibrillation, which increases the risk of blood stasis (motionless). This increases the risk of coagulation. Ascites and edema and hepatomegaly (if right-side heart failure develops)Fatigue and weakness increase with exercise and pregnancy. Natural history The natural history of mitral stenosis secondary to rheumatic fever (the most common cause) is an asymptomatic latent phase following the initial episode of rheumatic fever. This latent period lasts an average of 16.3 ± 5.2 years. Once symptoms of mitral stenosis begin to develop, progression to severe disability takes 9.2 ± 4.3 years.In individuals having been offered mitral valve surgery but refused, survival with medical therapy alone was 44 ± 6% at 5 years, and 32 ± 8% at 10 years after they were offered correction. Cause Almost all cases of mitral stenosis are due to disease in the heart secondary to rheumatic fever and the consequent rheumatic heart disease. Uncommon causes of mitral stenosis are calcification of the mitral valve leaflets, and as a form of congenital heart disease. However, there are primary causes of mitral stenosis that emanate from a cleft mitral valve. It is the most common valvular heart disease in pregnancy.Other causes include infective endocarditis where the vegetations may favor increase risk of stenosis. Other rare causes include mitral annular calcification, endomyocardial fibroelastosis, malignant carcinoid syndrome, systemic lupus erythematosus, whipple disease, fabry disease, and rheumatoid arthritis. hurler disease, hunters disease, amyloidosis. Pathophysiology The normal area of the mitral valve orifice is about 4 to 6 cm2. In normal cardiac physiology, the mitral valve opens during left ventricular diastole, to allow blood to flow from the left atrium to the left ventricle. A normal mitral valve will not impede the flow of blood from the left atrium to the left ventricle during (ventricular) diastole, and the pressures in the left atrium and the left ventricle during ventricular diastole will be equal. The result is that the left ventricle gets filled with blood during early ventricular diastole, with only a small portion of extra blood contributed by contraction of the left atrium (the "atrial kick") during late ventricular diastole.When the mitral valve area goes below 2 cm2, the valve causes an impediment to the flow of blood into the left ventricle, creating a pressure gradient across the mitral valve. This gradient may be increased by increases in the heart rate or cardiac output. As the gradient across the mitral valve increases, the amount of time necessary to fill the left ventricle with blood increases. Eventually, the left ventricle requires the atrial kick to fill with blood. As the heart rate increases, the amount of time that the ventricle is in diastole and can fill up with blood (called the diastolic filling period) decreases. When the heart rate goes above a certain point, the diastolic filling period is insufficient to fill the ventricle with blood and pressure builds up in the left atrium, leading to pulmonary congestion.When the mitral valve area goes less than 1 cm2, there will be an increase in the left atrial pressures (required to push blood through the stenotic valve). Since the normal left ventricular diastolic pressures is about 5 mmHg, a pressure gradient across the mitral valve of 20 mmHg due to severe mitral stenosis will cause a left atrial pressure of about 25 mmHg. This left atrial pressure is transmitted to the pulmonary vasculature and causes pulmonary hypertension. Pulmonary capillary pressures in this level cause an imbalance between the hydrostatic pressure and the oncotic pressure, leading to extravasation of fluid from the vascular tree and pooling of fluid in the lungs (congestive heart failure causing pulmonary edema).The constant pressure overload of the left atrium will cause the left atrium to increase in size. As the left atrium increases in size, it becomes more prone to develop atrial fibrillation (AF). When atrial fibrillation develops, the atrial kick is lost (since it is due to the normal atrial contraction).In individuals with severe mitral stenosis, the left ventricular filling is dependent on the atrial kick. The loss of the atrial kick due to atrial fibrillation ( i.e. blood cannot flow into the left ventricle thus accumulating in the left atrium ) can cause a precipitous decrease in cardiac output and sudden congestive heart failure.Patients with mitral stenosis prompts a series of hemodynamic changes that frequently cause deterioration of the patients clinical status. A reduction in cardiac output, associated with acceleration of heart rate and shortening of the diastolic time, frequently leads to congestive heart failure. In addition, when AF sets in, systemic embolization becomes a real danger.Mitral stenosis typically progresses slowly (over decades) from the initial signs of mitral stenosis to NYHA functional class II symptoms to the development of atrial fibrillation to the development of NYHA functional class III or IV symptoms. Once an individual develops NYHA class III or IV symptoms, the progression of the disease accelerates and the patients condition deteriorates. Diagnosis Physical examination Upon auscultation of an individual with mitral stenosis, the first heart sound is usually loud and may be palpable (tapping apex beat) because of increased force in closing the mitral valve. The first heart sound is made by the mitral and tricuspid heart valves closing. These are normally synchronous, and the sounds are termed M1 and T1, respectively. M1 becomes louder in mitral stenosis. It may be the most prominent sign.If pulmonary hypertension secondary to mitral stenosis is severe, the P2 (pulmonic) component of the second heart sound (S2) will become loud.An opening snap that is a high-pitch additional sound may be heard after the A2 (aortic) component of the second heart sound (S2), which correlates to the forceful opening of the mitral valve. The mitral valve opens when the pressure in the left atrium is greater than the pressure in the left ventricle. This happens in ventricular diastole (after closure of the aortic valve), when the pressure in the ventricle precipitously drops. In individuals with mitral stenosis, the pressure in the left atrium correlates with the severity of the mitral stenosis. As the severity of the mitral stenosis increases, the pressure in the left atrium increases, and the mitral valve opens earlier in ventricular diastole.A mid-diastolic rumbling murmur with presystolic accentuation will be heard after the opening snap. The murmur is best heard at the apical region and is not radiated. Since it is a low-pitch sound, it is heard best with the bell of the stethoscope. Its duration increases with worsening disease. Rolling the patient toward left as well as isometric exercise will accentuate the murmur. A thrill might be present when palpating at the apical region of the precordium.Advanced disease may present with signs of right-sided heart failure such as parasternal heave, jugular venous distension, hepatomegaly, ascites and/or pulmonary hypertension, the latter often presenting with a loud P2.Almost all signs increase with exercise and pregnancy.Other peripheral signs include: Malar flush - due to back pressure and buildup of carbon dioxide (CO2). CO2 is a natural vasodilator. Atrial fibrillation - irregular pulse and loss of a wave in jugular venous pressure Left parasternal heave - presence of right ventricular hypertrophy due to pulmonary hypertension Tapping apex beat that is not displacedMedical signs of atrial fibrillation include:Heart rate is about 100-150/min. Irregularly irregular pulse with a pulse deficit>10. Varying first heart sound intensity. Opening snap is not heard sometimes. Absent a waves in the neck veins. Presystolic accentuation of diastolic murmur disappears. Embolic manifestations may appear. Associated lesions With severe pulmonary hypertension, a pansystolic murmur produced by functional tricuspid regurgitation may be audible along the left sternal border. This murmur is usually louder during inspiration and diminishes during forced expiration (Carvallos sign). When the cardiac output is markedly reduced in MS, the typical auscultatory findings, including the diastolic rumbling murmur, may not be detectable (silent MS), but they may reappear as compensation is restored. The Graham Steell murmur of pulmonary regurgitation, a high-pitched, diastolic, decrescendo blowing murmur along the left sternal border, results from dilation of the pulmonary valve ring and occurs in patients with mitral valve disease and severe pulmonary hypertension. This murmur may be indistinguishable from the more common murmur produced by aortic regurgitation (AR), although it may increase in intensity with inspiration and is accompanied by a loud and often palpable P2. Echocardiography In most cases, the diagnosis of mitral stenosis is most easily made by echocardiography, which shows left atrial enlargement, thick and calcified mitral valve with narrow and "fish-mouth"-shaped orifice and signs of right ventricular failure in advanced disease. It can also show decreased opening of the mitral valve leaflets, and increased blood flow velocity during diastole. The trans-mitral gradient as measured by Doppler echocardiography is the gold standard in the evaluation of the severity of mitral stenosis. Cardiac chamber catheterization Another method of measuring the severity of mitral stenosis is the simultaneous left and right heart chamber catheterization. The right heart catheterization (commonly known as Swan-Ganz catheterization) gives the physician the mean pulmonary capillary wedge pressure, which is a reflection of the left atrial pressure. The left heart catheterization, on the other hand, gives the pressure in the left ventricle. By simultaneously taking these pressures, it is possible to determine the gradient between the left atrium and left ventricle during ventricular diastole, which is a marker for the severity of mitral stenosis. This method of evaluating mitral stenosis tends to overestimate the degree of mitral stenosis, however, because of the time lag in the pressure tracings seen on the right-heart catheterization and the slow Y descent seen on the wedge tracings. If a trans-septal puncture is made during right heart catheterization, however, the pressure gradient can accurately quantify the severity of mitral stenosis. Other techniques Chest X-ray may also assist in diagnosis, showing left atrial enlargement.Electrocardiography may show P mitrale, that is, broad, notched P waves in several or many leads with a prominent late negative component to the P wave in lead V1, and may also be seen in mitral regurgitation, and, potentially, any cause of overload of the left atrium. Thus, P-sinistrocardiale may be a more appropriate term. Treatment Treatment is not necessary in asymptomatic patients.The treatment options for mitral stenosis include mitral valve replacement by surgery, and percutaneous mitral valvuloplasty by balloon catheter.The indication for invasive treatment with either a mitral valve replacement or valvuloplasty is NYHA functional class III or IV symptoms.Another option is balloon dilatation. To determine which patients would benefit from percutaneous balloon mitral valvuloplasty, a scoring system has been developed. Scoring is based on 4 echocardiographic criteria: leaflet mobility, leaflet thickening, subvalvular thickening, and calcification. Individuals with a score of ≥ 8 tended to have suboptimal results. Superb results with valvotomy are seen in individuals with a crisp opening snap, score < 8, and no calcium in the commissures.Treatment also focuses on concomitant conditions often seen in mitral stenosis: Any angina is treated with short-acting nitrovasodilators, beta-blockers and/or calcium blockers Any hypertension is treated aggressively, but caution must be taken in administering beta-blockers Any heart failure is treated with digoxin, diuretics, nitrovasodilators and, if not contraindicated, cautious inpatient administration of ACE inhibitors Mitral valvuloplasty Mitral valvuloplasty is a minimally invasive therapeutic procedure to correct an uncomplicated mitral stenosis by dilating the valve using a balloon. Under local anaesthetic, a catheter with a special balloon is passed from the right femoral vein, up the inferior vena cava and into the right atrium. The interatrial septum is punctured and the catheter passed into the left atrium using a "trans-septal technique." The balloon is sub-divided into 3 segments and is dilated in 3 stages. First, the distal portion (lying in the left ventricle) is inflated and pulled against the valve cusps. Second, the proximal portion is dilated, in order to fix the centre segment at the valve orifice. Finally, the central section is inflated, this should take no longer than 30 seconds, since full inflation obstructs the valve and causes congestion, leading to circulatory arrest and flash pulmonary edema.With careful patient pre-selection, percutaneous balloon mitral valvuloplasty (PBMV) is associated with good success rates and a low rate of complications. By far the most serious adverse event is the occurrence of acute severe mitral regurgitation. Severe mitral regurgitation usually results from a tear in one of the valve leaflets or the subvalvular apparatus. It can lead to pulmonary edema and hemodynamic compromise, necessitating urgent surgical mitral valve replacement.Other serious complications with PBMV usually relate to the technique of trans-septal puncture (TSP). The ideal site for TSP is the region of the fossa ovalis in the inter-atrial septum. Occasionally, however, the sharp needle used for TSP may inadvertently traumatize other cardiac structures, leading to cardiac tamponade or serious blood loss.Although the immediate results of PBMV are often quite gratifying, the procedure does not provide permanent relief from mitral stenosis. Regular follow-up is mandatory, to detect restenosis. Long-term follow-up data from patients undergoing PBMV indicates that up to 70–75% individuals can be free of restenosis 10 years following the procedure. The number falls to about 40% 15 years post-PBMV. References == External links ==
Achlorhydria	Achlorhydria and hypochlorhydria refer to states where the production of hydrochloric acid in gastric secretions of the stomach and other digestive organs is absent or low, respectively. It is associated with various other medical problems. Signs and symptoms Irrespective of the cause, achlorhydria can result as known complications of bacterial overgrowth and intestinal metaplasia and symptoms are often consistent with those diseases: gastroesophageal reflux disease abdominal discomfort early satiety weight loss diarrhea constipation abdominal bloating anemia stomach infection malabsorption of food carcinoma of stomachSince acidic pH facilitates the absorption of iron, achlorhydric patients often develop iron deficiency anemia. Acidic environment of stomach helps conversion of pepsinogen into pepsin, which is highly important in digesting the protein into smaller components, such as a complex protein into simple peptides and amino acids inside the stomach, which are later absorbed by the gastrointestinal tract. Bacterial overgrowth and B12 deficiency (pernicious anemia) can cause micronutrient deficiencies that result in various clinical neurological manifestations, including visual changes, paresthesias, ataxia, limb weakness, gait disturbance, memory defects, hallucinations and personality and mood changes. Risk of particular infections, such as Vibrio vulnificus (commonly from seafood) is increased. Even without bacterial overgrowth, low stomach acid (high pH) can lead to nutritional deficiencies through decreased absorption of basic electrolytes (magnesium, zinc, etc.) and vitamins (including vitamin C, vitamin K, and the B complex of vitamins). Such deficiencies may be involved in the development of a wide range of pathologies, from fairly benign neuromuscular issues to life-threatening diseases. Causes The slowing of the bodys basal metabolic rate associated with hypothyroidism Pernicious anemia where there is antibody production against parietal cells which normally produce gastric acid. The use of antacids or drugs that decrease gastric acid production (such as H2-receptor antagonists) or transport (such as proton pump inhibitors). A symptom of rare diseases such as mucolipidosis (type IV). A symptom of Helicobacter pylori infection which neutralizes and decreases secretion of gastric acid to aid its survival in the stomach. A symptom of atrophic gastritis or of stomach cancer. Radiation therapy involving the stomach. Gastric bypass procedures such as a duodenal switch and RNY, where the largest acid producing parts of the stomach are either removed, or blinded. VIPomas (vasoactive intestinal peptides) and somatostatinomas are both islet cell tumors of the pancreas. Pellagra, caused by niacin deficiency. Chloride, sodium, potassium, zinc and/or iodine deficiency, as these elements are needed to produce adequate levels of stomach acid (HCl). Sjögrens syndrome, an autoimmune disorder that destroys many of the bodys moisture-producing enzymes Ménétriers disease, characterized by hyperplasia of mucous cells in the stomach also causing excess protein loss, leading to hypoalbuminemia. Presents with abdominal pain and edema Risk Factors Age It was found that the incidence of achlorhydria in patients under the age of 60 was around 2.3%, whereas it was 5% in patients over the age of 60. In a persons 30s, the prevalence is about 2.5%, and increases to 12% in a persons 80s. An absence of hydrochloric acid increases with advancing age. A lack of hydrochloric acid produced by the stomach is one of the most common age-related causes of a harmed digestive system.Among men and women, 27% experience a varying degree of achlorhydria. US researchers found that over 30% of women and men over the age of 60 have little to no acid secretion in the stomach. Additionally, 40% of postmenopausal women have shown to have no basal gastric acid secretion in the stomach, with 39.8% occurring in females 80 to 89 years old Autoimmune Disorders Autoimmune disorders are also linked to advancing age, specifically autoimmune gastritis, which is when the body produces unwelcomed antibodies and causes inflammation of the stomach. Autoimmune disorders are also a cause for small bacterial growth in the bowel and a deficiency of Vitamin B-12. These have also proved to be factors of acid secretion in the stomach.Hypothyroidism: Thyroid hormones are a factor in the decreasing of hydrochloric acid in the stomach, thus hypothyroidism is associated with a greater risk of developing achlorhydria.Autoimmune conditions are often managed using various treatments; however, these treatments have no known effect on achlorhydria. Other Other risk factors include, over the counter acid-blocking medications and antibiotics that may be used to block stomach acid. These medications are often taken by individuals for a longer than recommended period, even for years, despite causing adverse effects on stomach acid secretion.Stress has also been proven to be linked to symptoms associated with achlorhydria including constant belching, constipation, and abdominal pain. Diagnosis For practical purposes, gastric pH and endoscopy should be done in someone with suspected achlorhydria. Older testing methods using fluid aspiration through a nasogastric tube can be done, but these procedures can cause significant discomfort and are less efficient ways to obtain a diagnosis. A complete 24-hour profile of gastric acid secretion is best obtained during an esophageal pH monitoring study. Achlorhydria may also be documented by measurements of extremely low levels of pepsinogen A (PgA) (< 17 µg/L) in blood serum. The diagnosis may be supported by high serum gastrin levels (> 500–1000 pg/mL).The "Heidelberg test" is an alternative way to measure stomach acid and diagnose hypochlorhydria/achlorhydria. A check can exclude deficiencies in iron, calcium, prothrombin time, vitamin B-12, vitamin D, and thiamine. Complete blood count with indices and peripheral smears can be examined to exclude anemia. Elevation of serum folate is suggestive of small bowel bacterial overgrowth. Bacterial folate can be absorbed into the circulation. Once achlorhydria is confirmed, a hydrogen breath test can check for bacterial overgrowth. Treatment Treatment focuses on addressing the underlying cause of symptoms. Treatment of gastritis that leads to pernicious anemia consists of parenteral vitamin B-12 injection. Associated immune-mediated conditions (e.g., insulin-dependent diabetes mellitus, autoimmune thyroiditis) should also be treated. However, treatment of these disorders has no known effect in the treatment of achlorhydria. Achlorhydria associated with Helicobacter pylori infection may respond to H. pylori eradication therapy, although resumption of gastric acid secretion may only be partial and it may not always reverse the condition completely.Antimicrobial agents, including metronidazole, amoxicillin/clavulanate potassium, ciprofloxacin, and rifaximin, can be used to treat bacterial overgrowth. Achlorhydria resulting from long-term proton-pump inhibitor (PPI) use may be treated by dose reduction or withdrawal of the PPI. Prognosis Little is known on the prognosis of achlorhydria, although there have been reports of an increased risk of gastric cancer.A 2007 review article noted that non-Helicobacter bacterial species can be cultured from achlorhydric (pH > 4.0) stomachs, whereas normal stomach pH only permits the growth of Helicobacter species. Bacterial overgrowth may cause false-positive H. pylori test results due to the change in pH from urease activity.Small bowel bacterial overgrowth is a chronic condition. Retreatment may be necessary once every 1–6 months. Prudent use of antibacterials now calls for an antimicrobial stewardship policy to manage antibiotic resistance. See also Atrophic gastritis Fundic gland polyposis Hyperchlorhydria Isopropamide References == External links ==
Cavernous sinus	The cavernous sinus within the human head is one of the dural venous sinuses creating a cavity called the lateral sellar compartment bordered by the temporal bone of the skull and the sphenoid bone, lateral to the sella turcica. Structure The cavernous sinus is one of the dural venous sinuses of the head. It is a network of veins that sit in a cavity. It sits on both sides of the sphenoidal bone and pituitary gland, approximately 1 × 2 cm in size in an adult. The carotid siphon of the internal carotid artery, and cranial nerves III, IV, V (branches V1 and V2) and VI all pass through this blood filled space. Both sides of cavernous sinus is connected to each other via intercavernous sinuses. The cavernous sinus lies in between the inner and outer layers of dura mater. Nearby structures Above: optic tract, optic chiasma, internal carotid artery. Inferiorly: foramen lacerum, and the junction of the body and greater wing of sphenoid bone. Medially: pituitary gland (hypophysis cerebri), and sphenoidal air sinus. Laterally: temporal lobe with uncus. Anteriorly: superior orbital fissure, and the apex of the orbit. Posteriorly: apex of petrous temporal bone. Venous connections The cavernous sinus receives blood from: Superior and inferior ophthalmic veins Sphenoparietal sinus Superficial middle cerebral veins Inferior cerebral veinsBlood leaves the sinus via superior and inferior petrosal sinuses as well as via the emissary veins through the foramina of the skull (mostly through foramen ovale). There are also connections with the pterygoid plexus of veins via inferior ophthalmic vein, deep facial vein and emissary veins. Contents Apart from the blood which passes through a venous sinus, several anatomical structures, including some cranial nerves and their branches, also pass through the sinus.Structures within the outer (lateral) wall of the compartment from superior to inferior: Oculomotor nerve Trochlear nerve Ophthalmic and maxillary branches of the trigeminal nerveStructures passing through the midline (medial) wall: Abducens nerve Internal carotid artery accompanied by the internal carotid plexusThese nerves, with the exception of CN V2, pass through the cavernous sinus to enter the orbital apex through the superior orbital fissure. The maxillary nerve, division V2 of the trigeminal nerve travels through the lower portion of the sinus and exits via the foramen rotundum. The maxillary branch passes external to, but immediately adjacent to, the lateral wall of the sinus.The optic nerve lies just above and outside the cavernous sinus, superior and lateral to the pituitary gland on each side, and enters the orbital apex via the optic canal. Function Venous drainage As a venous sinus, the cavernous sinus receives blood from the superior and inferior ophthalmic veins and from superficial cortical veins, and is connected to the basilar plexus of veins posteriorly. The cavernous sinus drains by two larger channels, the superior and inferior petrosal sinuses, ultimately into the internal jugular vein via the sigmoid sinus, also draining with emissary vein to pterygoid plexus. Clinical significance It is the only anatomic location in the body in which an artery travels completely through a venous structure. If the internal carotid artery ruptures within the cavernous sinus, an arteriovenous fistula is created (more specifically, a carotid-cavernous fistula). Lesions affecting the cavernous sinus may affect isolated nerves or all the nerves traversing through it. The pituitary gland lies between the two paired cavernous sinuses. An abnormally growing pituitary adenoma, sitting on the bony sella turcica, will expand in the direction of least resistance and eventually invade the cavernous sinus. Cavernous sinus syndrome may result from mass effect of these tumors and cause ophthalmoplegia (from compression of the oculomotor nerve, trochlear nerve, and abducens nerve), ophthalmic sensory loss (from compression of the ophthalmic nerve), and maxillary sensory loss (from compression of the maxillary nerve). A complete lesion of the cavernous sinus disrupts CN III, IV, and VI, causing total ophthalmoplegia, usually accompanied by a fixed, dilated pupil. Involvement of CN V (V1 and variable involvement of V2) causes sensory loss in these divisions of the trigeminal nerve. Horners syndrome can also occur due to involvement of the carotid ocular sympathetics, but may be difficult to appreciate in the setting of a complete third nerve injury.Because of its connections with the facial vein via the superior ophthalmic vein, it is possible to get infections in the cavernous sinus from an external facial injury within the danger area of the face. In patients with thrombophlebitis of the facial vein, pieces of the clot may break off and enter the cavernous sinus, forming a cavernous sinus thrombosis. From there the infection may spread to the dural venous sinuses. Infections may also be introduced by facial lacerations and by bursting pimples in the areas drained by the facial vein.Potential causes of cavernous sinus syndrome include metastatic tumors, direct extension of nasopharyngeal tumours, meningioma, pituitary tumors or pituitary apoplexy, aneurysms of the intracavernous carotid artery, carotid-cavernous fistula, bacterial infection causing cavernous sinus thrombosis, aseptic cavernous sinus thrombosis, idiopathic granulomatous disease (Tolosa–Hunt syndrome), and fungal infections. Cavernous sinus syndrome is a medical emergency, requiring prompt medical attention, diagnosis, and treatment. Additional images See also Cavernous sinus thrombosis Dural venous sinuses References External links MedEd at Loyola grossanatomy/h_n/cn/dvs/dvs3.htm Anatomy figure: 28:03-06 at Human Anatomy Online, SUNY Downstate Medical Center – "Venous dural sinuses." Cavernous+Sinus at the US National Library of Medicine Medical Subject Headings (MeSH) lesson2 at The Anatomy Lesson by Wesley Norman (Georgetown University) Atlas image: n3a8p1 at the University of Michigan Health System
Male accessory gland infection	Male accessory gland infection (MAGI) is a condition with signs of inflammation involving one or more sites in the male genital tract. Diagnosis is made according to parameters defined by the World Health Organization, and it is particularly made in relation to infectious or inflammatory causes of male infertility. Although it is usually caused by infection spreading from the urethra, non-infectious causes also exist. Definition Along with testicles (orchitis), MAGI includes infections (bacterial, viral, fungal etc.) involving one or more of the following male genital organs or tracts: epididymis (epididymitis) vas deferens seminal vesicles (seminal vesiculitis) prostate gland (prostatitis) Cowpers glands urethra (urethritis) Diagnosis As infection has a negative impact on the secretory function of the accessory glands, findings that could indicate the presence of MAGI include: signs of inflammation in a semen analysis (leukocytes ≥ 1x106/mL and/or elastase ≥ 230 ng/mL) low semen volume elevated semen pH low levels of alpha-glucosidase, fructose and zinc WHO criteria MAGI can be diagnosed when there are two or more factors present that meet criteria defined by the World Health Organization (WHO): Biomarkers One study has proposed that elevated levels of soluble urokinase-type plasminogen activator receptor (SuPAR) in seminal plasma might be useful as a marker for MAGI. Causes The main infectious agents are Enterobacteriaceae (such as Escherichia coli and Klebsiella), Neisseria gonorrhoeae, and Chlamydia trachomatis.One study has shown that men with MAGI who have lower serum levels of total testosterone tend to have a more complicated form of MAGI, such as involving more than one site, than those with normal levels. Complications Potential complications include: obstruction of the epididymis impairment of spermatogenesis impairmentment of sperm function induction of sperm auto-antibodies dysfunctions of the male accessory glandsThese complications can result in sexual dysfunction and male subfertility. References == External links ==
Anejaculation	Anejaculation is the pathological inability to ejaculate despite an erection in males, with (orgasmic) or without (anorgasmic) orgasm. Causes It can depend on one or more of several causes, including: Sexual inhibition Pharmacological inhibition. They include mostly antidepressant and antipsychotic medication, and the patients experiencing that tend to quit them Autonomic nervous system malfunction Prostatectomy - surgical removal of the prostate. Ejaculatory duct obstruction Spinal cord injury causes sexual dysfunction including anejaculation. The rate of being able to ejaculate varies with the type of lesion, as detailed in the table at right. Old age Diabetes mellitusAnejaculation, especially the orgasmic variant, is usually indistinguishable from retrograde ejaculation. However, a negative urinalysis measuring no abnormal presence of spermatozoa in the urine will eliminate a retrograde ejaculation diagnosis. Thus, if the affected person has the sensations and involuntary muscle-contractions of an orgasm but no or very low-volume semen, ejaculatory duct obstruction is another possible underlying pathology of anejaculation. Management Anejaculation in spinal cord injury The first-line method for sperm retrieval in men with spinal cord injury is penile vibratory stimulation (PVS). The penile vibratory stimulator is a plier-like device that is placed around the glans penis to stimulate it by vibration. In case of failure with PVS, spermatozoa are sometimes collected by electroejaculation, or surgically by per cutaneous epididymal sperm aspiration (PESA) or testicular sperm extraction (TESE). == Notes ==
Rhinophyma	Rhinophyma is a condition causing development of a large, bulbous nose associated with granulomatous infiltration, commonly due to untreated rosacea. The condition is most common in older white males.Colloquial terms for the rhinophyma include "whiskey nose", "gin blossom", "toros nose", and "potato nose". Signs and symptoms Rhinophyma is characterised by prominent pores and a fibrous thickening of the nose, sometimes with papules. It is associated with the common skin condition rosacea and it can be classified clinically into 5 grades of increasing severity. Complications Tissue thickening may come to cause airway obstruction and impede breathing.Rhynophyma cause psychological distress due to its effect on ones personal appearance and social perceptions of a link with alcoholism. Causes Rhinophyma develops in certain individuals with an unknown predisposition from long-standing rosacea which has progressed to a severe form.Although rhinophyma has been commonly presumed to be linked to alcoholism, a direct causal relationship between the condition and excessive alcohol consumption has not been substantiated. Alcohol may cause increased flushing in those affected. Pathophysiology Rhinophyma develops in some individuals after long-standing rosacea that has progressed to acne rosacea.Rosacea usually commences in people between the age of 20-30 years. Rosacea begins with facial flushing (pre-rosacea). The nasal skin then thickens and hypervascularises, leading to persistent erythema (vascular rosacea). Papules and pustules then develop, marking the beginning of acne (inflammatory) rosacea. A subset of those affected by acne rosacea go on to develop rhinophyma. Chronic infection is common as the thickened sebaceous fluid traps bacteria.Rhinophyma is characterised by hypertrophy of nasal skin, with hyperplasia and fibrosis of the sebaceous glands and connective tissue. The nasal tip and alae are preferentially affected by the hypertrophy, and the lower portion of the nose is predominantly affected. The underlying bony structure is not affected.The exact pathophysiological mechanism underlying the development of rosacea and rhinophyma is unknown, but a combination of neurovascular and immune disturbance is thought to be involved, causing inflammation, fibrosis, and vascularisation. Male predisposition Even though females are more often affected by acne rosacea, they seldom go on to develop rhinophyma. It is thought that androgenic factors predispose men to develop rhynophyma. Diagnosis Rhinophyma is diagnosed clinically based on presentation (erythema, telangiectasias, and nasal skin hypertrophy). Diagnosis is confirmed by histology. Treatment Treatment consists of paring down the bulk of the tissue with a sharp instrument or carbon dioxide laser and allowing the area to re-epithelialise. Sometimes, the tissue is completely excised and the raw area skin-grafted. Epidemiology Rhynophyma is most common in males of European heritage over the age of 50. Males are 5 to 30 times as likely to be affected as females, possibly due to androgenic factors. In the United States, people of predominantly Asian and African ancestry are only rarely affected by the condition. Society Colloquial names for the condition include "whiskey nose", "gin blossom", and "potato nose". The condition has often been presumed to be a result of alcoholism (even though it remains unclear whether alcohol actually contributes to the development of rhynophyma) which has led to stigmatisation of people with the condition. In film, villainous characters have been portrayed as having rhynophyma, notably the evil queen in the animated film Snow White and the Seven Dwarfs. Among those people known to have had the disease was the American banker J. P. Morgan. References == External links ==
Mazzotti reaction	The Mazzotti reaction, first described in 1948, is a symptom complex seen in patients after undergoing treatment of nematode infestation, particularly with the medication diethylcarbamazine (DEC). Mazzotti reactions can be life-threatening, and are characterized by fever, urticaria, swollen and tender lymph nodes, tachycardia, hypotension, arthralgias, oedema, and abdominal pain that occur within seven days of treatment of microfilariasis. The Mazzotti reaction correlates with intensity of infection; however, there are probably multiple infection intensity-dependent mechanisms responsible for mediating this complex reaction.The phenomenon is so common when DEC is used for the treatment of onchocerciasis that this drug is the basis of a skin patch test used to confirm that diagnosis. The drug patch is placed on the skin, and if the patient is infected with the microfilaria of O. volvulus, localized pruritus and urticaria are seen at the application site. A case of the Mazzotti reaction has been reported after presumptive treatment of schistosomiasis and strongyloidiasis with ivermectin, praziquantel and albendazole. The patient had complete resolution of symptoms after intravenous therapy with methylprednisolone. == References ==
Melanosis	Melanosis is a form of hyperpigmentation associated with increased melanin.It can also refer to: Melanism Ocular melanosis Smokers melanosis Oral melanosis Riehl melanosis See also List of cutaneous conditions References == External links ==
Mediastinal shift	Mediastinal shift is the deviation of the mediastinal structures towards one side of the chest cavity, usually seen on chest radiograph. It indicates a severe asymmetry of intrathoracic pressures. Mediastinal shift may be caused by volume expansion on one side of the thorax, volume loss on one side of the thorax, mediastinal masses and vertebral or chest wall abnormalities. An emergent condition classically presenting with mediastinal shift is tension pneumothorax. It is also a useful indicator of malignant pleural effusion.Mediastinal shift may be detected on antenatal ultrasound in certain fetal conditions. == References ==
Monosomy 9p	Monosomy 9p (also known as Alfis Syndrome or simply 9P-) is a rare chromosomal disorder in which some DNA is missing or has been deleted on the short arm region, “p”, of one of the 9th Chromosomes (9p22.2-p23). This deletion either happens de novo or a result of a parent having the chromosome abnormality. This rare chromosome abnormality is often diagnosed after birth when development delay, irregular facial features, and structural irregularities within the heart, and genital defects are noticed. Treatments for this syndrome usually focus on fixing the common malformations associated with this syndrome. Chromosome 9p deletion syndrome was first discovered in 1973 when 3 infants with similar clinical features were observed to have a partial deletion of the short arm of Chromosome 9. Symptoms include microgenitalia, intellectual disability with microcephaly and dysmorphic features. Signs and Symptoms Psychomotor Development Delays Psychomotor development refers to the changes experienced directly after birth through adolescence. Development occurs in cognitive, emotional, motor, and social skills over the childs growth and a delay can result in lagging development of language, motor skills, cognition, or social skills, however these delays can vary in severity. Facial Dysmorphism Facial Dysmorphisms broadly describe any abnormalities in facial structure. Facial Dysmorphisms include slopping forehead, frontal bossing (prominent protruding forehead), hemifacial microsomia (one side of the face underdeveloped), and otocephaly (absence of mandible and fusion of ears under chin). Malformation of Limbs Congenital limb defects occur when a fetus limbs, either upper or lower, experience altered development. These developmental abnormalities include absence of the limb, failure of portions of the limb to separate (commonly fingers and toes), duplication of digits, or overgrowth or undergrowth of limbs. Genetics Inheritance Pattern The inheritance pattern for the Chromosome 9p deletion syndrome is inherited in an autosomal dominant inheritance pattern. This means that a single copy of the deletion is sufficient to cause the disease. Mutation The mutation, which occurs in the form of a deletion of the short arm of chromosome 9, causes the cell to not express the gene products normally controlled by the genes within the chromosome 9 deletion. Genes Involved The 9p deletion causes a loss of genes that would normally be there. Which genes are lost on the short arm of chromosome 9 dictates the symptoms that are present within the individual and the spectrum of disease severity. Most of the genes involved are associated with the development of tissues.There are many possible genes that can be deleted, but two particular genes that are proven to be involved in the emergence of the symptoms associated with Chromosome 9p deletion syndrome are DMRT1 and DMRT2. When DMRT1 and DMRT2 are deleted, genital malformations and mental retardation are evident although, the direct mechanisms as to how this occurs remains undefined. Location Geneticists originally had the syndrome narrowed down to the short arm region of Chromosome 9. Now, the location of the deletion has recently been narrowed to 9p22.2-p23. Diagnosis Diagnoses can occur at any age. Most of time chromosome 9p deletion syndrome is diagnosed after birth by the detection of symptoms via clinical evaluation. Common methods used to detect Monosomy 9p after birth include the use of a stethoscope, X-ray, and EKG. Monosomy 9p is also diagnosed before birth by ultrasound, amniocentesis, and chorionic villus sampling (CVS). Ultrasound can hint at the malformations of the face, limbs, and heart. While amniocentesis and CVS both use fluid and tissue to perform chromosomal studies to identify chromosomal abnormalities. Finally, karyotyping, a procedure used to examine a patients chromosomes, can be used to diagnose Monosomy 9p both before birth and after birth. Management Treatment of Monosomy 9p focuses mainly on fixing the malformations. For example, to fix facial malformations, physicians can perform facial surgery to repair the facial malformations. This can open airways for the infant or patient; especially the nose-to-throat pathway. Similarly, to fix heart malformations, physicians can recommend surgery or medication to improve the efficiency of the pumping of the heart. Lastly remedial education, speech therapy, and physical therapy can be used to improve the developmental delay associated with the syndrome. Epidemiology Chromosome 9p deletion syndrome occurs 1 in 50,000 births. Half of the cases occur sporadically, while the other half of cases result from parent translocations or the parent having deletion as well. References == External links ==
Steroid diabetes	Steroid diabetes is a medical term referring to prolonged hyperglycemia due to glucocorticoid therapy for another medical condition. It is usually, but not always, a transient condition. Cause The most common glucocorticoids which cause steroid diabetes are prednisolone and dexamethasone given systemically in "pharmacologic doses" for days or weeks. Typical medical conditions in which steroid diabetes arises during high-dose glucocorticoid treatment include severe asthma, organ transplantation, cystic fibrosis, inflammatory bowel disease, and induction chemotherapy for leukemia or other cancers. Mechanism Glucocorticoids oppose insulin action and stimulate gluconeogenesis, especially in the liver, resulting in a net increase in hepatic glucose output. Most people can produce enough extra insulin to compensate for this effect and maintain normal glucose levels, but those who cannot develop steroid diabetes. Diagnosis Steroid diabetes must be distinguished from stress hyperglycemia, hyperglycemia due to excessive intravenous glucose, or new-onset diabetes of another type. Because it is not unusual for steroid treatment to precipitate type 1 or type 2 diabetes in a person who is already in the process of developing it, it is not always possible to determine whether apparent steroid diabetes will be permanent or will go away when the steroids are finished. More commonly undiagnosed cases of type 2 diabetes are brought to clinical attention with corticosteroid treatment because subclinical hyperglycemia worsens and becomes symptomatic. Generally, steroid diabetes without preexisting type 2 diabetes will resolve upon termination of corticosteroid administration. Steroid diabetes does not occur with other steroid hormones, such as anabolic steroids or sex steroids because these other categories of steroids have actually shown to have positive effects on glucose metabolism. Criteria The diagnostic criteria for steroid diabetes are those of diabetes (fasting glucoses persistently above 125 mg/dl (7 mM) or random levels above 200 mg/dl (11 mM)) occurring in the context of high-dose glucocorticoid therapy. Insulin levels are usually detectable, and sometimes elevated, but inadequate to control the glucose. In extreme cases the hyperglycemia may be severe enough to cause nonketotic hyperosmolar coma. Treatment Treatment depends on the severity of the hyperglycemia and the estimated duration of the steroid treatment. Mild hyperglycemia in an immunocompetent patient may not require treatment if the steroids will be discontinued in a week or two. Moderate hyperglycemia carries an increased risk of infection, especially fungal, and especially in people with other risk factors such as immunocompromise or central intravenous lines. Insulin is the most common treatment. Further reading Fresh insights into glucocorticoid-induced diabetes mellitus and new therapeutic directions, Nature Reviews Endocrinology volume 18, pages540–557 (2022)Steroid-Induced Diabetes Mellitus and Related Risk Factors in Patients With Neurologic Disease - MedScape
Malassezia folliculitis	Malassezia folliculitis or Pityrosporum folliculitis, is a skin condition caused by infection by Malassezia (formerly Pityrosporum) yeast.: 314 The skin of the upper trunk area including the back, chest, arms and sometimes the neck is often affected and this condition is often seen in young to middle aged adults, although it has been known to occur in adults well into their sixties, and can also be found on the lower extremities as well. Its diagnosis is based on the pruritic (itchy) papulopustules found in a follicular pattern in these regions.Pustules are caused by an overgrowth of the yeast (a type of fungus) Malassezia furfur (Pityrosporum ovale), which plugs the follicles. M. furfur is lipophilic, requiring fatty acids like what is present in oily skin to proliferate. It has been shown that Malassezia yeast grows by consuming fatty acids with carbon chain lengths C11 to C24. Pityrosporum is part of the normal skin flora, but overgrows in certain conditions. Overgrowth is associated with oily skin, humidity or other pre-existing dermatologic conditions such as seborrheic dermatitis and severe dandruff. See also Skin lesion List of cutaneous conditions == References ==
Echinococcosis	Echinococcosis is a parasitic disease of tapeworms of the Echinococcus type. The two main types of the disease are cystic echinococcosis and alveolar echinococcosis. Less common forms include polycystic echinococcosis and unicystic echinococcosis.The disease often starts without symptoms and this may last for years. The symptoms and signs that occur depend on the cysts location and size. Alveolar disease usually begins in the liver, but can spread to other parts of the body, such as the lungs or brain. When the liver is affected, the patient may experience abdominal pain, weight loss, along with yellow-toned skin discoloration from developed jaundice. Lung disease may cause pain in the chest, shortness of breath, and coughing.The infection is spread when food or water that contains the eggs of the parasite is ingested or by close contact with an infected animal. The eggs are released in the stool of meat-eating animals that are infected by the parasite. Commonly infected animals include dogs, foxes, and wolves. For these animals to become infected they must eat the organs of an animal that contains the cysts such as sheep or rodents. The type of disease that occurs in human patients depends on the type of Echinococcus causing the infection. Diagnosis is usually by ultrasound though computer tomography (CT) or magnetic resonance imaging (MRI) may also be used. Blood tests looking for antibodies against the parasite may be helpful as may biopsy.Prevention of cystic disease is by treating dogs that may carry the disease and vaccination of sheep. Treatment is often difficult. The cystic disease may be drained through the skin, followed by medication. Sometimes this type of disease is just watched. The alveolar form often requires surgical intervention, followed by medications. The medication used is albendazole, which may be needed for years. The alveolar disease may result in death.The disease occurs in most areas of the world and currently affects about one million people. In some areas of South America, Africa, and Asia, up to 10% of the certain populations are affected. In 2015, the cystic form caused about 1,200 deaths; down from 2000 in 1990. The economic cost of the disease is estimated to be around US$3 billion a year. It is classified as a neglected tropical disease (NTD) and belongs to the group of diseases known as helminthiases (worm infections). It can affect other animals such as pigs, cows and horses.Terminology used in this field is crucial, since echinococcosis requires the involvement of specialists from nearly all disciplines. In 2020, an international effort of scientists, from 16 countries, led to a detailed consensus on terms to be used or rejected for the genetics, epidemiology, biology, immunology and clinical aspects of echinococcosis. Signs and symptoms In the human manifestation of the disease, E. granulosus, E. multilocularis, E. oligarthrus and E. vogeli are localized in the liver (in 75% of cases), the lungs (in 5–15% of cases) and other organs in the body such as the spleen, brain, heart, and kidneys (in 10–20% of cases). In people who are infected with E. granulosus and therefore have cystic echinococcosis, the disease develops as a slow-growing mass in the body. These slow-growing masses, often called cysts, are also found in people that are infected with alveolar and polycystic echinococcosis.The cysts found in those with cystic echinococcosis are usually filled with a clear fluid called hydatid fluid, are spherical, and typically consist of one compartment and are usually only found in one area of the body. While the cysts found in those with alveolar and polycystic echinococcosis are similar to those found in those with cystic echinococcosis, the alveolar and polycystic echinococcosis cysts usually have multiple compartments and have infiltrative as opposed to expansive growth.Depending on the location of the cyst in the body, the person could be asymptomatic even though the cysts have grown to be very large, or be symptomatic even if the cysts are absolutely tiny. If the person is symptomatic, the symptoms will depend largely on where the cysts are located. For instance, if the person has cysts in the lungs and is symptomatic, they will have a cough, shortness of breath and/or pain in the chest.On the other hand, if the person has cysts in the liver and is symptomatic, they will experience abdominal pain, abnormal abdominal tenderness, hepatomegaly with an abdominal mass, jaundice, fever and/or anaphylactic reaction. In addition, if the cysts were to rupture while in the body, whether during surgical extraction of the cysts or by trauma to the body, the person would most likely go into anaphylactic shock and have high fever, pruritus (itching), edema (swelling) of the lips and eyelids, dyspnea, stridor and rhinorrhea.Unlike intermediate hosts, definitive hosts are usually not hurt very much by the infection. Sometimes, a lack of certain vitamins and minerals can be caused in the host by the very high demand of the parasite.The incubation period for all species of Echinococcus can be months to years, or even decades. It largely depends on the location of the cyst in the body and how fast the cyst is growing. Cause Also like many other parasite infections, the course of Echinococcus infection is complex. The worm has a life cycle that requires definitive hosts and intermediate hosts. Definitive hosts are normally carnivores such as dogs, while intermediate hosts are usually herbivores such as sheep and cattle. Humans function as accidental hosts, because they are usually a dead end for the parasitic infection cycle, unless eaten by dogs or wolves after death. Hosts Life cycle An adult worm resides in the small intestine of a definitive host. A single gravid proglottid releases eggs that are passed in the feces of the definitive host. The egg is then ingested by an intermediate host. The egg then hatches in the small intestine of the intermediate host and releases an oncosphere that penetrates the intestinal wall and moves through the circulatory system into different organs, in particular the liver and lungs. Once it has invaded these organs, the oncosphere develops into a cyst. The cyst then slowly enlarges, creating protoscolices (juvenile scolices), and daughter cysts within the cyst. The definitive host then becomes infected after ingesting the cyst-containing organs of the infected intermediate host. After ingestion, the protoscolices attach to the intestine. They then develop into adult worms and the cycle starts all over again. Eggs Echinococcus eggs contain an embryo that is called an oncosphere or hexcanth. The name of this embryo stems from the fact that these embryos have six hooklets. The eggs are passed through the feces of the definitive host and it is the ingestion of these eggs that lead to infection in the intermediate host. Larval/hydatid cyst stage From the embryo released from an egg develops a hydatid cyst, which grows to about 5–10 cm within the first year and is able to survive within organs for years. Cysts sometimes grow to be so large that by the end of several years or even decades, they can contain several liters of fluid. Once a cyst has reached a diameter of 1 cm, its wall differentiates into a thick outer, non-cellular membrane, which covers the thin germinal epithelium. From this epithelium, cells begin to grow within the cyst. These cells then become vacuolated, and are known as brood capsules, which are the parts of the parasite from which protoscolices bud. Often, daughter cysts also form within cysts. Adult worm Echinococcus adult worms develop from protoscolices and are typically 6 mm or less in length and have a scolex, neck and typically three proglottids, one of which is immature, another of which is mature and the third of which is gravid (or containing eggs). The scolex of the adult worm contains four suckers and a rostellum that has about 25–50 hooks. Morphological differences The major morphological difference among different species of Echinococcus is the length of the tapeworm. E. granulosus is approximately 2 to 7 mm while E. multilocularis is often smaller and is 4 mm or less. On the other hand, E. vogeli is found to be up to 5.6 mm long and E. oligarthrus is found to be up to 2.9 mm long. In addition to the difference in length, there are also differences in the hydatid cysts of the different species. For instance, in E. multilocularis, the cysts have an ultra thin limiting membrane and the germinal epithelium may bud externally. Furthermore, E. granulosus cysts are unilocular and full of fluid while E. multilocularis cysts contain little fluid and are multilocular. For E. vogeli, its hydatid cysts are large and are actually polycystic since the germinal membrane of the hydatid cyst actually proliferates both inward, to create septa that divide the hydatid into sections, and outward, to create new cysts. Like E. granulosus cysts, E. vogeli cysts are filled with fluid. Transmission As one can see from the life cycles illustrated above, all disease-causing species of Echinococcus are transmitted to intermediate hosts via the ingestion of eggs and are transmitted to definitive hosts by means of eating infected, cyst-containing organs. Humans are accidental intermediate hosts that become infected by handling soil, dirt or animal hair that contains eggs.While there are no biological or mechanical vectors for the adult or larval form of any Echinococcus species, coprophagic flies, carrion birds and arthropods can act as mechanical vectors for the eggs. Aberrant cases There are a few aberrant cases in which carnivores play the role of the intermediate hosts. Examples are domestic cats with hydatid cysts of E. granulosus. Diagnosis Classification The most common form found in humans is cystic echinococcosis (also known as unilocular echinococcosis), which is caused by Echinococcus granulosus sensu lato. The second most common form is alveolar echinococcosis (also known as alveolar colloid of the liver, alveolar hydatid disease, alveolococcosis, multilocular echinococcosis, "small fox tapeworm"), which is caused by Echinococcus multilocularis and the third is polycystic echinococcosis (also known as human polycystic hydatid disease, neotropical echinococcosis), which is caused by Echinococcus vogeli and very rarely, Echinococcus oligarthrus. Alveolar and polycystic echinococcosis are rarely diagnosed in humans and are not as widespread as cystic echinococcosis, but polycystic echinococcosis is relatively new on the medical scene and is often left out of conversations dealing with echinococcosis, and alveolar echinococcosis is a serious disease that has a significantly high fatality rate, and may have the potential to become an emerging disease in many countries. Cystic A formal diagnosis of any type of echinococcosis requires a combination of tools that involve imaging techniques, histopathology, or nucleic acid detection and serology. For cystic echinococcosis diagnosis, imaging is the main method—while serology tests (such as indirect hemagglutination, ELISA (enzyme linked immunosorbent assay), immunoblots or latex agglutination) that use antigens specific for E. granulosus verify the imaging results. The imaging technique of choice for cystic echinococcosis is ultrasonography, since it is not only able to visualize the cysts in the bodys organs, but it is also inexpensive, non-invasive and gives instant results. In addition to ultrasonography, both MRI and CT scans can and are often used although an MRI is often preferred to CT scans when diagnosing cystic echinococcosis since it gives better visualization of liquid areas within the tissue. Alveolar As with cystic echinococcosis, ultrasonography is the imaging technique of choice for alveolar echinococcosis and is usually complemented by CT scans since CT scans are able to detect the largest number of lesions and calcifications that are characteristic of alveolar echinococcosis. MRIs are also used in combination with ultrasonography though CT scans are preferred. Like cystic echinococcosis, imaging is the major method used for the diagnosis of alveolar echinococcosis while the same types of serologic tests (except now specific for E. multilocularis antigens) are used to verify the imaging results. It is also important to note that serologic tests are more valuable for the diagnosis of alveolar echinococcosis than for cystic echinococcosis since they tend to be more reliable for alveolar echinococcosis since more antigens specific for E. multilocularis are available. In addition to imaging and serology, identification of E. multilocularis infection via PCR or a histological examination of a tissue biopsy from the person is another way to diagnose alveolar echinococcosis. Polycystic Similar to the diagnosis of alveolar echinococcosis and cystic echinococcosis, the diagnosis of polycystic echinococcosis uses imaging techniques, in particular ultrasonography and CT scans, to detect polycystic structures within the persons body. However, imaging is not the preferred method of diagnosis since the method that is currently considered the standard is the isolation of protoscoleces during surgery or after the persons death and the identification of definitive features of E. oligarthrus and E. vogeli in these isolated protoscoleces. This is the main way that PE is diagnosed, but some current studies show that PCR may identify E. oligarthrus and E. vogeli in peoples tissues. The only drawback of using PCR to diagnose polycystic echinococcosis is that there arent many genetic sequences that can be used for PCR that are specific only E. oligarthrus or E. vogeli. Prevention Cystic echinococcosis There are several different strategies that are currently being used to prevent and control cystic echinococcosis (CE). Most of these various methods try to prevent and control CE by targeting the major risk factors for the disease and the way it is transmitted. For instance, health education programs focused on cystic echinococcosis and its agents, and improved water sanitation attempt to target poor education and poor drinking water sources, which are both risk factors for contracting echinococcosis. Furthermore, since humans often come into contact with Echinococcus eggs via touching contaminated soil, animal feces and animal hair, another prevention strategy is improved hygiene. In addition to targeting risk factors and transmission, control and prevention strategies of cystic echinococcosis also aim at intervening at certain points of the parasites life cycle, in particular, the infection of hosts (especially dogs) that reside with or near humans. For example, many countries endemic to echinococcosis have researched programs geared at de-worming dogs and vaccinating dogs and other livestock, such as sheep, that also act as hosts for E. granulosus.Proper disposal of carcasses and offal after home slaughter is difficult in poor and remote communities and therefore dogs readily have access to offal from livestock, thus completing the parasite cycle of Echinococcus granulosus and putting communities at risk of cystic echinococcosis. Boiling livers and lungs that contain hydatid cysts for 30 minutes has been proposed as a simple, efficient and energy- and time-saving way to kill the infectious larvae. Alveolar echinococcosis A number of strategies are geared towards prevention and control of alveolar echinococcosis—most of which are similar to those for cystic echinococcosis. For instance, health education programs, improved water sanitation, improved hygiene and de-worming of hosts (particularly red foxes) are all effective to prevent and control the spread of alveolar echinococcosis. Unlike cystic echinococcosis, however, where there is a vaccine against E. granulosus, there is currently no canidae or livestock vaccine against E. multilocularis. Polycystic echinococcosis While a number of control and prevention strategies deal with cystic and alveolar echinococcosis, there are few methods to control and prevent polycystic echinococcosis. This is probably due to the fact that polycystic echinococcosis is restricted to Central and South America, and that the way that humans become accidental hosts of E. oligarthrus and E. vogeli is still not completely understood. Human vaccines Currently there are no human vaccines against any form of echinococcosis. However, there are studies being conducted that are looking at possible vaccine candidates for an effective human vaccine against echinococcosis. Treatment Cystic A number of therapy options are presently available. Treatment with albendazole, whether combined or not with praziquantel, is useful for smaller, uncomplicated cysts (< 5 cm). Only 30% of cysts disappear with medical treatment alone. Noramlly, albendazole is preferred twice a day for 1–5 months. An alternative to albendazole is mebendazole for at least 3 to 6 months. Surgery is indicated for bigger liver cysts (> 10 cm), and cysts at risk of rupture and/or complicated cysts. The laparoscopic approach is scarcely widespread although provides excellent cure rates with minimal morbidity and mortality. The radical technique (total cystopericystectomy) is preferable because of its lower risk for postoperative abdominal infection, biliary fistula, and overall morbidity. Conservative techniques are appropriate in endemic areas where surgery is performed by nonspecialist surgeons.PAIR (puncture-aspiration-injection-reaspiration) is an innovative technique representing an alternative to surgery. PAIR is a minimally invasive procedure that involves three steps: puncture and needle aspiration of the cyst, injection of a scolicidal solution for 20–30 min, and cyst-re-aspiration and final irrigation. People who undergo PAIR typically take albendazole or mebendazole from 7 days before the procedure until 28 days after the procedure. It is indicated for inoperable cases and/or patients who reject surgery, for recurrence after surgery, and for lack of response to medical treatment. There have been a number of studies that suggest that PAIR with medical therapy is more effective than surgery in terms of disease recurrence, and morbidity and mortality.There is currently research and studies looking at new treatment involving percutaneous thermal ablation (PTA) of the germinal layer in the cyst by means of a radiofrequency ablation device. This form of treatment is still relatively new and requires much more testing before being widely used.Active surveillance without treatment may be indicated for quiescent or inactive, uncomplicated liver cysts Alveolar For alveolar echinococcosis, surgical removal of cysts combined with chemotherapy (using albendazole and/or mebendazole) for up to two years after surgery is the only sure way to completely cure the disease. However, in inoperable cases, chemotherapy by itself can also be used. In treatment using just chemotherapy, one could use either mebendazole in three doses or albendazole in two doses. Since chemotherapy on its own is not guaranteed to completely rid of the disease, people are often kept on the drugs for extended periods of times (i.e. more than 6 months, years). In addition to surgery and chemotherapy, liver transplants are being looked into as a form of treatment for alveolar echinococcosis although it is seen as incredibly risky since it often leads to echinococcosis re-infection in the person afterwards. Polycystic Since polycystic echinococcosis is constrained to such a particular area of the world and is not well described or found in many people, treatment of polycystic echinococcosis is less defined than that of cystic and alveolar echinococcosis. While surgical removal of cysts was the treatment of choice for the previous two types of echinococcosis, chemotherapy is the recommended treatment approach for polycystic echinococcosis. While albendazole is the preferred drug, mebendazole can also be used if the treatment is to be for an extended period of time. Only if chemotherapy fails or if the lesions are very small is surgery advised. Epidemiology Regions Very few countries are considered to be completely free of E. granulosus. Areas of the world where there is a high rate of infection often coincide with rural, grazing areas where dogs are able to ingest organs from infected animals.E. multilocularis mainly occurs in the Northern hemisphere, including central Europe and the northern parts of Europe, Asia, and North America. However, its distribution was not always like this. For instance, until the end of the 1980s, E. multilocularis endemic areas in Europe were known to exist only in France, Switzerland, Germany, and Austria. But during the 1990s and early 2000s, there was a shift in the distribution of E. multilocularis as the infection rate of foxes escalated in certain parts of France and Germany.As a result, several new endemic areas were found in Switzerland, Germany, and Austria and surrounding countries such as the Netherlands, Belgium, Luxembourg, Poland, the Czech Republic, the Slovak Republic, and Italy. There is also evidence showing that the Baltic Countries are endemic areas.While alveolar echinococcosis is not extremely common, it is believed that in the coming years it will be an emerging or re-emerging disease in certain countries as a result of E. multilocularis’ ability to spread.Unlike the previous two species of Echinococcus, E. vogeli and E. oligarthrus are limited to Central and South America. Furthermore, infections by E. vogeli and E. oligarthrus (polycystic echinococcosis) are considered to be the rarest form of echinococcosis. Deaths As of 2010 it caused about 1200 deaths, down from 2000 in 1990. History Echinococcosis is a disease that has been recognized by humans for centuries. There has been mention of it in the Talmud. It was also recognized by ancient scholars such as Hippocrates, Aretaeus, Galen and Rhazes. The recommended treatments were based on herbs like thymus vulgaris and raw garlic. Although echinococcosis has been well known for the past two thousand years, it was not until the past couple of hundred years that real progress was made in determining and describing its parasitic origin. The first step towards figuring out the cause of echinococcosis occurred during the 17th century when Francesco Redi illustrated that the hydatid cysts of echinococcosis were of "animal" origin. Then, in 1766, Pierre Simon Pallas predicted that these hydatid cysts found in infected humans were actually larval stages of tapeworms.A few decades afterwards, in 1782, Goeze accurately described the cysts and the tapeworm heads, while in 1786 E. granulosus was accurately described by Batsch. Half a century later, during the 1850s, Karl von Siebold showed through a series of experiments that Echinococcus cysts do cause adult tapeworms in dogs. Shortly after this, in 1863, E. multilocularis was identified by Rudolf Leuckart. Then, during the early to mid 1900s, the more distinct features of E. granulosus and E. multilocularis, their life cycles and how they cause disease were more fully described as more and more people began researching and performing experiments and studies. While E. granulosus and E. multilocularis were both linked to human echinococcosis before or shortly after the 20th century, it was not until the mid-1900s that E. oligarthrus and E. vogeli were identified as and shown as being causes of human echinococcosis.Two calcified objects recovered from a 3rd- to 4th-century grave of an adolescent in Amiens (Northern France) were interpreted as probable hydatid cysts. A study of remains from two 8,000-year-old cemeteries in Siberia showed presence of echinococcosis. References Further reading Alimuddin I. Zumla; Gordon C. Cook; Patrick Manson (2003). "Section 10: Helminthic Infections 83. Echinococcosis/Hydatidosis". Mansons tropical diseases. Philadelphia: Saunders. ISBN 978-0-7020-2640-9. Vuitton DA, Millon L, Gottstein B, Giraudoux P (2014). "Proceedings of the international symposium — innovation for the management of echinococcosis. Besançon, March 27–29, 2014". Parasite. 21: 28. doi:10.1051/parasite/2014024. PMC 4071351. External links WHO Echinococcosis Page CDC Echinococcosis Page
Ganser syndrome	Ganser syndrome is a rare dissociative disorder characterized by nonsensical or wrong answers to questions and other dissociative symptoms such as fugue, amnesia or conversion disorder, often with visual pseudohallucinations and a decreased state of consciousness. The syndrome has also been called nonsense syndrome, balderdash syndrome, syndrome of approximate answers, hysterical pseudodementia or prison psychosis. The term prison psychosis is sometimes used because the syndrome occurs most frequently in prison inmates, where it may be seen as an attempt to gain leniency from prison or court officials. Psychological symptoms generally resemble the patients sense of mental illness rather than any recognized category. The syndrome may occur in persons with other mental disorders such as schizophrenia, depressive disorders, toxic states, paresis, alcohol use disorders and factitious disorders. Ganser syndrome can sometimes be diagnosed as merely malingering, but it is more often defined as dissociative disorder.The identification of Ganser syndrome is attributed to German psychiatrist Sigbert Ganser (1853–1931). In 1898, he described the disorder in prisoners awaiting trial in a penal institution in Halle, Germany. He named impaired consciousness and distorted communication, namely in the form of approximate answers (also referred to as Vorbeireden in the literature), as the defining symptoms of the syndrome. Vorbeireden involves the inability to answer questions precisely, although the content of the questions is understood.Ganser syndrome is described as a dissociative disorder not otherwise specified (NOS) in the DSM-IV, and is not currently listed in the DSM-5. It is a rare and an often overlooked clinical phenomenon. In most cases, it is preceded by extreme stress and followed by amnesia for the period of psychosis. In addition to approximate answers, other symptoms include a clouding of consciousness, somatic conversion disorder symptoms, confusion, stress, loss of personal identity, echolalia, and echopraxia. Cause To date, no definitive cause or reason of the disorder has been established. The sources that classify the syndrome as a dissociative disorder or a factitious disorder conflict in their proposed aetiologies. As a result, there are differing theories as to why the syndrome develops. Ganser syndrome was previously classified as a factitious disorder, explaining the symptoms as mimicking of what patients who do not experience psychosis believe is typical of the experience. However, the DSM-IV placed the syndrome under "Dissociative Disorders Not Otherwise Specified". There has been evidence of a strong correlation between approximate answers and amnesia, suggesting that these have an underlying dissociative mechanism.Both Gansers syndrome and the broader category of dissociative disorders have been linked to histories of hysteria, psychosis, conversion, multiple personality and possible feigning. Despite this, the conditions aetiology remains under question due to associations with established psychiatric disorders, as well as organic states. According to Stern and Whiles (1942), Ganser syndrome is a fundamentally psychotic illness. As evidence, they describe the case of a woman with recurrent mania and a head injury before being submitted to treatment and the report of a man with schizophrenia who suffered from alcoholism and had recently been in prison.Ganser syndrome is also sometimes referred to as "prison psychosis", emphasizing its prevalence among prisoners, generating discussion about whether the disorder only appears in this population. In a study of prisoners, Estes and New concluded that escaping an intolerable situation, such as being incarcerated, prompted the syndromes key symptoms. The study touched on the malingering controversy surrounding the syndrome, as well as the stress component that often precedes the disorder.According to consultant psychiatrist F. A. Whitlock, Ganser syndrome is a hysterical disorder, on par with Gansers description of the disorder. Whitlock pointed to the number of cases in which Ganser syndrome was reported in settings of organic brain disease or functional psychosis as evidence of its hysterical foundations. Kraepelin and Bumke also believed the syndrome to be of a hysterical nature. Bumke thought the syndrome hysterical because amnesia for a traumatic emotional event tends to occur in hysteria more than in other disorders. The giving of approximate answers is thought to be produced in hysterical personalities.According to Mayer-Gross and Bleuler, Ganser syndrome occurs mainly in epileptic or schizophrenic patients.Still others claim that an organic condition that could lead to the manifestation of Ganser syndrome symptoms would have to be at an advanced stage in which a diagnosis could be easily given.There have also been reports of trauma and stroke patients with the syndrome. A study investigating the neurological basis of Ganser syndrome described a patient with symptoms of the disorder who had a history of stroke and bifrontal infarcts. They discovered that hyperglutamatergic states, which are caused by both strokes and stress, share a relationship with dissociative symptoms, suggesting a possible organic pathology that can predispose individuals to the syndrome. Wirtz and colleagues (2008) described a patient with Ganser syndrome after a left-hemispheric middle cerebral artery infarct. A neuropsychological examination revealed atypical lateralisation of cognitive functions, leading to the conclusion that the giving of approximate answers might be related to frontal-executive cerebral dysfunction. Diagnosis Ganser syndrome was listed under Factitious Disorder with Psychological Symptoms in the DSM-III. The criteria of this category emphasized symptoms that cannot be explained by other mental disorders, psychological symptoms under the control of the individual, and the goal of assuming a patient role, not otherwise understandable given their circumstances.The DSM-IV-TR classified Ganser syndrome as a dissociative disorder defined by the giving of approximate answers to questions (e.g. 2 plus 2 equals 5 when not associated with dissociative amnesia or dissociative fugue). The ICD-10 and DSM-IV do not specify any diagnostic criteria—apart from approximate answers—as a requirement for a Ganser syndrome diagnosis. Most case studies of the syndrome also depend on the presence of approximate answers and at least one of the other symptoms described by Ganser in his original paper. Usually when giving wrong answers, individuals are only slightly off, showing that the individual understood the question For instance, when asked how many legs a horse has, they might say, "five". Although subjects appear confused in their answers, in other respects they appear to understand their surroundings. Amnesia, loss of personal identity, and clouding of consciousness were among the most common symptoms apart from approximate answers.Although there is currently no uniform way to diagnose the syndrome, a full neurological and mental state examination is recommended to determine its presence as well as tests that assess malingering. In addition to mental examination, other investigations should be done to exclude other underlying causes. These include computer tomography scans (CT) or magnetic resonance imaging (MRI) scans to exclude structural pathology, lumbar puncture to exclude meningitis or encephalitis, and electroencephalography (EEG), to exclude delirium or seizure disorder.Diagnosing Ganser syndrome is challenging because of its rarity and symptom variability. The manifested symptoms may be dependent on the individuals conception of what mental illness entails, creating the possibility of a wide range of combinations of symptoms present in an individual with Ganser syndrome. Treatment In many cases, the symptoms seem to dwindle after a few days, and patients are often left with amnesia for the period of psychosis. Hospitalization may be necessary during the acute phase of symptoms, and psychiatric care if the patient is a danger to self or others. A neurological consult is advised to rule out any organic cause. Psychotherapy may also recommended for ensuring and maintaining safety. Ganser patients typically recover quickly and completely. Since Ganser syndrome can be a response to psychic deterioration, its resolution may be followed by other psychiatric symptoms, such as schizophrenia and depression, hence the rationale behind the recommendation of psychotherapy. Medication is usually not required. Epidemiology With about 100 case studies, the incidence of the disorder is not precisely known. Individuals of multiple backgrounds have been reported as having the disorder. The syndrome was historically thought to be more common in men. However, Whitlock speculates that the higher reported rate of Ganser in men might be due to the greater proportion of men who are incarcerated. It has been most frequently seen in individuals ages 15 to 40 and has also been observed in children. This wide age range is derived from case studies, and therefore may not be an accurate estimate. Ganser syndrome has also been observed in groups other than prison populations. Controversy There is controversy regarding whether Ganser syndrome is a valid clinical entity. For example, Bromberg (1986) has argued that the syndrome is not due to or related to mental illness, but rather a sort of defense against legal punishment. Some see it as conscious lying, denial and repression, presenting Ganser syndrome symptoms as malingering instead of a dissociative or factitious disorder.One case study of Ganser syndrome presented a middle-aged man who had been in a car crash and wanted disability insurance benefits. Since he had a big incentive, psychologists took careful measures and implemented testing with malingering instruments, which showed that the man performed below chance on simple memory tests and claimed to experience non-existent symptoms. Upon further inspection of the collateral information, they found that the patient took part in high-level sports and other activities that were inconsistent with the cognitive dysfunctions he reported, and they determined it to be a case of malingering.Estes and New (1948) concluded that the motivation for the symptoms of the syndrome was escaping an "intolerable situation". Stern and Whiles proposed an alternative explanation, citing Ganser syndrome presented itself in individuals who, although not psychologically well, do not realize it, and want to appear so. Still others attribute the syndrome to inattention, purposeful evasion, suppression, alcoholic excess, head injury, and to unconscious attempts to deceive others as a means to free themselves from responsibility for their actions. This denial of behaviour can be seen as a way to overcome anxiety and helplessness brought on by the stressful event that often precedes the syndrome.These aetiological debates focus on the main symptom of Ganser syndrome and its importance in its diagnosis. Approximate answers are prominent in the Ganser syndrome literature, causing concern in those who believe that this is a relatively simple symptom to feign.Ganser syndrome was regarded as an Adjustment Reaction of Adult Life in the DSM-II and later was moved under the category of Factitious Disorder with Psychological Symptoms in the DSM-III. Ganser syndrome can also be found under the Dissociative Disorder Not Otherwise Specified (DDNOS) section of the DSM-IV-TR, however it is not listed in the DSM-5, which got rid of the DDNOS section and replaced it with Other Specified Dissociative Disorder (OSDD) and Unspecified Dissociative Disorder (USDD). Despite this, the International Classification of Diseases has Ganser syndrome listed under dissociative disorders. See also Paraphasia References Further reading Schutzman, Mady (2003). "Being Approximate: The Ganser Syndrome and Beyond" (PDF). Journal of Medical Humanities. 24 (1/2): 147–158. doi:10.1023/A:1021318118143. S2CID 141323730. Retrieved 14 December 2010. == External links ==
Rhabdomyoma	A rhabdomyoma is a benign tumor of striated muscle. Rhabdomyomas may be either "cardiac" or "extra cardiac" (occurring outside the heart). Extracardiac forms of rhabdomyoma are sub classified into three distinct types: adult type, fetal type, and genital type. Cardiac rhabdomyomas are the most common primary tumor of the heart in infants and children. It has an association with tuberous sclerosis. In those with tuberous sclerosis, the tumor may regress and disappear completely, or remain consistent in size. A common histological feature is the presence of Spider Cells, which are cardiac myocytes with enlarged glycogen vacuoles separated by eosinophilic strands, resembling the legs of a spider. It is most commonly associated with the tongue, and heart, but can also occur in other locations, such as the vagina.Malignant skeletal muscle tumors are referred to as rhabdomyosarcoma. Only rare cases of possible malignant change have been reported in fetal rhabdomyoma. The differential diagnosis in the tongue includes ectomesenchymal chondromyxoid tumor. Additional images == References ==
Fissured tongue	Fissured tongue is a benign condition characterized by deep grooves (fissures) in the dorsum of the tongue. Although these grooves may look unsettling, the condition is usually painless. Some individuals may complain of an associated burning sensation.It is a relatively common condition, with a prevalence of between 6.8% and 11% found also in children. The prevalence of the condition increases significantly with age, occurring in 40% of the population after the age of 40. Presentation The clinical appearance is considerably varied in both the orientation, number, depth and length of the fissure pattern. There are usually multiple grooves/furrows 2–6 mm in depth present. Sometimes there is a large central furrow, with smaller fissures branching perpendicularly. Other patterns may show a mostly dorsolateral position of the fissures (i.e. sideways running grooves on the tongues upper surface). Some patients may experience burning or soreness. Associated conditions Fissured tongue is seen in Melkersson–Rosenthal syndrome (along with facial nerve paralysis and granulomatous cheilitis). It is also seen in most patients with Down syndrome, in association with geographic tongue, in patients with oral manifestations of psoriasis, and in healthy individuals. Fissured tongue is also sometimes a feature of Cowdens syndrome. Cause The cause is unknown, but it may be partly a genetic trait. Aging and environmental factors may also contribute to the appearance. Prevalence It is a relatively common condition, with an estimated prevalence of 6.8%–11%. Males are more commonly affected. The condition may be seen at any age, but generally affects older people more frequently. The condition also generally becomes more accentuated with age. The prevalence of the condition increases significantly with age, occurring in 40% of the population after the age of 40. References == External links ==
Pruritic urticarial papules and plaques of pregnancy	Pruritic urticarial papules and plaques of pregnancy (PUPPP), known in United Kingdom as polymorphic eruption of pregnancy (PEP), is a chronic hives-like rash that strikes some women during pregnancy. Some skin changes are known to occur in people who are pregnant while other skin conditions, or dermatoses, that people have prior to getting pregnant will become altered or symptoms will increase. Pruritic urticarial papules and plaques of pregnancy (PUPPP) is one of many skin conditions that is specific to pregnancy and occurs in about 1 in every 160 (0.625%) of pregnancies.It presents no long-term risk for either the woman or fetus as there is no statistical increase of risk of premature labor or fetal loss, despite frequently severe pruritus.PUPPP usually first appears on the abdomen and often spreads to the legs, feet, arms, chest, and neck. The face is usually not affected. Skin distension (stretching) is thought to be a possible trigger for PUPPP as it most commonly affects primigravida (women in their first pregnancy), those with large fundal measurements (distance from the pubic bone to the top of the uterus) and/or those who are carrying large babies or multiples. The papules and plaques often first appear within stretch marks before changing appearance and spreading to other areas of the body. It is important that those who are pregnant heavily consider the recommendations of their full healthcare team. For those who may be experiencing signs and symptoms of PUPPP, it is strongly recommended they speak with their primary care physician and receive a consult from a dermatologist regarding skin changes during pregnancy. Signs and Symptoms PUPPP most commonly presents as a rash that starts within the stretch marks. This rash may then move to other areas of the body, including, but not limited to the trunk of the body, arms, legs, feet, chest, and neck. Very few people experiencing PUPPP have reported the rash spreading to the face, palms of hands, or soles of feet.This rash usually begins with the skin looking abnormally red and feeling itchy, accompanied by notable swelling of skin tissue that appears raised and within the stretch marks. Over time, individual segments of this rash can join to form one whole, larger rash with the same characteristics. As this happens, people report noticing the skin surrounding the rash to appear white in color (blanched) and in the shape of "halos". Multiple features of the disease can continue with time and have been reported as widespread erythema (a red skin rash due to damage of underlying capillaries) and patches of inflamed, itchy, rough, and cracked patches of skin that appear similarly to eczema. Other features have been reported in some cases of those experiencing PUPPP, such as tiny vesicles, however these are not as common and develop after more time. Certain reports have shown there is a positive correlation between PUPPP and excessive maternal weight gain along with increased newborn birth weight. Additionally, a study from Ghazeeri and al. showed that 89% of people who underwent conception through in vitro fertilization were Rh-positive.The timeline of onset for these symptoms has been reported with some variability. However, most people report experiencing symptoms during the third trimester (last few weeks of pregnancy) where 15% of the women who have PUPPP reported that symptoms actually began immediately after delivery of the baby. As mentioned above, the papules and plaques usually first appear on the abdomen (although not on the umbilicus/belly button) and often spread to the legs, chest, underarms, etc. However, lesions on or above the breasts are rare. Thats why the face is usually spared and does not become affected. As a result of these papules and plaques from PUPPP, it causes the skin to be very itchy (pruritic) and immensely affects the patients sleep quality throughout the night. Cause PUPPP is the most common dermatosis of pregnancy and is the most frequent in pregnant women habitating a male fetus, women who had quick and conspicuous weight gain during a short period, and women who ultimately deliver by a c-section. Although the exact cause of the condition is not known and varying amongst individuals, there have been theories linking the cause of PUPPP to hormonal alterations, damage to the connective tissue during pregnancy, and autoimmune disorder where the evidence for these theories is currently low.This skin condition occurs mostly in first pregnancies (primigravida), in the third trimester and is more likely with multiple pregnancies (more so with triplets than twins or singletons). Estimated 75% of people with typical PUPPP people have never given birth. Occasionally, this condition may also occur postpartum, but rarely does this ever occur in the first and second trimester.Other than additional associations with hypertension and induction of labour, there are no observed difference in the outcome of the pregnancy for mothers or babies. Dermatological Causes During pregnancy as the abdominal wall rapid stretching, it is hypothesized that there is an inflammatory reaction that occurs due to the exposure of collagen. This reaction has been seen more frequently in those who are having twins or triplets compared to those with single births. This is hypothesized to be due to increased stretching of the abdominal wall while carrying twins or triplets, causing an earlier onset of PUPPP when compared to those undergoing single births. Hormonal Causes Throughout pregnancy, there are hormonal changes that occur where it has been hypothesized that these changes may contribute to the onset of PUPPP. Although current research is low on this hypothesis, it has been seen that those who have had multiple gestations can exhibit an increased level of progesterone. With this increase in progesterone, it causes there to be an increased level of progesterone receptors present eliciting an immune reaction seen by skin lesions in PUPPP. With multiple gestations, there is an increase in sex hormones that has been seen those with the condition such as an increase in progesterone as previously discussed but also higher levels of estradiol. Currently evidence is weak in the role that sex hormones play when contributing to PUPPP where further research is needed. Immunological Causes Inflammatory Mediated From those with PUPPP, it has been seen from an immunohistology profile which is used to determine the of tissue components present within an individual via the use of antibodies, that there are certain immune cells that are in greater amount compared to that of those without PUPPP. Immunohistology profile have shown cells consistent with a delayed hypersensitivity with T helper cell infiltrates, dendritic cells and epidermal Langerhans cells.It has been hypothesized that PUPPP appears in response to fetal antigens that circulate throughout the body. For example, a study showed that fetal male DNA was found within the lesions of the mothers skin which was thought to be caused by the fetal cells seen in the mothers blood throughout pregnancy. Autoimmune Although this condition has not been determined as an autoimmune condition, from a single study it has been seen that Immunoglobulin M (IgM) deposition at the dermal-epidermal membrane has been associated with a variety of dermatosis including PUPPP. The problem with the hypothesis that has been proposed is that this condition does not reoccur and it does not progressively worsen. Currently there has been no evidence of detecting circulating antibodies that are associated with the onset on PUPPP in an individual. Diagnosis PUPPP is often a diagnosis of exclusion and may need laboratory testing to rule out other dermatoses. Lab tests may include complete blood count, comprehensive metabolic panel, liver function tests, serum human choriogonadotropin and serum cortisol. Additional specialized tests may include serum for indirect immunofluorescence or biopsy of the lesions for direct immunofluorescence to rule out pemphigoid gestationis.A common misdiagnosis is urticarial pemphigoid gestationis, hence it is needed to exclude it while diagnosing PUPPP as clinical features can overlap. Therefore, histological and immunological studies are necessary to ensure there is no mis-diagnosis. During the case of pemphigoid gestationis, lesions usually occur during the earlier periods of gestation and often involve the umbilicus; as well as, having a positive immunofluorescence of perilesional skin. If there is eczema, people generally have a history of atopy, be it personal or through family. The eruption is identified by pruritic erythematous lesions on flexural areas. Furthermore, other clinical differential diagnosis could be from drug eruptions, urticaria, or viral exanthems.Sometimes, people may require a 3- or 4-mm punch biopsy to exclude herpes gestationis, which is a variant of bullous pemphigoid occurring during or immediately after pregnancy. Usually the biopsy has features that are consistent with PUPPP but there are no pathognomonic symptoms of the particular disorder. Additionally, a biopsy of unaffected perilesional skin could be used for direct immunofluorescence studies to have a more precise exclusion of herpes gestationis. Treatment It is important to note that diagnosis should be conducted by a trusted medical professional. In the case that a woman is experiencing symptoms of PUPPP, it is recommended that they contact their primary care physician for referral to a dermatologist for treatment guidance and should not self-treat.In the majority of cases, PUPPP resolves within a few days or weeks upon initial onset or spontaneously within a week of delivery. However, a few women continue to experience symptoms long into the postpartum period. One of the most recent forms of treatment suggested is the intramuscular injection of autologous whole blood as an alternative treatment option for people affected by PUPPP right after childbirth, as it seems to have both subjective and objective improvements of the symptoms. This is a very good option for the people who are worried about taking medications during pregnancy or breastfeedingAntihistamine tablets may be prescribed to provide relief from the itch, although they are generally considered much less effective than corticosteroid treatments, and may decrease itching through blocking histamine release as well as improving sleep quality. Furthermore, first-generation antihistamines, such as chlorpheniramine, have proven to be safe in pregnancy and can be a supplement treatment for pruritus. Second-generation antihistamines such as loratadine and cetirizine are non-sedating and may also be effective in controlling pruritus in pregnant people.Knowing that oral antihistamines are generally ineffective, high-potency topical steroids are used to treat PUPPP, and ideally tapering it off after 7 days of therapy. Class I or II corticosteroid creams and ointments are used in more aggressive cases, and oral (systemic) corticosteroids can be used to treat very severe cases—although the benefits of a pregnant womans ingesting high-potency corticosteroids must be weighed carefully against possible (and mostly unknown) risks to the developing fetus or fetuses. The use of high-potency topical corticosteroids over 300 grams throughout the pregnancy may increase the risk of low birth weight for the baby. Rarely, in unusually persistent and distressing cases, some women have had their labor induced as soon as they are considered to be at term (37 weeks).When the pruritus is unbearable to the patient with PUPPP, oral prednisone in doses of 10 to 40 mg/day has been generally used for these type of severe cases. With this treatment, symptoms are usually relieved after 24 hours of the oral treatment. Sometimes, if the cases are too severe and the symptoms are extremely unbearable, early delivery can be discussed with the patient if the other treatments are ineffective. However, early delivery of the baby still does not guarantee that the symptoms will be gone. Luckily, in most cases, steroid treatment works efficiently and symptoms are generally greatly improved within several days. As with most steroid treatments, the usage of it is a controversial topic. Nonetheless, short-term or one-time use is advisable, and tends to be safer while using it during the third trimester compared to the first trimester.Pine tar soap/body wash can also bring relief as can keeping the skin chilled such as through a cold shower or iced cloths. See also Intrahepatic cholestasis of pregnancy List of cutaneous conditions References == External links ==
Sphincter of Oddi dysfunction	Sphincter of Oddi dysfunction refers to a group of functional disorders leading to abdominal pain due to dysfunction of the Sphincter of Oddi: functional biliary sphincter of Oddi and functional pancreatic sphincter of Oddi disorder. The sphincter of Oddi is a sphincter muscle, a circular band of muscle at the bottom of the biliary tree which controls the flow of pancreatic juices and bile into the second part of the duodenum. The pathogenesis of this condition is recognized to encompass stenosis or dyskinesia of the sphincter of Oddi (especially after cholecystectomy); consequently the terms biliary dyskinesia, papillary stenosis, and postcholecystectomy syndrome have all been used to describe this condition. Both stenosis and dyskinesia can obstruct flow through the sphincter of Oddi and can therefore cause retention of bile in the biliary tree and pancreatic juice in the pancreatic duct. Individuals with sphincter of Oddi dysfunction present with abdominal pain resembling that of structural or inflammatory disorders of the gallbladder, biliary tree or pancreas. Among other characteristics, the pain is typically in the upper part of the abdomen or in the right upper quadrant of the abdomen, lasts 30 minutes or longer, and is not associated with a structural abnormality that could lead to these symptoms. The disorder is classified into two subtypes: functional biliary sphincter of Oddi disorder, where there is no disturbance in pancreatic enzyme measurements, such as amylase and lipase; and, functional pancreatic sphincter of Oddi disorder, where pancreatic enzyme measurements are elevated. Attacks can be precipitated by opioid analgesics, particularly in patients having undergone a cholecystectomy or bariatric surgery. Classification Functional disorders of the gallbladder, bile duct and pancreas have been defined and classified by the Rome criteria for functional gastrointestinal disorders. The criteria outline three variants of functional disorders of the gallbladder, bile duct and pancreas, termed functional gallbladder disorder, functional biliary sphincter of Oddi disorder and functional pancreatic sphincter of Oddi disorder. All of the following criteria need to be met for as part of the definition of a functional disorder of the gallbladder: the pain must be located in the upper part of the abdomen and/or the right upper quadrant of the abdomen episodes of pain must last at least 30 minutes the symptoms must be recurrent, and occur at differing intervals the pain must incrementally increase to a "steady level" the pain must be severe enough the patients daily activities are affected, or that the patient must attend the emergency department the pain must not be relieved by any of bowel movements, change in posture, or antacids; and, other structural disorders that could explain the symptoms must be excluded. Functional gallbladder disorder Individuals are classified as having a functional gallbladder disorder if the above criteria are met, if the gallbladder is present, and if the testing of liver enzymes, conjugated bilirubin, and pancreatic enzymes (amylase and lipase) are normal. Functional biliary sphincter of Oddi disorder If all of the above criteria are met, individuals are classified as having a functional biliary sphincter of Oddi disorder, if the testing of pancreatic enzymes (amylase and lipase) is normal.The old Milwaukee classification of biliary sphincter of Oddi dysfunction (SOD) used to divide the condition into three subtypes: but it is no longer in use. Type I included patients with biliary-type abdominal pain, with all of altered liver enzymes on blood testing, dilated biliary ducts on ultrasound or ERCP, and delayed bile clearance on HIDA scan. Type II included patients with biliary-type abdominal pain associated with at least one of the following: altered liver enzymes on blood testing, dilated biliary ducts on imaging tests, and delayed bile clearance on HIDA scan. Biliary-type pain in the absence of any sign of biliary or pancreatic alteration was the so-called Type III biliary SOD. The hypothesis that this pain could be linked to SOD has been studied in a large trial published in JAMA (2014) where patients were randomized to sphincterotomy or sham surgery. Contrary to expectations, patients who were not subjected to sphincterotomy fared better. Overall, the investigators found that only 23% of the patients who underwent sphincterotomy improved versus 37% of the control group. The EPISOD trial has substantiated the ineffectiveness of endoscopic sphincterotomy in patients with these symptoms and SOD Type III is no longer considered to be a clinical entity. Characteristics Sphincter of Oddi dysfunction may be suggested by pain which seems to come from a biliary origin, which may or may not be associated with transient increases of liver or pancreatic enzymes. Common bile duct dilation and episodes of pancreatitis are also signs. Pathophysiology Two mechanisms are involved in the development of sphincter of Oddi dysfunction, either or both of which may be contributory to the condition: stenosis, or narrowing of the sphincter of Oddi (also termed papillary stenosis), and dyskinesia, or alteration in the function of the sphincter of Oddi (also termed biliary dyskinesia). Individuals with stenosis of the sphincter of Oddi typically have an elevated baseline pressure of the sphincter of Oddi, due to an anatomical problem that leads to narrowing of the sphincter, such as recurrent passage of gallstones through the ampulla of Vater, trauma to the sphincter from procedures such as endoscopic retrograde cholangiopancreatography or biliary surgery, or infections of the common bile duct. In contrast, dyskinesia of the sphincter of Oddi is a purely functional disorder, wherein there is intermittent obstruction of the bile duct due to inappropriate spasms. The reasons for dyskinesia of the sphincter of Oddi are not completely understood, but believed to be due to alteration in local gut hormones and peptides, such as cholecystokinin, which act on the sphincter or to altered neuronal control of the sphincter. Diagnosis For diagnosis, measures of liver biochemistry and pancreatic enzymes are performed. Along with ruling out structural abnormalities, normally by performing an abdominal ultrasound and endoscopic retrograde cholangiopancreatography (ERCP). Measurements of bile transit when performing ERCP are taken to help evaluate different treatment options. Sphincter of Oddi dysfunction is best diagnosed using manometry-an internal test done to measure the pressures within surrounding ducts to determine whether or not the muscle is functioning normally. Treatment Medication (to prevent spasms) or sphincterotomy (surgical procedure to cut the muscle) are the standard treatments for sphincter of Oddi dysfunction. One or the other may be better based on the classification of the condition. See also Stenosis Dyskinesia Bile References External links http://www.ddc.musc.edu/public/symptomsDiseases/diseases/pancreas/SOD.html
Subconjunctival bleeding	Subconjunctival bleeding, also known as subconjunctival hemorrhage or subconjunctival haemorrhage, is bleeding from a small blood vessel over the whites of the eye. It results in a red spot in the white of the eye. There is generally little to no pain and vision is not affected. Generally only one eye is affected.Natural causes can include coughing, vomiting, heavy lifting, straining to pass hard stools during acute constipation or the act of "pushing" or "bearing down" during labour/childbirth as these activities can increase the blood pressure in the vascular systems supplying the retina. There are up to four vascular retinal plexuses that are supplied by tiny, delicate capillaries whose walls if encountered with a sudden amount of force from blood will rupture. External causes can include direct impact/injury from an accidental bump or a physical altercation resulting in blunt force trauma. Risk factors include hypertension, diabetes, old age, and blood thinners. They occur in about 2% of newborns following a vaginal delivery. The blood occurs between the conjunctiva and the episclera. Diagnosis is generally based on the appearance.Generally no specific treatment is required and the condition improves in two to three weeks. Artificial tears may be used to help with any irritation. They occur relatively commonly. Both sexes are affected equally. Spontaneous bleeding occurs more commonly over the age of 50 while the traumatic type occurs more often in young males. Signs and symptoms A subconjunctival bleeding usually does not result in pain, although occasionally the affected eye may feel dry, rough, or scratchy. A subconjunctival bleeding initially appears bright-red underneath the transparent conjunctiva. Later, the bleeding may spread and become green or yellow as the hemoglobin is metabolized. It usually disappears within 2 weeks. Causes Mechanical Increased venous pressure (e.g. extreme g-force, straining, vomiting, choking, coughing or strangling) or from straining due to constipation External pressure changes:Atmospheric pressure changes due to aircraft altitude changes. Mask squeeze from diving without equalizing mask pressure during descent or from diving deeply in water Eye injury Head injury Laser eye surgery or other eye surgery Zygoma fracture (results in lateral subconjunctival bleeding) Medical conditions that cause increased venous pressure: Whooping cough or other extreme sneezing or coughing Severe hypertension Medical conditions that affect blood or blood vessels: Certain infections of the outside of the eye (conjunctivitis) where a virus or a bacterium weaken the walls of small blood vessels under the conjunctiva Coagulation disorder (congenital or acquired) including Ebola Acute hemorrhagic conjunctivitis (caused by Enterovirus 70 or Coxsackie A virus) LeptospirosisSubconjunctival bleeding in infants may be associated with scurvy (a vitamin C deficiency),abuse or traumatic asphyxia syndrome. Diagnosis Diagnosis is by visual inspection, by noting the typical finding of bright red discoloration confined to the white portion (sclera) of the eye. Management A subconjunctival bleeding is typically a self-limiting condition that requires no treatment unless there is evidence of an eye infection or there has been significant eye trauma. Artificial tears may be applied four to six times a day if the eye feels dry or scratchy. The elective use of aspirin is typically discouraged. References == External links ==
Grisels syndrome	Grisels syndrome is a non-traumatic subluxation of the atlanto-axial joint caused by inflammation of the adjacent tissues. This is a rare disease that usually affects children. Progressive throat and neck pain and neck stiffness can be followed by neurologic symptoms such as pain or numbness radiating to arms (radiculopathies). In extreme cases, the condition can lead to quadriplegia and even death from acute respiratory failure. The condition often follows soft tissue inflammation in the neck such as in cases of upper respiratory tract infections, peritonsillar or retropharyngeal abscesses. Post-operative inflammation after certain procedures such as adenoidectomy can also lead to this condition in susceptible individuals such as those with Down syndrome. Pathophysiology Pathophysiology of this disease consists of relaxation of the transverse ligament of the atlanto-axial joint. Diagnosis Diagnosis can be established using plain film x-rays as well as CT scan of the neck/cervical spine. Children with Down syndrome have inherently lax ligaments making them susceptible to this condition. In select cases, these children may require pre-operative imaging to assess the risk for complications after procedures such as adenoidectomy. Treatment Treatment includes anti-inflammatory medications and immobilization of the neck in addition to treatment of the offending infectious cause (if any) with appropriate antibiotics. Early treatment is crucial to prevent long-term sequelae. Surgical fusion may be required for residual instability of the joint. References Grisel P. Enucléation de latlas et torticollis naso-pharyngien Presse Med 1930;38:50–4. Mathern GW, Batzdorf U. Grisels syndrome: Cervical spine clinical, pathologic, and neurologic manifestations. Clin Orthop Relat Res. 1989 Jul;(244):131-46. C Bocciolini, D DallOlio, E Cunsolo, PP Cavazzuti, and P Laudadio, Grisels syndrome: a rare complication following adenoidectomy, Acta Otorhinolaryngol Ital. 2005 August; 25(4): 245–249. == External links ==
Pelvic congestion syndrome	Pelvic congestion syndrome, also known as pelvic vein incompetence, is a long term condition believed to be due to enlarged veins in the lower abdomen. The condition may cause chronic pain, such as a constant dull ache, which can be worsened by standing or sex. Pain in the legs or lower back may also occur.While the condition is believed to be due to blood flowing back into pelvic veins as a result of faulty valves in the veins, this hypothesis is not certain. The condition may occur or worsen during pregnancy. The presence of estrogen is believed to be involved in the mechanism. Diagnosis may be supported by ultrasound, CT scan, MRI, or laparoscopy.Early treatment options include medroxyprogesterone or nonsteroidal anti-inflammatory drugs (NSAIDs). Surgery to block the varicose veins may also be done. About 30% of women of reproductive age are affected. It is believed to be the cause of about a third of chronic pelvic pain cases. While pelvic venous insufficiency was identified in the 1850s it was only linked with pelvic pain in the 1940s. Signs and symptoms Women with this condition experience a constant pain that may be dull and aching, but is occasionally more acute. The pain is worse at the end of the day and after long periods of standing, and those affected get relief when they lie down. The pain is worse during or after sexual intercourse, and can be worse just before the onset of the menstrual period.Women with pelvic congestion syndrome have a larger uterus and a thicker endometrium. 56% of women manifest cystic changes to the ovaries, and many report other symptoms, such as dysmenorrhea, back pain, vaginal discharge, abdominal bloating, mood swings or depression, and fatigue. Causes Local pelvic hormonal milieu Venous outflow obstruction, such as May-Thurner syndrome, Nutcracker syndrome, Budd-Chiari syndrome, or left renal vein thrombosis External compression due to tumor (including fibroids, endometriosis), or scarring Diagnosis Diagnosis can be made using ultrasound or laparoscopy testing. The condition can also be diagnosed with a venogram, CT scan, or an MRI. Ultrasound is the diagnostic tool most commonly used. Some research has suggested that transvaginal duplex ultrasound is the best test for pelvic venous reflux. Treatment Early treatment options include pain medication using nonsteroidal anti-inflammatory drugs, and suppression of ovarian function.More advanced treatment includes a minimally invasive procedure performed by an Interventional Radiologist. This minimally invasive procedure involves stopping blood within the pelvic varicose veins using a minimally invasive procedure called a catheter directed embolization. The procedure rarely requires an overnight stay in hospital and is usually performed as an outpatient procedure, and is done using local anesthetic and moderate sedation. Patients report an 80% success rate, as measured by the amount of pain reduction experienced. See also Ovarian vein syndrome Nutcracker syndrome References == External links ==
Diaphragmatic rupture	Diaphragmatic rupture (also called diaphragmatic injury or tear) is a tear of the diaphragm, the muscle across the bottom of the ribcage that plays a crucial role in breathing. Most commonly, acquired diaphragmatic tears result from physical trauma. Diaphragmatic rupture can result from blunt or penetrating trauma and occurs in about 0.5% of all people with trauma.Diagnostic techniques include X-ray, computed tomography, and surgical techniques such as an explorative surgery. Diagnosis is often difficult because signs may not show up on X-ray, or signs that do show up appear similar to other conditions. Signs and symptoms include chest and abdominal pain, difficulty breathing, and decreased lung sounds. When a tear is discovered, surgery is needed to repair it. Injuries to the diaphragm are usually accompanied by other injuries, and they indicate that more severe injury may have occurred. The outcome often depends more on associated injuries than on the diaphragmatic injury itself. Since the pressure is higher in the abdominal cavity than the chest cavity, rupture of the diaphragm is almost always associated with herniation of abdominal organs into the chest cavity, which is called a diaphragmatic hernia. This herniation can interfere with breathing. Signs and symptoms Symptoms may include pain, orthopnea, (shortness of breath when lying flat), and coughing. In people with herniation of abdominal organs, signs of intestinal blockage or sepsis in the abdomen may be present. Bowel sounds may be heard in the chest, and shoulder or epigastric pain may be present. When the injury is not noticed right away, the main symptoms are those that indicate bowel obstruction. Causes Diaphragmatic rupture may be caused by blunt trauma, penetrating trauma, and by iatrogenic causes (as a result of medical intervention), for example during surgery to the abdomen or chest. It has also occurred spontaneously at the time of pregnancy or for no discernible reason. Injury to the diaphragm is reported to be present in 8% of cases of blunt chest trauma. In cases of blunt trauma, vehicle accidents and falls are the most common causes. Penetrating trauma has been reported to cause 12.3–20% of cases, but it has also been proposed as a more common cause than blunt trauma; discrepancies could be due to varying regional, social, and economic factors in the areas studied. Stab and gunshot wounds can cause diaphragmatic injuries. Clinicians are trained to suspect diaphragmatic rupture particularly if penetrating trauma has occurred to the lower chest or upper abdomen. With penetrating trauma, the contents of the abdomen may not herniate into the chest cavity right away, but they may do so later, causing the presentation to be delayed. Since the diaphragm moves up and down during breathing, penetrating trauma to various parts of the torso may injure the diaphragm; penetrating injuries as high as the third rib and as low as the twelfth have been found to injure the diaphragm. Iatrogenic cases have occurred as a complication of medical procedures involving the thorax or abdomen. It has occurred as a complication of thoracentesis and radiofrequency ablation. Mechanism Although the mechanism is unknown, it is proposed that a blow to the abdomen may raise the pressure within the abdomen so high that the diaphragm ruptures. Blunt trauma creates a large pressure gradient between the abdominal and thoracic cavities; this gradient, in addition to causing the rupture, can also cause abdominal contents to herniate into the thoracic cavity. Abdominal contents in the pleural space interfere with heart function and lung function. High intrathoracic pressure results in an increase in right atrial pressure, disrupting the filling of the heart and venous return of blood. As venous return determines cardiac output, this results in a reduction of cardiac output. If ventilation of the lung on the side of the tear is severely inhibited, hypoxemia (low blood oxygen) results. Usually, the rupture is on the same side as an impact. A blow to the side is three times more likely to cause diaphragmatic rupture than a blow to the front. Diagnosis Physical examinations are not accurate, as there is usually no specific physical sign that can be used to diagnose this condition. Thoracoscopic and laparoscopic methods can be accurate. Chest X-ray is known to be unreliable in diagnosing diaphragmatic rupture; it has low sensitivity and specificity for the injury. Often another injury such as pulmonary contusion masks the injury on the X-ray film. Half the time, initial X-rays are normal; in most of those that are not, hemothorax or pneumothorax is present. A nasogastric tube from the stomach may appear on the film in the chest cavity; this sign is pathognomonic for diaphragmatic rupture, but it is rare. The X-ray is better able to detect the injury when taken from the back with the person upright, but this is not usually possible because the person is usually not stable enough; thus it is usually taken from the front with the person lying supine. Positive pressure ventilation helps keep the abdominal organs from herniating into the chest cavity, but this also can prevent the injury from being discovered on an X-ray.A CT scan has an increased accuracy of diagnosis over X-ray, but no specific findings on a CT scan exist to establish a diagnosis. The free edge of a ruptured diaphragm may curl and become perpendicular to the chest wall, a sign known as a dangling diaphragm. A herniated organ may constrict at the location of a rupture, a sign known as the collar sign. If the liver herniates through a rupture on the right side, it may produce two signs known as the hump and band signs. The hump sign is a form of the collar sign on the right. The band sign is a bright line that intersects the liver. it is believed to result due to the ruptured diaphragm compressing. Although CT scanning increases chances that diaphragmatic rupture will be diagnosed before surgery, the rate of diagnosis before surgery is still only 31–43.5%. Another diagnostic method is laparotomy, but this misses diaphragmatic ruptures up to 15% of the time. Often diaphragmatic injury is discovered during a laparotomy that was undertaken because of another abdominal injury. Because laparotomies are more common in those with penetrating trauma than compared to those who experienced a blunt force injury, diaphragmatic rupture is found more often in these people. Thoracoscopy is more reliable in detecting diaphragmatic tears than laparotomy and is especially useful when chronic diaphragmatic hernia is suspected. Location Between 50 and 80% of diaphragmatic ruptures occur on the left side. It is possible that the liver, which is situated in the right upper quadrant of the abdomen, cushions the diaphragm. However, injuries occurring on the left side are also easier to detect in X-ray films. Half of diaphragmatic ruptures that occur on the right side are associated with liver injury. Injuries occurring on the right are associated with a higher rate of death and more numerous and serious accompanying injuries. Bilateral diaphragmatic rupture, which occurs in 1–2% of ruptures, is associated with a much higher death rate (mortality) than injuries that occur on just one side. Treatment Since the diaphragm is in constant motion with respiration, and because it is under tension, lacerations will not heal on their own. The injury usually becomes larger with time if not repaired. The main goals of surgery are to repair any injuries to the diaphragm and to move any herniated abdominal organs back to their original place. This is done be debriding nonviable tissue and closing the rupture. Most of the time, the injury is repaired during laparotomy. Early surgery is important, as diaphragmatic atrophy and adhesions occur over time. Sutures are used in the repair. Other injuries, such as hemothorax, may present a more immediate threat and may need to be treated first if they accompany diaphragmatic rupture. Video-assisted thoracoscopy may be used. Prognosis In most cases, isolated diaphragmatic rupture is associated with good outcome if it is surgically repaired. The death rate (mortality) for diaphragmatic rupture after blunt and penetrating trauma is estimated to be 15–40% and 10–30% respectively, but other injuries play a large role in determining outcome. Herniation of abdominal organs is present in 3–4% of people with abdominal trauma who present to a trauma center. Epidemiology Diaphragmatic injuries are present in 1–7% of people with significant blunt trauma and an average of 3% of abdominal injuries. A high body mass index may be associated with a higher risk of diaphragmatic rupture in people involved in vehicle accidents. Over 90% occur due to trauma from vehicle accidents. Due to the great force needed to rupture the diaphragm, it is rare for the diaphragm alone to be injured, especially in blunt trauma; other injuries are associated in as many as 80–100% of cases. In fact, if the diaphragm is injured, it is an indication that more severe injuries to organs may have occurred. Thus, the mortality after a diagnosis of diaphragmatic rupture is 17%, with most deaths due to lung complications. Common associated injuries include head injury, injuries to the aorta, fractures of the pelvis and long bones, and lacerations of the liver and spleen. Associated injuries occur in over three quarters of cases. History In 1579, Ambroise Paré made the first description of diaphragmatic rupture in a French artillery captain who had been shot eight months before his death. He died from complications of the rupture. Using autopsies, Paré also described diaphragmatic rupture in people who had suffered blunt and penetrating trauma. Reports of diaphragmatic herniation due to injury date back at least as far as the 17th century. Petit was the first to establish the difference between acquired and congenital diaphragmatic hernia, which results from a congenital malformation of the diaphragm. In 1888, Naumann repaired a hernia of the stomach into the left chest that was caused by trauma. Other animals Diaphragmatic rupture is a common and well-known complication of blunt abdominal trauma in cats and dogs. The organs that herniate into the pleural cavity are determined by the location of the rupture. They are most commonly circumferential tears that occur at the attachment of the diaphragm and rib. Is these cases, the organs that herniate may include the liver, small intestine, stomach, spleen, omentum, and/or uterus. Dorsal tears are uncommon, and may cause a kidney to herniate into the thorax. Symptoms include difficulty breathing, vomiting, collapse, and an absence of palpable organs in the abdomen. Symptoms can worsen quickly and be lethal, especially in the case of severe bleeding, bruised heart, or strangulation of herniated intestine. It is also possible that there may only be subtle signs, and the condition is only incidentally detected months to years after the injury during a medical scan. See also Diaphragmatic hernia Chest injury References == External links ==
Drug withdrawal	Drug withdrawal, drug withdrawal syndrome, or substance withdrawal syndrome, is the group of symptoms that occur upon the abrupt discontinuation or decrease in the intake of pharmaceutical or recreational drugs. In order for the symptoms of withdrawal to occur, one must have first developed a form of drug dependence. This may occur as physical dependence, psychological dependence or both. Drug dependence develops from consuming one or more substances over a period of time. Dependence arises in a dose-dependent manner and produces withdrawal symptoms that vary with the type of drug that is consumed. For example, prolonged use of an antidepressant medication is likely to cause a rather different reaction when discontinued compared to discontinuation of an opioid, such as heroin. Withdrawal symptoms from opiates include anxiety, sweating, vomiting, and diarrhea. Alcohol withdrawal symptoms include irritability, fatigue, shaking, sweating, and nausea. Withdrawal from nicotine can cause irritability, fatigue, insomnia, headache, and difficulty concentrating. Many prescription and legal nonprescription substances can also cause withdrawal symptoms when individuals stop consuming them, even if they were taken as directed by a physician. The route of administration, whether intravenous, intramuscular, oral or otherwise, can also play a role in determining the severity of withdrawal symptoms. There are different stages of withdrawal as well; generally, a person will start to feel bad (crash or come down), progress to feeling worse, hit a plateau, and then the symptoms begin to dissipate. However, withdrawal from certain drugs (barbiturates, benzodiazepines, alcohol, glucocorticoids) can be fatal. While it is seldom fatal to the user, withdrawal from opiates (and some other drugs) can cause miscarriage, due to fetal withdrawal. The term "cold turkey" is used to describe the sudden cessation use of a substance and the ensuing physiologic manifestations. The symptoms from withdrawal may be even more dramatic when the drug has masked prolonged malnutrition, disease, chronic pain, infections (common in intravenous drug use), or sleep deprivation, conditions that drug abusers often develop as a secondary consequence of the drug. When the drug is removed, these conditions may resurface and be confused with withdrawal symptoms. Genes that encode for the Alpha5 Nicotinic Acetylcholine Receptor affect nicotine and alcohol withdrawal symptoms. Effect on homeostasis Homeostasis is the bodys ability to maintain a certain chemical equilibrium in the brain and throughout the body. For example, the function of shivering in response to cold is to produce heat maintaining internal temperature at around 37 °C (98.6 °F). Homeostasis is impacted in many ways by drug usage and withdrawal. The internal systems perpetuate homeostasis by using different counter-regulatory methods in order to create a new state of balance based on the presence of the drug in the system. These methods include adapting the bodys levels of neurotransmitters, hormones, and other substances present to adjust for the addition of the drug to the body. Substances Examples (and ICD-10 code) of withdrawal syndrome include: F10.3 alcohol withdrawal syndrome (which can lead to delirium tremens) F11.3 opioid withdrawal, including methadone withdrawal F12.3 cannabis withdrawal F13.3 benzodiazepine withdrawal F14.3 cocaine withdrawal F15.3 caffeine withdrawal F17.3 nicotine withdrawal Prescription medicine As noted above, many drugs should not be stopped abruptly without the advice and supervision of a physician, especially if the medication induces dependence or if the condition they are being used to treat is potentially dangerous and likely to return once medication is stopped, such as diabetes, asthma, heart conditions and many psychological or neurological conditions, like epilepsy, depression, hypertension, schizophrenia and psychosis. The stopping of antipsychotics in schizophrenia and psychoses needs monitoring. The stopping of antidepressants for example, can lead to antidepressant discontinuation syndrome. With careful physician attention, however, medication prioritization and discontinuation can decrease costs, simplify prescription regimens, decrease risks of adverse drug events and poly-pharmacy, focus therapies where they are most effective, and prevent cost-related under-use of medications.Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D) warns that people with dementia are more likely to experience adverse effects, and to monitor carefully for withdrawal symptoms when ceasing medications for these people as they are both more likely to experience symptoms and less likely to be able to reliably report symptoms. Anti-hypertensive drugs The latest evidence does not have evidence of an effect due to discontinuing vs continuing medications used for treating elevated blood pressure or prevention of heart disease in older adults on all-case mortality and incidence of heart attack. The findings are based on low quality evidence suggesting it may be safe to stop anti-hypertensive medications. However, older adults should not stop any of their medications without talking to a healthcare professional. See also Chemical dependency Craving, a psychological withdrawal symptom Drug detoxification Drug tolerance Hangover Neonatal withdrawal Rebound effect Post-acute withdrawal syndrome (PAWS) == References ==
Lichen aureus	Lichen aureus is a skin condition characterized by the sudden appearance of one or several golden or rust-colored, closely packed macules or lichenoid papules.: 830 See also Pigmentary purpuric eruptions List of cutaneous conditions References == External links ==
Luteal phase	The menstrual cycle is on average 28 days in length. It begins with menses (day 1–7) during the follicular phase (day 1–14) and followed by ovulation (day 14) and ending with the luteal phase (day 14–28). Unlike the follicular phase which can vary in length among individuals, the luteal phase is typically fixed at approximately 14 days (i.e. days 14–28) and is characterized by changes to hormone levels, such as an increase in progesterone and estrogen levels, decrease in gonadotropins such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH), changes to the endometrial lining to promote implantation of the fertilized egg, and development of the corpus luteum. In the absence of fertilization by sperm, the corpus luteum atrophies leading to a decrease in progesterone and estrogen, an increase in FSH and LH, and shedding of the endometrial lining (menses) to begin the menstrual cycle again. Hormonal events After ovulation and release of the oocyte, the anterior pituitary hormones–follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are released and cause the remaining parts of the dominant follicle to transform into the corpus luteum. It continues to grow during the luteal phase after ovulation and produces significant amounts of hormones, particularly progesterone, and, to a lesser extent, estrogen and inhibin. Progesterone plays a vital role in making the endometrium receptive to implantation of the embryo and supportive of early pregnancy. High levels of progesterone inhibit the follicular growth. The increase in estrogen and progesterone also lead to increased basal body temperature during the luteal phase.The LH surge that occurs during ovulation triggers the release of the oocyte and its cumulus oophorus from the ovary and into the fallopian tube and triggers the oocyte to divide and enter metaphase of meiosis II (46 or 2n chromosome) and extrude its first polar body. The oocyte will only continue through meiosis and extrude its second polar body once it is fertilized. Ovulation occurs ~35 hours after the beginning of the LH surge or ~10 hours following the LH surge. Several days after ovulation, the increasing amount of estrogen produced by the corpus luteum may cause one or two days of fertile cervical mucus, lower basal body temperatures, or both. This is known as a "secondary estrogen surge".The hormones released by the corpus luteum suppress production of the FSH and LH from the anterior pituitary gland. The corpus luteum relies on LH activation on its receptors in order to survive. The loss of the corpus luteum can be prevented by implantation of an embryo: after implantation, human embryos produce human chorionic gonadotropin (hCG), which is structurally similar to LH and can preserve the corpus luteum. If implantation occurs, the corpus luteum will continue to produce progesterone for eight to twelve weeks, after which the placenta takes over this function. In the absence of fertilization, hCG is not produced and the corpus luteum will atrophy in 10–12 days (Luteolysis or luteal regression). The death of the corpus luteum results in falling levels of progesterone and estrogen. The drop in ovarian hormones releases negative feedback on LH and FSH, thereby increasing LH and FSH concentrations and leading to shedding of the endometrium and another round of ovarian follicle selection. Uterine events During the follicular phase in the menstrual cycle, the uterine endometrium is in the proliferative phase which is characterized by an increase in circulating estrogen produced by the developing follicle. Increased estradiol alters the endometrial lining and promotes proliferation of epithelial cells, thickening of the tissue, and elongation of the spiral arteries that provide nutrients to the growing tissue. Estrogen also makes the endometrium more sensitive to progesterone in preparation for the luteal phase. After ovulation and during the luteal phase, the uterine endometrium is in the secretory phase which is characterized by the production of progesterone from the growing corpus luteum. Progesterone inhibits endometrial proliferation, and preserves uterine tissue in preparation for fertilized egg implantation. At the end of the luteal phase, progesterone levels fall and the corpus luteum atrophies. The drop in progesterone leads to endometrial ischemia which will subsequently shed in the beginning of the next cycle at the start of menses. This last stage in the luteal or secretory phase may be called the ischemic phase and lasts just for one or two days. Symptoms Changes in the level of progesterone during this phase may cause typical symptoms of pre-menstrual syndrome (PMS), such as: Anxiety Headaches Mood swings Irritability Tender breasts Weight gain Trouble sleeping Changes in sexual desire Bloating == References ==
Brunner syndrome	Brunner syndrome is a rare genetic disorder associated with a mutation in the MAOA gene. It is characterized by lower than average IQ (typically about 85), problematic impulsive behavior (such as pyromania, hypersexuality and violence), sleep disorders and mood swings. It was identified in fourteen males from one family in 1993. It has since been discovered in additional families. Signs and symptoms Causes Brunner syndrome is caused by a monoamine oxidase A (MAOA) deficiency, which leads to an excess of monoamines in the brain, such as serotonin, dopamine, and norepinephrine (noradrenaline). In both mice and humans, a mutation was located on the eighth exon of the MAO-A gene, which created a dysfunctional MAO-A gene. The regular function of MAO-A, breaking down monoamines, is disrupted, and monoamines build up within the brain. Mice that lacked a functional MAO-A gene displayed higher levels of aggression, in comparison to mice with a functional MAO-A gene. Diagnosis Upon suspicion of Brunner syndrome and after having eliminated other potential suspects via means of differential diagnosis, Brunner syndrome is diagnosed by genetic testing for specific mutations of the MAOA gene. Since the syndrome is so rare, it is usually only suspected and tested for if there are other diagnosed instances of the syndrome in ones direct family. Treatment Progesterone & Rauwolfia serpentina (containing Reserpine) are a possible treatment as they both increase MAO-A activity. History Brunner Syndrome was described in 1993 by H.G. Brunner and his colleagues upon the discovery of a particular genetic defect in male members of a large Dutch family. Brunner found that all of the male family members with this defect reacted aggressively when angry, fearful, or frustrated. The defect discovered was later found to be a mutation in the gene that codes for monoamine oxidase A (MAOA gene). Brunner said that an "MAO-A deficiency is associated with a recognizable behavioural phenotype that included disturbed regulation of impulsive aggression".A letter published by Hebebrand and Klug (1995) criticized Brunners findings for not using strict DSM criteria. Society and culture Brunners findings have been used to argue that genetics, rather than decision-making processes, can cause criminal activity. Evidence supporting the genetic defense stems from both Brunners findings and a series of studies on mice. To prove the correlation between MAO-A deficiency and aggression in courts, it is often contended that individuals cannot be held accountable for their genes, and as a result, should not be held responsible for their dispositions and resulting actions. References == External links ==
Dural arteriovenous fistula	A dural arteriovenous fistula (DAVF) or malformation is an abnormal direct connection (fistula) between a meningeal artery and a meningeal vein or dural venous sinus. Signs and symptoms The most common signs/symptoms of DAVFs are: Pulsatile tinnitus Occipital bruit Headache Visual impairment PapilledemaPulsatile tinnitus is the most common symptom in patients, and it is associated with transverse-sigmoid sinus DAVFs. Carotid-cavernous DAVFs, on the other hand, are more closely associated with pulsatile exophthalmos. DAVFs may also be asymptomatic (e.g. cavernous sinus DAVFs). Location Most commonly found adjacent to dural sinuses in the following locations: Transverse (lateral) sinus, left-sided slightly more common than right Intratentorial From the posterior cavernous sinus, usually draining to the transverse or sigmoid sinuses Vertebral artery (posterior meningeal branch) Causes It is still unclear whether DAVFs are congenital or acquired. Current evidence supports transverse-sigmoid sinus junction dural malformations are acquired defects, occurring in response to thrombosis and collateral revascularization of a venous sinus. Diagnosis Cerebral angiography is the diagnostic standard. MRIs are typically normal but can identify venous hypertension as a result of arterial-venous shunting. Classification Borden Classification The Borden Classification of dural arteriovenous malformations or fistulas, groups into three types based upon their venous drainage: Type I: dural arterial supply drains anterograde into venous sinus. Type II: dural arterial supply drains into venous sinus. High pressure in sinus results in both anterograde drainage and retrograde drainage via subarachnoid veins. Type III: dural arterial supply drains retrograde into subarachnoid veins. Type I Type I dural arteriovenous fistulas are supplied by meningeal arteries and drain into a meningeal vein or dural venous sinus. The flow within the draining vein or venous sinus is anterograde. Type Ia – simple dural arteriovenous fistulas have a single meningeal arterial supply Type Ib – more complex arteriovenous fistulas are supplied by multiple meningeal arteriesThe distinction between Types Ia and Ib is somewhat specious as there is a rich system of meningeal arterial collaterals. Type I dural fistulas are often asymptomatic, do not have a high risk of bleeding and do not necessarily need to be treated. Type II The high pressure within a Type II dural AV fistula causes blood to flow in a retrograde fashion into subarachnoid veins which normally drain into the sinus. Typically this is because the sinus has outflow obstruction. Such draining veins form venous varices or aneurysms which can bleed. Type II fistulas need to be treated to prevent hemorrhage. The treatment may involve embolization of the draining sinus as well as clipping or embolization of the draining veins. Type III Type III dural AV fistulas drain directly into subarachnoid veins. These veins can form aneurysms and bleed. Type III dural fistulas need to be treated to prevent hemorrhage. Treatment can be as simple as clipping the draining vein at the site of the dural sinus. If treatment involves embolization, it will only typically be effective if the glue traverses the actual fistula and enters, at least slightly, the draining vein.The Cognard et al. Classification correlates venous drainage patterns with increasingly aggressive neurological clinical course. To simplify the above systems of DAVF classification, the two main factors that should be considered to determine aggressiveness of these lesions are: DAVF that have bleed (as opposed to those that have not before) DAVF resulting in cortical venous refluxTreatment decisions are more complicated and require consultation with a neurosurgeon and team familiar with these lesions. Treatment Indications Hemorrhage Neurologic dysfunction or refractory symptoms Interventions Embolization One approach used for treatment is embolization. A six-vessel angiogram is employed to determine the vascular supply to the fistula. Detachable coils, liquid embolic agents like NBCA, and onyx, or combinations of both are injected into the blood vessel to occlude the DAVF. Preoperative embolization can also be used to supplement surgery. Surgery DAVFs are also managed surgically. The operative approach varies depending on the location of the lesion. Stereotactic radiosurgery Stereotactic radiosurgery is used for obliterating DAVFs sometimes in conjunction with embolization or surgery, and is considered an important adjunct and sometimes a primary treatment method for non-aggressive DAVFs. Use of this method, however, is limited as obliteration occurs over the course of up to 2–3 years after the delivery of radiation. Epidemiology 10–15% of intracranial AV malformations are DAVFs. There is a higher preponderance in females (61–66%), and typically patients are in their fourth or fifth generation of life. DAVFs are rarer in children. Research External Manual Carotid Compression is Effective in Patients with Cavernous Sinus Dural Arteriovenous Fistulaetreatment. The patients were instructed to compress the carotid artery and jugular vein with the contralateral hand for ten seconds several times each hour (about 6 to 15 times per day).[1] See also Arteriovenous fistula References == External links ==
Testicular dysgenesis syndrome	Testicular dysgenesis syndrome is a male reproduction-related condition characterized by the presence of symptoms and disorders such as hypospadias, cryptorchidism, poor semen quality, and testicular cancer. The concept was first introduced by N.E. Skakkaebaek in a research paper along with the department of Growth and Reproduction in Copenhagen University. The paper suggests the origin and underlying cause of TDS can be detected as early as in fetal life, where environmental and genomic factors could affect the development of the male reproductive system. Causes Central to the cause of irreversible TDS are disruptions to early fetal testes development. This has genetic, environmental, and lifestyle components, however the rapid increase in the incidence of the disorders associated with TDS in the last decades indicates that it is under a powerful environmental influence. The fetal origins of TDS are reinforced by the high incidence of TDS disorders found occurring together in one individual. Associated with mutation of Insulin like Factor 3 (INSL3) Genetic Many genes have been implicated in the disorders of TDS, with genome wide association studies (GWAS) regularly identifying new gene variants that play a role in abnormal testes development. Some of these are specific to certain disorders, and some are part of a risk factor network that connect TGCC, hypospadias, cryptorchidism, poor semen quality. The majority of these genes are involved in fetal gonad development. Mutations in androgen receptor genes are highly implicated, as these are involved in penile development, testes descent, and testes development. Testicular germ cell cancer (TGCC) shows a strong genetic disposition, with the most significant gene variants being those linked to gonad formation and germ cell function. Environmental Exposure of a male fetus to substances that disrupt hormone systems, particularly chemicals that inhibit the action of androgens (male sex hormones) during the development of the reproductive system, has been shown to cause many of the characteristic TDS disorders. These include environmental estrogens and anti-androgens found in food and water sources that have been contaminated with synthetic hormones and pesticides used in agriculture. In historical cases, medicines given to pregnant women, like diethylstilbestrol (DES), have caused many of the features of TDS in fetuses exposed to this chemical during gestation. The impact of environmental chemicals is well documented in animal models. If a substance affects Sertoli and Leydig cell differentiation (a common feature of TDS disorders) at an early developmental stage, germ cell growth and testosterone production will be impaired. These processes are essential for testes descent and genitalia development, meaning that genital abnormalities like cryptorchidism or hypospadias may be present from birth, and fertility problems and TGCC become apparent during adult life. Severity or number of disorders may therefore be dependent on the timing of the environmental exposure. Environmental factors can act directly, or via epigenetic mechanisms, and it is likely that a genetic susceptibility augmented by environmental factors is the primary cause of TDS. Lifestyle Links between maternal smoking and TDS are tenuous, but there are stronger associations between maternal alcohol consumption and incidences of cryptorchidism in sons. Smoking does however affect the growth of a fetus, and low birth weight is shown to increase the likelihood of all the disorders encompassed by TDS. Maternal obesity, resulting in gestational diabetes, has also been shown to be a risk factor for impaired testes development and TDS symptoms in sons. Pathogenesis The TDS hypothesis proposes that testicular dysgenesis, which has various primary causes, can lead to abnormalities in Sertoli and/or Leydig cell function. This leads to both impaired germ cell development and hormonal changes during male sexual differentiation. For instance, insufficient production of testosterone can result in incomplete masculinisation, whilst reduced expression of insulin-like factor 3 can lead to incomplete testes descent. The downstream disorders of such abnormalities can include both genital malformations (e.g. hypospadias and cryptorchidism) and delayed reproductive disorders (e.g. testicular cancer and poor semen quality) which comprise TDS. Diagnosis Hypospadias Hypospadias presents as an abnormal location for the end of the urethra which is typically found on the distal end of the penis. It is generally diagnosed at birth from visual confirmation of the hallmark features. As well as an unusual location of the urethra, the prepuce (foreskin) is typically incomplete as well. The abnormal ‘hooded’ prepuce is what often draws attention to the condition but can occur separately to hypospadias. Cryptorchidism In Cryptorchidism a diagnosis is made from a physical examination which is performed when the baby is lacking one or both testes in the dependant portion of the scrotal sac. 70% of cryptorchid testes can be felt and are unable to be pulled into the scrotum or retreats quickly after being pulled into a higher position. In 30% of cases the testes cannot be felt indicating an intra-abdominal location. The risk factors for Cryptorchidism are: A family history of the condition Low birth weight Prematurity Poor semen quality Poor semen quality is measured not only by the number of sperm a man produces but also by how effective the sperm is at fertilising an egg. The motility and shape of the sperm are important for this role. A man with poor semen quality will often present with fertility problems which is defined as a couple trying to conceive for over 1 year with no success. Diagnosis can be made from semen analysis, taking a sample of the mans semen and running tests to count numbers and quality of the individual sperm. Testicular cancer The most common presentation of testicular cancer is a hard, painless lump which can be felt on one of the testis. It is either noticed by a clinician during a routine examination, or the patient themselves. Risk factors for TC include: Cryptorchidism Family history Previous testicular cancerThe diagnosis is confirmed in different ways. An ultrasound scan can be used to diagnose to a 90-95% accuracy. Bloods can also be taken to look for elevated tumour markers which is also used to analyse the patients response to treatment. 80% of testicular cancer cases are from the 20-34 year old age range == References ==
Keshan disease	Keshan disease is a congestive cardiomyopathy caused by a combination of dietary deficiency of selenium and the presence of a mutated strain of Coxsackievirus, named after Keshan County of Heilongjiang province, Northeast China, where symptoms were first noted. These symptoms were later found prevalent in a wide belt extending from northeast to southwest China, all due to selenium-deficient soil. The disease peaked in 1960–1970, killing thousands of people.Often fatal, the disease affects children and women of child-bearing age, characterized by heart failure and pulmonary edema. Over decades, supplementation with selenium reduced this condition.It had been linked to the coxsackie B virus. Current research suggests that the lack of selenium results in a more virulent strain of the coxsackievirus becoming the dominant viral species present in the population of virus, but the mechanism of this selection event is unclear.Keshan disease can also lead to higher rates of cancer, cardiovascular disease, hypertension, and strokes. In addition, an individual can experience eczema, psoriasis, arthritis, cataracts, alcoholism, and infections. Signs and symptoms Cardiac arrythmias,dizziness,fast breathing,shortness of breath(PULMONARY EDEMA) Diagnosis Prevention It is hard to consider Keshan disease extremely preventable because the only way to ensure that the individual is getting enough selenium would be to test the soil in the area. However, one way that selenium intake can be improved is to increase intake of foods that are rich with selenium. Examples include Brazil nuts, onions, canned tuna, beef, cod, turkey, chicken breast, enriched pasta, egg, cottage cheese, oatmeal, white or brown rice, and garlic. If the individual lives in an area that does not have selenium enriched soil, dietary supplementation should be considered. To determine whether or not an individual is selenium deficient, blood testing is performed. Treatments The treatment for Keshan disease is selenium supplementation. The recommended amounts are fifty-five micrograms of selenium per day for adult men and women, sixty micrograms a day for women during pregnancy and seventy micrograms per day for women after pregnancy. A doctor may insist that if a man is sexually active, he may have to take up to seventy micrograms of selenium per day. A doctor may also recommend that the individual take vitamin E; selenium and vitamin E are medically linked and seem to work together. An individual will also be advised to have a diet that includes seafood, meats such as kidney, and liver, and some grains and seeds; all of these are high in selenium. Brewers yeast and wheat germ both contain high levels of selenium. Garlic, onions, mushroom, broccoli, tomatoes, radishes, and Swiss chard may be good sources of selenium if the soil in which they are grown contains it. An individual will have to be monitored once they begin to take the selenium supplements, due to the fact that too much of it can cause balding, intestinal distress, weakness, and slow mental functioning. Individuals in China with the disease treat it with a herb called Astragalus, which accumulates selenium from the soil. Living with Keshan disease An individual will most likely be prescribed selenium supplements (in the form of selenomethionine) or have injections of this mineral. Other recommendations for managing Keshan disease are to increase consumption of foods rich in selenium in addition to supplements, avoid alcohol, monitor side effects to medications, and increase sleep. Cardiac surgery (implants, stents or full heart transplant) may be advised. See also Selenium deficiency Kashin–Beck disease References == External links ==
Adverse drug reaction	An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. The meaning of this term differs from the term "side effect" because side effects can be beneficial as well as detrimental. The study of ADRs is the concern of the field known as pharmacovigilance. An adverse drug event (ADE) refers to any unexpected and inappropriate occurrence at the time a drug is used, whether or not associated with the administration of the drug. An ADR is a special type of ADE in which a causative relationship can be shown. ADRs are only one type of medication-related harm, as harm can also be caused by omitting to take indicated medications. Classification ADRs may be classified by e.g. cause and severity. Cause Type A: Augmented pharmacologic effects - dose dependent and predictableType A reactions, which constitute approximately 80% of adverse drug reactions, are usually a consequence of the drugs primary pharmacological effect (e.g. bleeding when using the anticoagulant warfarin) or a low therapeutic index of the drug (e.g. nausea from digoxin), and they are therefore predictable. They are dose-related and usually mild, although they may be serious or even fatal (e.g. intracranial bleeding from warfarin). Such reactions are usually due to inappropriate dosage, especially when drug elimination is impaired. The term side effects is often applied to minor type A reactions.Type B: IdiosyncraticTypes A and B were proposed in the 1970s, and the other types were proposed subsequently when the first two proved insufficient to classify ADRs. Seriousness The U.S Food and Drug Administration defines a serious adverse event as one when the patient outcome is one of the following: Death Life-threatening Hospitalization (initial or prolonged) Disability - significant, persistent, or permanent change, impairment, damage or disruption in the patients body function/structure, physical activities or quality of life. Congenital abnormality Requires intervention to prevent permanent impairment or damageSeverity is a point on an arbitrary scale of intensity of the adverse event in question. The terms "severe" and "serious", when applied to adverse events, are technically very different. They are easily confused but can not be used interchangeably, requiring care in usage. A headache is severe if it causes intense pain. There are scales like "visual analog scale" that help clinicians assess the severity. On the other hand, a headache is not usually serious (but may be in case of subarachnoid haemorrhage, subdural bleed, even a migraine may temporally fit criteria), unless it also satisfies the criteria for seriousness listed above. Location Adverse effects may be local, i.e. limited to a certain location, or systemic, where medication has caused adverse effects throughout the systemic circulation. For instance, some ocular antihypertensives cause systemic effects, although they are administered locally as eye drops, since a fraction escapes to the systemic circulation. Mechanisms As research better explains the biochemistry of drug use, fewer ADRs are Type B and more are Type A. Common mechanisms are: Abnormal pharmacokinetics due to genetic factors comorbid disease states Synergistic effects between either a drug and a disease two drugs Antagonism effects between either a drug and a disease two drugs Abnormal pharmacokinetics Comorbid disease states Various diseases, especially those that cause renal or hepatic insufficiency, may alter drug metabolism. Resources are available that report changes in a drugs metabolism due to disease states.The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D) criteria warns that people with dementia are more likely to experience adverse effects, and that they are less likely to be able to reliably report symptoms. Genetic factors Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation. Pharmacogenomics is the study of the inherited basis for abnormal drug reactions. Phase I reactions Inheriting abnormal alleles of cytochrome P450 can alter drug metabolism. Tables are available to check for drug interactions due to P450 interactions.Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine Phase II reactions Inheriting abnormal N-acetyltransferase which conjugated some drugs to facilitate excretion may affect the metabolism of drugs such as isoniazid, hydralazine, and procainamide.Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine. Interactions with other drugs The risk of drug interactions is increased with polypharmacy. Protein binding These interactions are usually transient and mild until a new steady state is achieved. These are mainly for drugs without much first-pass liver metabolism. The principal plasma proteins for drug binding are: albumin α1-acid glycoprotein lipoproteinsSome drug interactions with warfarin are due to changes in protein binding. Cytochrome P450 Patients have abnormal metabolism by cytochrome P450 due to either inheriting abnormal alleles or due to drug interactions. Tables are available to check for drug interactions due to P450 interactions. Synergistic effects An example of synergism is two drugs that both prolong the QT interval. Assessing causality Causality assessment is used to determine the likelihood that a drug caused a suspected ADR. There are a number of different methods used to judge causation, including the Naranjo algorithm, the Venulet algorithm and the WHO causality term assessment criteria. Each have pros and cons associated with their use and most require some level of expert judgement to apply. An ADR should not be labeled as certain unless the ADR abates with a challenge-dechallenge-rechallenge protocol (stopping and starting the agent in question). The chronology of the onset of the suspected ADR is important, as another substance or factor may be implicated as a cause; co-prescribed medications and underlying psychiatric conditions may be factors in the ADR.Assigning causality to a specific agent often proves difficult, unless the event is found during a clinical study or large databases are used. Both methods have difficulties and can be fraught with error. Even in clinical studies some ADRs may be missed as large numbers of test individuals are required to find that adverse drug reaction. Psychiatric ADRs are often missed as they are grouped together in the questionnaires used to assess the population. Monitoring bodies Many countries have official bodies that monitor drug safety and reactions. On an international level, the WHO runs the Uppsala Monitoring Centre, and the European Union runs the European Medicines Agency (EMA). In the United States, the Food and Drug Administration (FDA) is responsible for monitoring post-marketing studies. In Canada, the Marketed Health Products Directorate of Health Canada is responsible for the surveillance of marketed health products. In Australia, the Therapeutic Goods Administration (TGA) conducts postmarket monitoring of therapeutic products. In the UK the Yellow Card Scheme was established in 1963. Epidemiology A study by the Agency for Healthcare Research and Quality (AHRQ) found that in 2011, sedatives and hypnotics were a leading source for adverse drug events seen in the hospital setting. Approximately 2.8% of all ADEs present on admission and 4.4% of ADEs that originated during a hospital stay were caused by a sedative or hypnotic drug. A second study by AHRQ found that in 2011, the most common specifically identified causes of adverse drug events that originated during hospital stays in the U.S. were steroids, antibiotics, opiates/narcotics, and anticoagulants. Patients treated in urban teaching hospitals had higher rates of ADEs involving antibiotics and opiates/narcotics compared to those treated in urban nonteaching hospitals. Those treated in private, nonprofit hospitals had higher rates of most ADE causes compared to patients treated in public or private, for-profit hospitals.MRH is common after hospital discharge in older adults, but methodological inconsistencies between studies and a paucity of data on risk factors limits clear understanding of the epidemiology. There was a wide range in incidence, from 0.4% to 51.2% of participants, and 35% to 59% of harm was preventable. Medication related harm incidence within 30 days after discharge ranged from 167 to 500 events per 1,000 individuals discharged (17–51% of individuals).In the U.S., females had a higher rate of ADEs involving opiates and narcotics than males in 2011, while male patients had a higher rate of anticoagulant ADEs. Nearly 8 in 1,000 adults aged 65 years or older experienced one of the four most common ADEs (steroids, antibiotics, opiates/narcotics, and anticoagulants) during hospitalization. A study showed that 48% of patients had an adverse drug reaction to at least one drug, and pharmacist involvement helps to pick up adverse drug reactions.In 2012, McKinsey & Company concluded that the cost of the 50-100 million preventable error-related adverse drug events would be between US$18–115 billion. See also References Further reading Incidence of adverse drug reactions in human immune deficiency virus-positive patients using highly active antiretroviral therapy PMC 3312730 == External links ==
Narcolepsy	Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affected also experience episodes of sudden loss of muscle strength, known as cataplexy. Narcolepsy paired with cataplexy is evidenced to be an autoimmune disorder. These experiences of cataplexy can be brought on by strong emotions. Less commonly, there may be vivid hallucinations or an inability to move (sleep paralysis) while falling asleep or waking up. People with narcolepsy tend to sleep about the same number of hours per day as people without, but the quality of sleep tends to be lessened.Narcolepsy is a clinical syndrome of hypothalamic disorder, however, the exact cause of narcolepsy is unknown, with potentially several causes. In up to 10% of cases, there is a family history of the disorder. Often, those affected have low levels of the neuropeptide orexin, which may be due to an autoimmune disorder triggered in genetically susceptible individuals by infection with H1N1 influenza. In rare cases, narcolepsy can be caused by traumatic brain injury, tumors, or other diseases affecting the parts of the brain that regulate wakefulness or REM sleep. Diagnosis is typically based on the symptoms and sleep studies, after ruling out other potential causes. Excessive daytime sleepiness can also be caused by other sleep disorders such as sleep apnea, major depressive disorder, anemia, heart failure, drinking alcohol and not getting enough sleep. Cataplexy may be mistaken for seizures.While there is no cure, a number of lifestyle changes and medications may help. Lifestyle changes include taking regular short naps and sleep hygiene. Medications used include modafinil, sodium oxybate and methylphenidate. While initially effective, tolerance to the benefits may develop over time. Tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) may improve cataplexy.Estimates of frequency range from 0.2 to 600 per 100,000 people in various countries. The condition often begins in childhood, with males and females being affected equally. Untreated narcolepsy increases the risk of motor vehicle collisions and falls.Narcolepsy can occur anytime between early childhood and 50 years typically, however, there is no upper age limit to getting it, 15 and 36 years of age being the peak time periods of when it occurs. Signs and symptoms There are two main characteristics of narcolepsy: excessive daytime sleepiness and abnormal REM sleep. Excessive daytime sleepiness occurs even after adequate night time sleep. A person with narcolepsy is likely to become drowsy or fall asleep, often at inappropriate or undesired times and places, or just be very tired throughout the day. Narcoleptics may not be able to experience the amount of restorative deep sleep that healthy people experience due to abnormal REM regulation – they are not "over-sleeping". Narcoleptics typically have higher REM sleep density than non-narcoleptics, but also experience more REM sleep without atonia. Many narcoleptics have sufficient REM sleep, but do not feel refreshed or alert throughout the day. This can feel like living their entire lives in a constant state of sleep deprivation.Excessive sleepiness can vary in severity, and it appears most commonly during monotonous situations that dont require much interaction. Daytime naps may occur with little warning and may be physically irresistible. These naps can occur several times a day. They are typically refreshing, but only for a few hours or less. Vivid dreams may be experienced on a regular basis, even during very brief naps. Drowsiness may persist for prolonged periods or remain constant. In addition, night-time sleep may be fragmented, with frequent awakenings. A second prominent symptom of narcolepsy is abnormal REM sleep. Narcoleptics are unique in that they enter into the REM phase of sleep in the beginnings of sleep, even when sleeping during the day.The classic symptoms of the disorder, often referred to as the "tetrad of narcolepsy," are cataplexy, sleep paralysis, hypnagogic hallucinations, and excessive daytime sleepiness. Other symptoms may include automatic behaviors and night-time wakefulness. These symptoms may not occur in all people with narcolepsy. Cataplexy is an episodic loss of muscle function, ranging from slight weakness such as limpness at the neck or knees, sagging facial muscles, weakness at the knees often referred to as "knee buckling", or inability to speak clearly, to a complete body collapse. Episodes may be triggered by sudden emotional reactions such as laughter, anger, surprise, or fear. The person remains conscious throughout the episode. In some cases, cataplexy may resemble epileptic seizures. Usually speech is slurred and vision is impaired (double vision, inability to focus), but hearing and awareness remain normal. Cataplexy also has a severe emotional impact on narcoleptics, as it can cause extreme anxiety, fear, and avoidance of people or situations that might elicit an attack. Cataplexy is generally considered to be unique to narcolepsy and is analogous to sleep paralysis in that the usually protective paralysis mechanism occurring during sleep is inappropriately activated. The opposite of this situation (failure to activate this protective paralysis) occurs in rapid eye movement behavior disorder. Periods of wakefulness at night Sleep paralysis is the temporary inability to talk or move when waking (or less often, when falling asleep). It may last a few seconds to minutes. This is often frightening but is not dangerous. Hypnagogic hallucinations are vivid, often frightening, dreamlike experiences that occur while dozing or falling asleep. Hypnopompic hallucinations refer to the same sensations while awakening from sleep. These hallucinations may manifest in the form of visual or auditory sensations.In most cases, the first symptom of narcolepsy to appear is excessive and overwhelming daytime sleepiness. The other symptoms may begin alone or in combination months or years after the onset of the daytime naps. There are wide variations in the development, severity, and order of appearance of cataplexy, sleep paralysis, and hypnagogic hallucinations in individuals. Only about 20 to 25 percent of people with narcolepsy experience all four symptoms. The excessive daytime sleepiness generally persists throughout life, but sleep paralysis and hypnagogic hallucinations may not. Many people with narcolepsy also have insomnia for extended periods of time. The excessive daytime sleepiness and cataplexy often become severe enough to cause serious problems in a persons social, personal, and professional life. Normally, when an individual is awake, brain waves show a regular rhythm. When a person first falls asleep, the brain waves become slower and less regular, which is called non-rapid eye movement (NREM) sleep. After about an hour and a half of NREM sleep, the brain waves begin to show a more active pattern again, called REM sleep (rapid eye movement sleep), when most remembered dreaming occurs. Associated with the EEG-observed waves during REM sleep, muscle atonia is present called REM atonia.In narcolepsy, the order and length of NREM and REM sleep periods are disturbed, with REM sleep occurring at sleep onset instead of after a period of NREM sleep. Also, some aspects of REM sleep that normally occur only during sleep, like lack of muscular control, sleep paralysis, and vivid dreams, occur at other times in people with narcolepsy. For example, the lack of muscular control can occur during wakefulness in a cataplexy episode; it is said that there is an intrusion of REM atonia during wakefulness. Sleep paralysis and vivid dreams can occur while falling asleep or waking up. Simply put, the brain does not pass through the normal stages of dozing and deep sleep but goes directly into (and out of) rapid eye movement (REM) sleep.As a consequence night time sleep does not include as much deep sleep, so the brain tries to "catch up" during the day, hence excessive daytime sleepiness. People with narcolepsy may visibly fall asleep at unpredicted moments (such motions as head bobbing are common). People with narcolepsy fall quickly into what appears to be very deep sleep, and they wake up suddenly and can be disoriented when they do (dizziness is a common occurrence). They have very vivid dreams, which they often remember in great detail. People with narcolepsy may dream even when they only fall asleep for a few seconds. Along with vivid dreaming, people with narcolepsy are known to have audio or visual hallucinations prior to falling asleep.Narcoleptics can gain excess weight; children can gain 20 to 40 lb (9 to 18 kg) when they first develop narcolepsy; in adults the body-mass index is about 15% above average. Causes The exact cause of narcolepsy is unknown, and it may be caused by several distinct factors. The mechanism involves the loss of orexin-releasing neurons within the lateral hypothalamus (about 70,000 neurons).Some researches indicated that people with type 1 narcolepsy (narcolepsy with cataplexy) have a lower level of orexin (hypocretin), which is a chemical contributing to the regulation of wakefulness and REM Sleep. It also acts as a neurotransmitter to enable nerve cells to communicate.In up to 10% of cases there is a family history of the disorder. Family history is more common in narcolepsy with cataplexy. There is a strong link with certain genetic variants, which may make T-cells susceptible to react to the orexin-releasing neurons (autoimmunity) after being stimulated by infection with H1N1 influenza. In addition to genetic factors, low levels of orexin peptides have been correlated with a history of infection, diet, contact with toxins such as pesticides, and brain injuries due to head trauma, brain tumors or strokes. Genetics The primary genetic factor that has been strongly implicated in the development of narcolepsy involves an area of chromosome 6 known as the human leukocyte antigen (HLA) complex. Specific variations in HLA genes are strongly correlated with the presence of narcolepsy (HLA DQB106:02, frequently in combination with HLA DRB115:01); however, these variations are not required for the condition to occur and sometimes occur in individuals without narcolepsy. These genetic variations in the HLA complex are thought to increase the risk of an auto-immune response to orexin-releasing neurons in the lateral hypothalamus.The allele HLA-DQB106:02 of the human gene HLA-DQB1 was reported in more than 90% of people with narcolepsy, and alleles of other HLA genes such as HLA-DQA101:02 have been linked. A 2009 study found a strong association with polymorphisms in the TRAC gene locus (dbSNP IDs rs1154155, rs12587781, and rs1263646). A 2013 review article reported additional but weaker links to the loci of the genes TNFSF4 (rs7553711), Cathepsin H (rs34593439), and P2RY11-DNMT1 (rs2305795). Another gene locus that has been associated with narcolepsy is EIF3G (rs3826784). H1N1 Influenza Type 1 narcolepsy is caused by hypocretin/orexin neuronal loss. T-cells have been demonstrated to be cross-reactive to both a particular piece of the hemagglutinin flu protein of the pandemic 2009 H1N1 and the amidated terminal ends of the secreted hypocretin peptides.Genes associated with narcolepsy mark the particular HLA heterodimer (DQ0602) involved in presentation of these antigens and modulate expression of the specific T cell receptor segments (TRAJ24 and TRBV4-2) involved in T cell receptor recognition of these antigens, suggesting causality.A link between GlaxoSmithKlines H1N1 flu vaccine Pandemrix and narcolepsy has been found in both children and adults. In 2010, Finlands National Institute of Health and Welfare recommended that Pandemrix vaccinations be suspended pending further investigation into narcolepsy. In 2018, it was demonstrated that T-cells stimulated by Pandemrix were cross-reactive by molecular mimicry with part of the hypocretin peptide, the loss of which is associated with type I narcolepsy. Pathophysiology Loss of neurons Orexin, otherwise known as hypocretin, is a neuropeptide that acts within the brain to regulate appetite and wakefulness as well as a number of other cognitive and physiological processes. Loss of these orexin-producing neurons causes narcolepsy and most individuals with narcolepsy have a reduced number of these neurons in their brains. Selective destruction of the HCRT/OX neurons with preservation of proximate structures suggests a highly specific autoimmune pathophysiology. Cerebrospinal fluid HCRT-1/OX-A is undetectable in up to 95% of patients with type 1 narcolepsy.The system which regulates sleep, arousal, and transitions between these states in humans is composed of three interconnected subsystems: the orexin projections from the lateral hypothalamus, the reticular activating system, and the ventrolateral preoptic nucleus. In narcoleptic individuals, these systems are all associated with impairments due to a greatly reduced number of hypothalamic orexin projection neurons and significantly fewer orexin neuropeptides in cerebrospinal fluid and neural tissue, compared to non-narcoleptic individuals. Those with narcolepsy generally experience the REM stage of sleep within five minutes of falling asleep, while people who do not have narcolepsy (unless they are significantly sleep deprived) do not experience REM until after a period of slow-wave sleep, which lasts for about the first hour or so of a sleep cycle. Disturbed sleep states The neural control of normal sleep states and the relationship to narcolepsy are only partially understood. In humans, narcoleptic sleep is characterized by a tendency to go abruptly from a waking state to REM sleep with little or no intervening non-REM sleep. The changes in the motor and proprioceptive systems during REM sleep have been studied in both human and animal models. During normal REM sleep, spinal and brainstem alpha motor neuron hyperpolarization produces almost complete atonia of skeletal muscles via an inhibitory descending reticulospinal pathway. Acetylcholine may be one of the neurotransmitters involved in this pathway. In narcolepsy, the reflex inhibition of the motor system seen in cataplexy has features normally seen only in normal REM sleep. Diagnosis The third edition of the International Classification of Sleep Disorders (ICSD-3) differentiates between narcolepsy with cataplexy (type 1) and narcolepsy without cataplexy (type 2), while the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) uses the diagnosis of narcolepsy to refer to type 1 narcolepsy only. The DSM-5 refers to narcolepsy without cataplexy as hypersomnolence disorder. The most recent edition of the International Classification of Diseases, ICD-11, currently identifies three types of narcolepsy: type 1 narcolepsy, type 2 narcolepsy, and unspecified narcolepsy.ICSD-3 diagnostic criteria posits that the individual must experience "daily periods of irrepressible need to sleep or daytime lapses into sleep" for both subtypes of narcolepsy. This symptom must last for at least three months. For a diagnosis of type 1 narcolepsy, the person must present with either cataplexy, a mean sleep latency of less than 8 minutes, and two or more sleep-onset REM periods (SOREMPs), or they must present with a hypocretin-1 concentration of less than 110 pg/mL. A diagnosis of type 2 narcolepsy requires a mean sleep latency of less than 8 minutes, two or more SOREMPs, and a hypocretin-1 concentration of more than 110 pg/mL. In addition, the hypersomnolence and sleep latency findings cannot be better explained by other causes.DSM-5 narcolepsy criteria requires that the person to display recurrent periods of "an irrepressible need to sleep, lapsing into sleep, or napping" for at least three times a week over a period of three months. The individual must also display one of the following: cataplexy, hypocretin-1 concentration of less than 110 pg/mL, REM sleep latency of less than 15 minutes, or a multiple sleep latency test (MSLT) showing sleep latency of less than 8 minutes and two or more SOREMPs. For a diagnosis of hypersomnolence disorder, the individual must present with excessive sleepiness despite at least 7 hours of sleep as well as either recurrent lapses into daytime sleep, nonrestorative sleep episodes of 9 or more hours, or difficulty staying awake after awakening. In addition, the hypersomnolence must occur at least three times a week for a period of three months, and must be accompanied by significant distress or impairment. It also cannot be explained by another sleep disorder, coexisting mental or medical disorders, or medication. Tests Diagnosis is relatively easy when all the symptoms of narcolepsy are present, but if the sleep attacks are isolated and cataplexy is mild or absent, diagnosis is more difficult. Three tests that are commonly used in diagnosing narcolepsy are polysomnography (PSG), the multiple sleep latency test (MSLT), and the Epworth Sleepiness Scale (ESS). These tests are usually performed by a sleep specialist.Polysomnography involves the continuous recording of sleep brain waves and a number of nerve and muscle functions during night time sleep. When tested, people with narcolepsy fall asleep rapidly, enter REM sleep early, and may often awaken during the night. The polysomnogram also helps to detect other possible sleep disorders that could cause daytime sleepiness.The Epworth Sleepiness Scale is a brief questionnaire that is administered to determine the likelihood of the presence of a sleep disorder, including narcolepsy.The multiple sleep latency test is performed after the person undergoes an overnight sleep study. The person will be asked to sleep once every 2 hours, and the time it takes for them to do so is recorded. Most individuals will fall asleep within 5 to 8 minutes, as well as display REM sleep faster than non-narcoleptic people.Measuring orexin levels in a persons cerebrospinal fluid sampled in a spinal tap may help in diagnosing narcolepsy, with abnormally low levels serving as an indicator of the disorder. This test can be useful when MSLT results are inconclusive or difficult to interpret. Treatment Orexin replacement People with narcolepsy can be substantially helped, but not cured. However, the technology exists in early form such as experiments in using the prepro-orexin transgene via gene editing restored normal function in mice models by making other neurons produce orexin after the original set have been destroyed, or replacing the missing orexinergic neurons with hypocretin stem cell transplantation, are both steps in that direction for fixing the biology effectively permanently once applied in humans. Additionally effective ideal non-gene editing and chemical-drug methods involve hypocretin treatments methods such as future drugs like hypocretin agonists (such as danavorexton) or hypocretin replacement, in the form of hypocretin 1 given intravenous (injected into the veins), intracisternal (direct injection into the brain), and intranasal (sprayed through the nose), the latter being low in efficacy, at the low amount used in current experiments but may be effective at very high doses in the future. Behavioral General strategies like people and family education, sleep hygiene and medication compliance, and discussion of safety issues for example driving license can be useful. Potential side effects of medication can also be addressed. Regular follow-up is useful to be able to monitor the response to treatment, to assess the presence of other sleep disorders like obstructive sleep apnea, and to discuss psychosocial issues.In many cases, planned regular short naps can reduce the need for pharmacological treatment of the EDS, but only improve symptoms for a short duration. A 120-minute nap provided benefit for 3 hours in the persons alertness whereas a 15-minute nap provided no benefit. Daytime naps are not a replacement for night time sleep. Ongoing communication between the health care provider, person, and their family members is important for optimal management of narcolepsy. Medications The main treatment of excessive daytime sleepiness in narcolepsy is central nervous system stimulants such as methylphenidate, amphetamine, dextroamphetamine, modafinil, and armodafinil. In late 2007 an alert for severe adverse skin reactions to modafinil was issued by the FDA. Pemoline was previously used but was withdrawn due to toxicity.Another drug that is used is atomoxetine, a non-stimulant and a norepinephrine reuptake inhibitor (NRI), which has no addiction liability or recreational effects. Other NRIs like viloxazine and reboxetine have also been used in the treatment of narcolepsy. Additional related medications include mazindol and selegiline.Another FDA-approved treatment option for narcolepsy is sodium oxybate, also known as sodium gamma-hydroxybutyrate (GHB). It can be used for cataplexy associated with narcolepsy and excessive daytime sleepiness associated with narcolepsy. Several studies also showed that sodium oxybate is effective to treat cataplexy.Solriamfetol is a new molecule indicated for narcolepsy of type 1 and 2. Solriamfetol works by inhibiting the reuptake of the monoamines via the interaction with both the dopamine transporter and the norepinephrine transporter. This mechanism differs from that of the wake-promoting agents modafinil and armodafinil. These are thought to bind primarily at the dopamine transporter to inhibit the reuptake of dopamine. Solriamfetol also differs from amphetamines as it does not promote the release of norepinephrine in the brain.Narcolepsy has sometimes been treated with selective serotonin reuptake inhibitors and tricyclic antidepressants, such as clomipramine, imipramine, or protriptyline, as well as other drugs that suppress REM sleep. Venlafaxine, an antidepressant which blocks the reuptake of serotonin and norepinephrine, has shown usefulness in managing symptoms of cataplexy, however, it has notable side-effects including sleep disruption. The antidepressant class is used mainly for the treatment of cataplexy, for people with narcolepsy without cataplexy these are usually not used. Children Common behavioral treatments for childhood narcolepsy include improved sleep hygiene, scheduled naps, and physical exercise.Many medications are used in treating adults and may be used to treat children. These medications include central nervous system stimulants such as methylphenidate, modafinil, amphetamine, and dextroamphetamine. Other medications, such as sodium oxybate or atomoxetine may also be used to counteract sleepiness. Medications such as sodium oxybate, venlafaxine, fluoxetine, and clomipramine may be prescribed if the child presents with cataplexy. Epidemiology Estimates of frequency range from 0.2 per 100,000 in Israel to 600 per 100,000 in Japan. These differences may be due to how the studies were conducted or the populations themselves.In the United States, narcolepsy is estimated to affect as many as 200,000 Americans, but fewer than 50,000 are diagnosed. The prevalence of narcolepsy is about 1 per 2,000 persons. Narcolepsy is often mistaken for depression, epilepsy, the side effects of medications, poor sleeping habits or recreational drug use, making misdiagnosis likely. While narcolepsy symptoms are often confused with depression, there is a link between the two disorders. Research studies have mixed results on co-occurrence of depression in people with narcolepsy, as the numbers quoted by different studies are anywhere between 6% and 50%.Narcolepsy can occur in both men and women at any age, although typical symptom onset occurs in adolescence and young adulthood. There is about a ten-year delay in diagnosing narcolepsy in adults. Cognitive, educational, occupational, and psychosocial problems associated with the excessive daytime sleepiness of narcolepsy have been documented. For these to occur in the crucial teen years when education, development of self-image, and development of occupational choice are taking place is especially devastating. While cognitive impairment does occur, it may only be a reflection of the excessive daytime somnolence. Society and culture In 2015, it was reported that the British Department of Health was paying for sodium oxybate medication at a cost of £12,000 a year for 80 people who are taking legal action over problems linked to the use of the Pandemrix swine flu vaccine. Sodium oxybate is not available to people with narcolepsy through the National Health Service. Name The term "narcolepsy" is from the French narcolepsie. The French term was first used in 1880 by Jean-Baptiste-Édouard Gélineau, who used the Greek νάρκη (narkē), meaning "numbness", and λῆψις (lepsis) meaning "attack". Research Histamine-directed medications It remains to be seen whether H3 antagonists (i.e., compounds such as pitolisant that promote the release of the wakefulness-promoting molecule amine histamine) will be particularly useful as wake-promoting agents. However, usage now does exist in various nations such as in France, United Kingdoms (NHS as of September 2016) after being given marketing authorisation by European Commission on the advice of the European Medicines Agency and in the United States by the approval of the Food and Drug Administration (FDA) as of August 2019. GABA-directed medications Given the possible role of hyper-active GABAA receptors in the primary hypersomnias (narcolepsy and idiopathic hypersomnia), medications that could counteract this activity are being studied to test their potential to improve sleepiness. These currently include clarithromycin and flumazenil. Flumazenil Flumazenil is the only GABAA receptor antagonist on the market as of Jan 2013, and it is currently manufactured only as an intravenous formulation. Given its pharmacology, researchers consider it to be a promising medication in the treatment of primary hypersomnias. Results of a small, double-blind, randomized, controlled clinical trial were published in November 2012. This research showed that flumazenil provides relief for most people whose CSF contains the unknown "somnogen" that enhances the function of GABAA receptors, making them more susceptible to the sleep-inducing effect of GABA. For one person, daily administration of flumazenil by sublingual lozenge and topical cream has proven effective for several years. A 2014 case report also showed improvement in primary hypersomnia symptoms after treatment with a continuous subcutaneous flumazenil infusion. The supply of generic flumazenil was initially thought to be too low to meet the potential demand for treatment of primary hypersomnias. However, this scarcity has eased, and dozens of people are now being treated with flumazenil off-label. Clarithromycin In a test tube model, clarithromycin (an antibiotic approved by the FDA for the treatment of infections) was found to return the function of the GABA system to normal in people with primary hypersomnias. Investigators therefore treated a few people with narcolepsy with off-label clarithromycin, and most felt their symptoms improved with this treatment. In order to help further determine whether clarithromycin is truly beneficial for the treatment of narcolepsy and idiopathic hypersomnia, a small, double-blind, randomized, controlled clinical trial was completed in 2012. "In this pilot study, clarithromycin improved subjective sleepiness in GABA-related hypersomnia. Larger trials of longer duration are warranted." In 2013, a retrospective review evaluating longer-term clarith
Narcolepsy	romycin use showed efficacy in a large percentage of people with GABA-related hypersomnia. "It is important to note that the positive effect of clarithromycin is secondary to a benzodiazepine antagonist-like effect, not its antibiotic effects, and treatment must be maintained." Orexin receptor agonists Orexin-A (a.k.a. hypocretin-1) has been shown to be strongly wake-promoting in animal models, but it does not cross the blood–brain barrier. The first line treatment for narcolepsy, modafinil, has been found to interact indirectly with the orexin system. It is also likely that an orexin receptor agonist will be found and developed for the treatment of hypersomnia. One such agent which is currently in clinical trials is danavorexton. L-carnitine Abnormally low levels of acylcarnitine have been observed in people with narcolepsy. These same low levels have been associated with primary hypersomnia in general in mouse studies. “Mice with systemic carnitine deficiency exhibit a higher frequency of fragmented wakefulness and rapid eye movement (REM) sleep, and reduced locomotor activity.” Administration of acetyl-L-carnitine was shown to improve these symptoms in mice. A subsequent human trial found that people with narcolepsy given L-carnitine spent less total time in daytime sleep than people who were given a placebo. Animal models Animal studies try to mimic the disorder in humans by either modifying the Hypocretin/Orexin receptors or by eliminating this peptide. An orexin deficit caused by the degeneration of hypothalamic neurons is suggested to be one of the causes of narcolepsy. More recent clinical studies on both animals and humans have also revealed that hypocretin is involved in other functions beside regulation of wakefulness and sleep. These functions include autonomic regulation, emotional processing, reward learning behaviour or energy homeostasis. In studies where the concentration of the hypocretin was measured under different circumstances, it was observed that the hypocretin levels increased with the positive emotion, anger or social interaction but stayed low during sleep or during pain experience.The most reliable and valid animal models developed are the canine (narcoleptic dogs) and the rodent (orexin-deficient mice) ones which helped investigating the narcolepsy and set the focus on the role of orexin in this disorder. Dog models Dogs, as well as other species like cats or horses, can also exhibit spontaneous narcolepsy with similar symptoms as the ones reported in humans. The attacks of cataplexy in dogs can involve partial or full collapse. Narcolepsy with cataplexy was identified in a few breeds like Labrador retrievers or Doberman pinschers where it was investigated the possibility to inherit this disorder in the autosomal recessive mode. According to a reliable canine model for narcolepsy would be the one in which the narcoleptic symptoms are the result of a mutation in the gene HCRT 2. The animals affected exhibited excessive daytime sleepiness with a reduced state of vigilance and severe cataplexy resulted after palatable food and interactions with the owners or with other animals. Rodent models Mice that are genetically engineered to lack orexin genes demonstrate many similarities to human narcolepsy. During nocturnal hours, when mice are normally present, those lacking orexin demonstrated murine cataplexy and displayed brain and muscle electrical activity similar to the activity present during REM and NREM sleep. This cataplexy is able to be triggered through social interaction, wheel running, and ultrasonic vocalizations. Upon awakening, the mice also display behavior consistent with excessive daytime sleepiness.Mice models have also been used to test whether the lack of orexin neurons is correlated with narcolepsy. Mice whose orexin neurons have been ablated have shown sleep fragmentation, SOREMPs, and obesity.Rat models have been used to demonstrate the association between orexin deficiency and narcoleptic symptoms. Rats who lost the majority of their orexinergic neurons exhibited multiple SOREMPs as well as less wakefulness during nocturnal hours, shortened REM latency, and brief periods of cataplexy. References External links "Narcolepsy Information Page". National Institute of Neurological Disorders and Stroke.
New daily persistent headache	New daily persistent headache (NDPH) is a primary headache syndrome which can mimic chronic migraine and chronic tension-type headache. The headache is daily and unremitting from very soon after onset (within 3 days at most), usually in a person who does not have a history of a primary headache disorder. The pain can be intermittent, but lasts more than 3 months. Headache onset is abrupt and people often remember the date, circumstance and, occasionally, the time of headache onset. One retrospective study stated that over 80% of patients could state the exact date their headache began.The cause of NDPH is unknown, and it may have more than one etiology. NDPH onset is commonly associated with an infection or flu-like illness, stressful life event, minor head trauma, and extra cranial surgery. Infection or flu-like illness and stressful life event are most often cited. The pathophysiology of NDPH is poorly understood. The syndrome is difficult to treat and may persist for years. The age of onset ranges from 6 to greater than 70 years old, with a mean of 35 years. It is found to be more common in females in both the adult and pediatric populations. NDPH is rare. The Akershus study of chronic headache, a population based cross sectional study of 30,000 persons aged 30–44 years in Norway, found a one-year prevalence of 0.03 percent in the population.In 1986, Vanast was the first author to describe the new daily-persistent headache (NDPH) as a benign form of chronic daily headache (CDH). The criteria for the diagnosis of NDPH were proposed in 1994 (the Silberstein–Lipton criteria) but not included in the International Classification of Headache Disorders (ICHD) until 2004. Signs and symptoms The headaches can vary greatly in their clinical presentation and duration.Quality of the headache has been described as dull and/or pressure-like sensation, and throbbing and/or pulsating sensation. The pain is usually on both sides of the head (in 88–93% of people with NDPH), but may be unilateral, and may be localized to any head region. The pain can fluctuate in intensity and duration, is daily, and lasts more than 3 months.There may be accompanying photophobia, phonophobia, lightheadedness or mild nausea. Co-morbidity with mood disorders has been reported in a subset of patients.Cranial autonomic nervous symptoms occur with painful exacerbations in 21%, and cutaneous allodynia may be present in 26%.In 2002, Li and Rozen conducted a study of 56 patients at the Jefferson Headache Center in Philadelphia and published the following results: 82% of patients were able to pinpoint the exact day their headache started. 30% of the patients, the onset of the headache occurred in correlation with an infection or flu-like illness. 38% of the patients had a prior personal history of headache. 29% of the patients had a family history of headache. 68% reported nausea. 66% reported photophobia. 61% reported phonophobia. 55% reported lightheadedness.Imaging and laboratory testing were unremarkable except for an unusually high number of patients who tested positive for a past Epstein-Barr virus infection. Diagnosis Although NDPH is classified as a primary headache syndrome, it must be remembered that a number of important conditions can present with a new-onset persisting headache, and these must be excluded prior to making a diagnosis of a primary headache disorder.The diagnosis is one of excluding the many secondary types or NDPH mimics, which is especially critical early in the course of the disease when a secondary etiology is more likely. NDPH mimics include but are not limited to: neoplasms subarachnoid hemorrhage idiopathic intracranial hypertension temporal arteritis chronic subdural hematoma post-traumatic headaches sphenoid sinusitis hypertension spontaneous cerebrospinal fluid leak cervical artery dissections pseudotumor cerebri without papilledema cerebral venous thrombosis Chiari malformation NDPH with medication overuse headacheMany doctors state that the condition is best viewed as a syndrome rather than a diagnosis. Once a diagnosis of NDPH is made, clinicians argue that patients are best managed according to the more detailed pathophysiology-based diagnosis than lumped together into a single group, since a single disorder is unlikely to exist.NDPH is classified as a Primary Headache Disorder by the ICHD-2 classification system (by the IHS) using number 4.8. It is one of the types of primary headache syndromes that present as a chronic daily headache, which is a headache present for more than 15 days a month for more than 3 months. ICHD criteria The ICHD diagnostic criteria are: Headache that, within 3 days of onset, fulfils criteria 2-4 Headache is present daily, and is unremitting, for > 3 months At least two of the following pain characteristics: bilateral location pressing/tightening (non-pulsating) quality mild or moderate intensity not aggravated by routine physical activity such as walking or climbing Both of the following: no more than one of photophobia, phonophobia or mild nausea neither moderate or severe nausea nor vomiting Not attributed to another disorderNotes: Headache may be unremitting from the moment of onset or very rapidly build up to continuous and unremitting pain. Such onset or rapid development must be clearly recalled and unambiguously described by the patient. Otherwise it is coded as 2.3 chronic tension-type headache. History and physical and neurological examinations do not suggest any of the disorders listed in groups 5-12 (including 8.2 medication overuse headaches and its subforms), or history and/or physical and/or neurological examinations do suggest such disorder but it is ruled out by appropriate investigations, or such disorder is present but headache does not occur for the first time in close temporal relation to the disorder. Criteria revision Although the original Silberstein–Lipton criteria and the original description by Vanast make no suggestion for the exclusion of migrainous features in NDPH, the current ICHD criteria exclude patients with migrainous features. When migraine features are present, classification thus becomes problematic. It has been reported that migraine symptoms may be present in over 50% of NDPH patients. The current criteria definition thus excludes more than half of patients with new onset of daily headache. This exclusion due to migrainous features could have adverse scientific, diagnostic, and treatment consequences.One proposal for reclassification of the criteria is from a study conducted on retrospective analysis of the records of 1348 patients regularly treated at the headache clinic of the Department of Neurology of Santa Casa de São Paulo, Brazil, and would be the following subdivision: NDPH with migraine features and without migraine features that would allow the inclusion of all individuals present who has a daily and persistent headache from the beginning.Another proposed reclassification of the criteria is from a study conducted as a retrospective chart review of patients seen at the Headache Center at Montefiore Medical Center in Bronx, New York, from September 2005 to April 2009. The revised criteria for NDPH definition does not exclude migraine features (NDPH-R), and three subdivisions were created and described based on prognosis: Persisting, remitting, and relapsing–remitting. Additionally, this revised criteria would not include parts C or D currently required by the ICHD diagnostic criteria for NDPH. Pathophysiology The pathophysiology of NDPH is poorly understood. Research points to an immune-mediated, inflammatory process. Cervical joint hypermobility and defective internal jugular venous drainage have also been suggested as causes.In 1987, Vanast first suggested autoimmune disorder with a persistent viral trigger for CDH (now referred to as NDPH). Post-infectious origins have been approximated to make up anywhere between 30 and 80% of NDPH patients in different studies. Viruses that have been implicated include Epstein-Barr virus, herpes simplex virus and cytomegalovirus.Non-specific upper respiratory infections including rhinitis and pharyngitis are most often cited by patients. In one study, 46.5% patients recalled a specific trigger with a respiratory tract illness being the most common. In children, almost half report headache onset during an infection. A study by Rozen and Swindan in 2007 found elevated levels of tumor necrosis factor alpha, a proinflammatory cytokine, in the cerebrospinal fluid but not the blood of patients with NDPH, chronic migraine, and post-traumatic headaches suggesting inflammation as the cause of the headaches.NDPH as an inflammatory, post-infectious manifestation indicates a potential meningoencephalitis event in NDPH patients. Tissue specificity is a general feature of post-infectious, immune-mediated conditions, and the meninges are a type of connective tissue membrane. Inflammation of the meninges was first proposed as a possible pathophysiology for migraine in the 1960s and has recently been explored again. This hypothesis is based on meningeal mast cell activation. Reactive arthritis (ReA) is a post-infectious disease entity of synovium/joints with connective tissue membrane (synovial membrane of the joints) which provides a corollary. NDPH has been reported in Hashimotos encephalopathy, an immune-mediated type of encephalitis. A mean 5-year retrospective analysis of 53 patients with a history of viral meningitis and 17 patients with a history of bacterial meningitis showed an increased onset of subsequent new onset headache and increased severity of those with prior primary headaches. Treatment There is no specific treatment for NDPH. Often they are treated similar to migraines.A number of medications have been used including amitriptyline, gabapentin, pregabalin, propranolol, and topiramate. There are no prospective placebo controlled trials of preventive treatment. In those with migrainous features treatment may be similar to migraines.Opiates, or narcotics, tend to be avoided because of their side effects, including the development of medication overuse headaches and potential for dependency. NDPH is often associated with medication overuse. To avoid the development of medication overuse headaches, it is advised not to use pain relievers for more than nine days a month. NDPH, like other primary headaches, has been linked to comorbid psychiatric conditions, mainly mood and anxiety and panic disorders. The spectrum of anxiety disorders, particularly panic disorder, should be considered in NDPH patients presenting with psychiatric symptoms. Simultaneous treatment of both disorders may lead to good outcomes.Medications within the tetracycline family, mexiletine, corticosteroids and nerve blocks are being studied. Occipital nerve block have been reported to be helpful for some people. 23/71 people had undergone a nerve block for their severe headache. The NDPH-ICHD group responded to the nerve block much more often (88.9%) than the NDPH with migraine features (42.9% responded to nerve block). Prognosis Most patients have persistent headaches, although about 15% will remit, and 8% will have a relapsing-remitting type. It is not infrequent for NDPH to be an intractable headache disorder that is unresponsive to standard headache therapies. References External links Evans, Randolph W.; Seifert, Tad D. (2011). "The Challenge of New Daily Persistent Headache". Headache: The Journal of Head and Face Pain. 51 (1): 145–154. doi:10.1111/j.1526-4610.2010.01812.x. PMID 21198576. Robert, Teri (2004). "New Daily Persistent Headache - The Basics". Health Central.
Methylmercury	Methylmercury (sometimes methyl mercury) is an organometallic cation with the formula [CH3Hg]+. Methylmercury is extremely toxic, and its derivatives are the major source of organic mercury for humans. It is a bioaccumulative environmental toxicant. Structure and chemistry "Methylmercury" is a shorthand for the hypothetical "methylmercury cation", sometimes written "methylmercury(1+) cation" or "methylmercury(II) cation". This functional group is composed of a methyl group bonded to an atom of mercury. Its chemical formula is CH3Hg+ (sometimes written as MeHg+). Methylmercury exists as a substituent in many complexes of the type [MeHgL]+ (L = Lewis base) and MeHgX (X = anion).As a positively charged ion it readily combines with anions such as chloride (Cl−), hydroxide (OH−) and nitrate (NO−3). It has particular affinity for sulfur-containing anions, particularly thiols (RS−). Thiols are generated when the amino acid cysteine and the peptide glutathione form strong complexes with methylmercury: [MeHg]+ + RSH → MeHg−SR + H+ Sources Environmental sources Methylmercury is formed from inorganic mercury by the action of microbes that live in aquatic systems including lakes, rivers, wetlands, sediments, soils and the open ocean. This methylmercury production has been primarily attributed to anaerobic bacteria in the sediment. Significant concentrations of methylmercury in ocean water columns are strongly associated with nutrients and organic matter remineralization, which indicate that remineralization may contribute to methylmercury production. Direct measurements of methylmercury production using stable mercury isotopes have also been observed in marine waters, but the microbes involved are still unknown. Increased methylmercury concentrations in water and fish have been detected after flooding of soils associated with reservoir creation (e.g. for hydroelectric power generation) and in thermokarst wetlands that form after permafrost thaw.There are various sources of inorganic mercury that may indirectly contribute to the production of methylmercury from microbes in the environment. Natural sources of mercury released to the atmosphere include volcanoes, forest fires, volatilization from the ocean and weathering of mercury-bearing rocks. Anthropogenic sources of mercury include the burning of wastes containing inorganic mercury and from the burning of fossil fuels, particularly coal. Although inorganic mercury is only a trace constituent of such fuels, their large scale combustion in utility and commercial/industrial boilers in the United States alone results in release of some 80.2 tons (73 metric tons) of elemental mercury to the atmosphere each year, out of total anthropogenic mercury emissions in the United States of 158 tons (144 metric tons)/year.In the past, methylmercury was produced directly and indirectly as part of several industrial processes such as the manufacture of acetaldehyde. However, currently there are few direct anthropogenic sources of methylmercury pollution in the United States.Whole-lake ecosystem experiments at IISD-ELA in Ontario, Canada showed that mercury falling directly on a lake had the fastest impacts on aquatic ecosystems as opposed to mercury falling on the surrounding land. This inorganic mercury is converted to methylmercury by bacteria. Different stable isotopes of mercury were added to lakes, wetlands, and uplands, simulating rain, and then mercury concentrations in fish were analyzed to find their source. The mercury applied to lakes was found in young-of-the-year yellow perch within two months, whereas the mercury applied to wetlands and uplands had a slower but longer influx.Acute methylmercury poisoning can occur either directly from the release of methylmercury into the environment or indirectly from the release of inorganic mercury that is subsequently methylated in the environment. For example, methylmercury poisoning occurred at Grassy Narrows in Ontario, Canada (see Ontario Minamata disease) as a result of mercury released from the mercury-cell Chloralkali process, which uses liquid mercury as an electrode in a process that entails electrolytic decomposition of brine, followed by mercury methylation in the aquatic environment. An acute methylmercury poisoning tragedy occurred also in Minamata, Japan following release of methylmercury into Minamata Bay and its tributaries (see Minamata disease). In the Ontario case, inorganic mercury discharged into the environment was methylated in the environment; whereas, in Minamata, Japan, there was direct industrial discharge of methylmercury. Dietary sources Because methylmercury is formed in aquatic systems, and because it is not readily eliminated from organisms, it is biomagnified in aquatic food chains from bacteria, to plankton, through macroinvertebrates, to herbivorous fish and to piscivorous (fish-eating) fish. At each step in the food chain, the concentration of methylmercury in the organism increases. The concentration of methylmercury in the top level aquatic predators can reach a level a million times higher than the level in the water. This is because methylmercury has a half-life of about 72 days in aquatic organisms resulting in its bioaccumulation within these food chains. Organisms, including humans, fish-eating birds, and fish-eating mammals such as otters and cetaceans (i.e. whales and dolphins) that consume fish from the top of the aquatic food chain receive the methylmercury that has accumulated through this process, plus the toxins in their habitat. Fish and other aquatic species are the main source of human methylmercury exposure.The concentration of mercury in any given fish depends on the species of fish, the age and size of the fish and the type of water body in which it is found. In general, fish-eating fish such as shark, swordfish, marlin, larger species of tuna, walleye, largemouth bass, and northern pike, have higher levels of methylmercury than herbivorous fish or smaller fish such as tilapia and herring. Within a given species of fish, older and larger fish have higher levels of methylmercury than smaller fish. Fish that develop in water bodies that are more acidic also tend to have higher levels of methylmercury. Biological impact Human health effects Ingested methylmercury is readily and completely absorbed by the gastrointestinal tract. It is mostly found complexed with free cysteine and with proteins and peptides containing that amino acid. The methylmercuric-cysteinyl complex is recognized by amino acids transporting proteins in the body as methionine, another essential amino acid. Because of this mimicry, it is transported freely throughout the body including across the blood–brain barrier and across the placenta, where it is absorbed by the developing fetus. Also for this reason as well as its strong binding to proteins, methylmercury is not readily eliminated. Methylmercury has a half-life in human blood of about 50 days.Several studies indicate that methylmercury is linked to subtle developmental deficits in children exposed in utero such as loss of IQ points, and decreased performance in tests of language skills, memory function and attention deficits. Methylmercury exposure in adults has also been linked to increased risk of cardiovascular disease including heart attack. Some evidence also suggests that methylmercury can cause autoimmune effects in sensitive individuals. Despite some concerns about the relationship between methylmercury exposure and autism, there are few data that support such a link. Although there is no doubt that methylmercury is toxic in several respects, including through exposure of the developing fetus, there is still some controversy as to the levels of methylmercury in the diet that can result in adverse effects. Recent evidence suggests that the developmental and cardiovascular toxicity of methylmercury may be mitigated by co-exposures to omega-3 fatty acids and perhaps selenium, both found in fish and elsewhere.There have been several episodes in which large numbers of people were severely poisoned by food contaminated with high levels of methylmercury, notably the dumping of industrial waste that resulted in the pollution and subsequent mass poisoning in Minamata and Niigata, Japan and the situation in Iraq in the 1960s and 1970s in which wheat treated with methylmercury as a preservative and intended as seed grain was fed to animals and directly consumed by people (see Basra poison grain disaster). These episodes resulted in neurological symptoms including paresthesias, loss of physical coordination, difficulty in speech, narrowing of the visual field, hearing impairment, blindness, and death. Children who had been exposed in utero through their mothers ingestion were also affected with a range of symptoms including motor difficulties, sensory problems and intellectual disability. At present, exposures of this magnitude are rarely seen and are confined to isolated incidents. Accordingly, concern over methylmercury pollution is currently focused on more subtle effects that may be linked to levels of exposure presently seen in populations with high to moderate levels of dietary fish consumption. These effects are not necessarily identifiable on an individual level or may not be uniquely recognizable as due to methylmercury. However, such effects may be detected by comparing populations with different levels of exposure. There are isolated reports of various clinical health effects in individuals who consume large amounts of fish; however, the specific health effects and exposure patterns have not been verified with larger, controlled studies. Many governmental agencies, the most notable ones being the United States Environmental Protection Agency (EPA), the United States Food and Drug Administration (FDA), Health Canada, and the European Union Health and Consumer Protection Directorate-General, as well as the World Health Organization (WHO) and the United Nations Food and Agriculture Organization (FAO), have issued guidance for fish consumers that is designed to limit methylmercury exposure from fish consumption. At present, most of this guidance is based on protection of the developing fetus; future guidance, however, may also address cardiovascular risk. In general, fish consumption advice attempts to convey the message that fish is a good source of nutrition and has significant health benefits, but that consumers, in particular pregnant women, women of child-bearing age, nursing mothers, and young children, should avoid fish with high levels of methylmercury, limit their intake of fish with moderate levels of methylmercury, and consume fish with low levels of methylmercury no more than twice a week. Effects on fish and wildlife In recent years, there has been increasing recognition that methylmercury affects fish and wildlife health, both in acutely polluted ecosystems and ecosystems with modest methylmercury levels. Two reviews document numerous studies of diminished reproductive success of fish, fish-eating birds, and mammals due to methylmercury contamination in aquatic ecosystems. In public policy Reported methylmercury levels in fish, along with fish consumption advisories, have the potential to disrupt peoples eating habits, fishing traditions, and the livelihoods of the people involved in the capture, distribution, and preparation of fish as a foodstuff for humans. Furthermore, proposed limits on mercury emissions have the potential to add costly pollution controls on coal-fired utility boilers. Nevertheless, substantial benefits can be achieved globally by introducing mercury emission reduction measures because they reduce human and wildlife exposure to methyl mercury.About 30% of the distributed mercury depositional input is from current anthropogenic sources, and 70% is from natural sources. The natural sources category includes re-emission of mercury previously deposited from anthropogenic sources. According to one study, based on modeled concentrations, pre-Anthropocene tissue-bound levels in fish may not have differed markedly from current levels. However, based on a comprehensive set of global measurements, the ocean contains about 60,000 to 80,000 tons of mercury from pollution, and mercury levels in the upper ocean have tripled since the beginning of the industrial revolution. Higher mercury levels in shallower ocean waters could increase the amount of the toxicant accumulating in food fish, exposing people to a greater risk of mercury poisoning. See also Canadian Reference Materials include some with methylmercury, e.g. DORM Dimethylmercury, mercury with a second methyl group Ethylmercury, a related cation Mercury poisoning Mercury regulation in the United States References External links ATSDR - ToxFAQs: Mercury ATSDR - Public Health Statement: Mercury ATSDR - ALERT! Patterns of Metallic Mercury Exposure, 6/26/97 ATSDR - MMG: Mercury ATSDR - Toxicological Profile: Mercury National Pollutant Inventory - Mercury and compounds Fact Sheet Methylmercury-in-fish exposure calculator provided by GotMercury.Org, which uses FDA mercury data with the EPAs calculated safe exposure levels. Methylmercury Contamination in Fish and Shellfish Archived 2013-11-02 at the Wayback Machine nytimes.com, Tuna Fish Stories: The Candidates Spin the Sushi U.S. Environmental Protection Agencys mercury site U.S. Geological Surveys mercury site Archived 2013-11-02 at the Wayback Machine Environment Canadas mercury site Health Canadas mercury site International Conference on Mercury as a Global Pollutant 2006-Madison, WI USA 2009-Guizhou, China 2011-Halifax, NS Canada
Pagets disease of the breast	Pagets disease of the breast is a type of cancer that outwardly may have the appearance of eczema, with skin changes involving the nipple of the breast. The condition is an uncommon disease accounting for 1 to 4.3% of all breast cancers and was first described by Sir James Paget in 1874. The condition in itself often appears innocuous, limited to a surface appearance and it is sometimes dismissed, although actually indicative of underlying breast cancer. Immunohistochemistry of Paget cells and underlying breast cancer show a more aggressive, HER2-enriched, molecular subtype of breast cancer. Signs and symptoms Pagets disease of the breast can affect the nipple and areola. Symptoms typically only affect one breast. Symptoms may include: Skin. The first symptom is usually an eczema-like rash. The skin of the nipple and areola may be red, itchy and inflamed. After a period of time, the skin may become flaky or scaly. Discharge. A discharge, which may be straw-colored or bloody, may ooze from the area. Sensation. Some women have a burning sensation. These symptoms usually occur in more advanced stages, when serious destruction of the skin often prompts the patient to consult. Lumps or masses in the breast occur in 50% of the patients. In more advanced stages, the disease may cause tingling, increased sensitivity and pain. Nipple changes. The nipple may become inverted. Breast changes. There may or may not be a lump in the breast, and there may be redness, oozing and crusting, and a sore that does not heal.The symptoms usually affect the nipple and then spread to the areola and then the breast. It is common for the symptoms to wax and wane. Most women do not visit the doctor because they assume Pagets disease to be minor contact dermatitis or eczema. A lump or skin irritation that does not seem to heal for over a month indicates that attention by a specialist is needed. Pathophysiology Pagets disease of the breast is characterised by Paget cells. Paget cells are large cells with clear cytoplasm (clear halo) and eccentric, hyperchromic nuclei found throughout the epidermis.There is some controversy as to whether these cells arise from the ductal system of the breast, or whether these cells are a result of in situ malignant transformation.According to the migratory theory, ductal carcinoma in situ cells migrate into the lactiferous sinuses and the nipple skin. Cancer cells disrupt the normal epithelial barrier and extracellular fluid accumulates on the surface of the skin, resulting in the crusting of the areola skin. Diagnosis Recommended tests are a mammogram and a biopsy to confirm the diagnosis, and cytopathology may also be helpful. Pagets disease is difficult to diagnose due to its resemblance to dermatitis and eczema; even in patients after ductal carcinoma in situ surgery. Eczema tends to affect the areola first, and then the nipple, whereas Pagets spreads from the nipple. During a physical examination, the doctor examines the unusual areas of the breast, especially the appearance of the skin on and around the nipples and feeling for any lumps or areas of thickening.The most common test used to diagnose Pagets disease is the biopsy, removal of a tissue sample from the affected area which is then examined under the microscope by a pathologist, who distinguishes Paget cells from other cell types by staining tissues to identify specific cells (immunohistochemistry). CD138 and p53 can be used, both being positive in Pagets disease, and negative in Toker cells, which are normal epithelial cells with clear cytoplasm that can be difficult to distinguish from Pagets disease. Besides, Paget cells stain positive for CK7 in >90% of the cases. Similarly, GATA3 and HER-2 are expressed in around 90% of the cases, and can be used for the confirmation, including CK7 negative Paget disease.Samples of nipple discharge may also be examined under the microscope to determine whether Paget cells are present. Imprint or scrape cytopathology may be useful: scraping cells from the affected area, or pressing them onto a glass slide to be examined under the microscope.On average, a woman may experience signs and symptoms for six to eight months before a diagnosis is made. Treatment Pagets disease of the breast is a type of cancer of the breast. Treatment usually involves a lumpectomy or mastectomy to surgically remove the tumour. Chemotherapy and/or radiotherapy may be necessary, but the specific treatment often depends on the characteristics of the underlying breast cancer. Invasive cancer or extensive ductal carcinoma in situ is primarily treated with modified radical mastectomies. The procedure consists in the removal of the breast, the lining over the chest muscles and a part of the lymph nodes from under the arm. In cases of noninvasive cancers, simple mastectomies are performed in which only the breast with the lining over the chest muscles is removed. Patients with cancer that has not spread beyond the nipple and the surrounding area are often treated with breast-conserving surgery or lumpectomy. They usually undergo radiation therapy after the actual procedure to prevent recurrence. A breast-conserving surgery consists in the removal of the nipple, areola and the part of the breast that is affected by cancer. In most cases, adjuvant treatment is part of the treatment schema. This type of treatment is normally given to patients with cancer to prevent a potential recurrence of the disease. Whether adjuvant therapy is needed depends upon the type of cancer and whether the cancer cells have spread to the lymph nodes. In Pagets disease, the most common type of adjuvant therapy is radiation following breast-conservative surgery. Adjuvant therapy may also consist of anticancer drugs or hormone therapies. Hormonal therapy reduces the production of hormones within the body, or prevents the hormones from stimulating the cancer cells to grow, and it is commonly used in cases of invasive cancer by means of drugs such as tamoxifen and anastrozole. Prognosis The presence of three factors for the prognosis has been suggested, whether there is a palpable mass of the disease, whether lymph nodes are positive and whether there is an underlying malignant cancer. If there is none of these, the five- and 10-year survival is 85% and 80% respectively, with adjuvant chemotherapy even 95% and 90%. If there is a palpable mass, it is 32% and 31% respectively, with adjuvant chemotherapy (40% and 35%).Positive lymph-nodes have been positively associated with a palpable mass and affect the prognosis to be now just 28% survival after 10 years (vs 79% without palpable mass and without affected lymph-nodes). Involvement of the lymph nodes does not directly cause any harm, but is merely an indicator of systemic spread.Furthermore, patients with an identifiable associated underlying breast tumor have a survival rate of 38-40% at five years and a survival rate of 22-33% at 10 years. The death rate of metastatic breast carcinoma in patients with mammary Pagets disease and underlying cancer is 61.3%, with a 10-year cumulative survival rate of 33%. Epidemiology Most patients diagnosed with Pagets disease of the nipple are over age 50, but rare cases have been diagnosed in patients in their 20s. The average age at diagnosis is 62 for women and 69 for men. The disease is rare among both women and men. History The condition is named after Sir James Paget, an English surgeon who first described the condition in 1874. See also List of cutaneous conditions References External links National Cancer Institute fact sheet
Schizophreniform disorder	Schizophreniform disorder is a mental disorder diagnosed when symptoms of schizophrenia are present for a significant portion of time (at least a month), but signs of disturbance are not present for the full six months required for the diagnosis of schizophrenia. The symptoms of both disorders can include delusions, hallucinations, disorganized speech, disorganized or catatonic behavior, and social withdrawal. While impairment in social, occupational, or academic functioning is required for the diagnosis of schizophrenia, in schizophreniform disorder an individuals level of functioning may or may not be affected. While the onset of schizophrenia is often gradual over a number of months or years, the onset of schizophreniform disorder can be relatively rapid. Like schizophrenia, schizophreniform disorder is often treated with antipsychotic medications, especially the atypicals, along with a variety of social supports (such as individual psychotherapy, family therapy, occupational therapy, etc.) designed to reduce the social and emotional impact of the illness. The prognosis varies depending upon the nature, severity, and duration of the symptoms, but about two-thirds of individuals diagnosed with schizophreniform disorder go on to develop schizophrenia. Signs and symptoms Schizophreniform disorder is a type of mental illness that is characterized by psychosis and closely related to schizophrenia. Both schizophrenia and schizophreniform disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), have the same symptoms and essential features except for two differences: the level of functional impairment and the duration of symptoms. Impairment in social, occupational, or academic functioning is usually present in schizophrenia, particularly near the time of first diagnosis, but such impairment may or may not be present in schizophreniform disorder. In schizophreniform disorder, the symptoms (including prodromal, active, and residual phases) must last at least 1 month but not more than 6 months, while in schizophrenia the symptoms must be present for a minimum of 6 months. Cause The exact cause of the disorder remains unknown, and relatively few studies have focused exclusively on the etiology of schizophreniform disorder. Like other psychotic disorders, a diathesis–stress model has been proposed, suggesting that some individuals have an underlying multifactorial genetic vulnerability to the disorder that can be triggered by certain environmental factors. Schizophreniform disorder is more likely to occur in people with family members who have schizophrenia or bipolar disorder. Diagnosis If the symptoms have persisted for at least one month, a provisional diagnosis of schizophreniform disorder can be made while waiting to see if recovery occurs. If the symptoms resolve within 6 months of onset, the provisional qualifier is removed from the diagnosis. However, if the symptoms persist for 6 months or more, the diagnosis of schizophreniform disorder must be revised. The diagnosis of brief psychotic disorder may be considered when the duration of symptoms is less than one month. The main symptoms of both schizophreniform disorder and schizophrenia may include: delusions, hallucinations, disorganized speech resulting from formal thought disorder, disorganized or catatonic behavior, and negative symptoms, such as an inability to feel a range of emotions (flat affect), an inability to experience pleasure (anhedonia), impaired or decreased speech (aphasia), a lack of desire to form relationships (asociality), and a lack of motivation (avolition). Treatment Various modalities of treatment, including pharmacotherapy, psychotherapy, and various other psychosocial and educational interventions, are used in the treatment of schizophreniform disorder. Pharmacotherapy is the most commonly used treatment modality as psychiatric medications can act quickly to both reduce the severity of symptoms and shorten their duration. The medications used are largely the same as those used to treat schizophrenia, with an atypical antipsychotic as the usual drug of choice. Patients who do not respond to the initial atypical antipsychotic may benefit from being switched to another atypical antipsychotic, the addition of a mood stabilizer such as lithium or an anticonvulsant, or being switched to a typical antipsychotic.Treatment of schizophreniform disorder can occur in inpatient, outpatient, and partial hospitalization settings. In selecting the treatment setting, the primary aims are to minimize the psychosocial consequences for the patient and maintain the safety of the patient and others. While the need to quickly stabilize the patients symptoms almost always exists, consideration of the patients severity of symptoms, family support, and perceived likelihood of compliance with outpatient treatment can help determine if stabilization can occur in the outpatient setting. Patients who receive inpatient treatment may benefit from a structured intermediate environment, such as a sub-acute unit, step-down unit, partial hospital, or day hospital, during the initial phases of returning to the community.As improvement progresses during treatment, help with coping skills, problem-solving techniques, psychoeducational approaches, and eventually occupational therapy and vocational assessments are often very helpful for patients and their families. Virtually all types of individual psychotherapy are used in the treatment of schizophreniform disorder, except for insight-oriented therapies as patients often have limited insight as a symptom of their illness.Since schizophreniform disorder has such rapid onset of severe symptoms, patients are sometimes in denial about their illness, which also would limit the efficacy of insight-oriented therapies. Supportive forms of psychotherapy such as interpersonal psychotherapy, supportive psychotherapy, and cognitive behavioral therapy are particularly well suited for the treatment of the disorder. Group psychotherapy is usually not indicated for patients with schizophreniform disorder because they may be distressed by the symptoms of patients with more advanced psychotic disorders. Prognosis The following specifiers for schizophreniform disorder may be used to indicate the presence or absence of features that may be associated with a better prognosis: With Good Prognostic Features, used if at least two of the following features are present: Onset of prominent psychotic symptoms within 4 weeks of the first noticeable change in usual behavior or functioning Confusion or perplexity at the height of the psychotic episode Good premorbid social and occupational functioning Absence of blunted or flat affect Without Good Prognostic Features, used if two or more of the above features have not been present.The presence of negative symptoms and poor eye contact both appear to be prognostic of a poor outcome. Many of the anatomic and functional changes seen in the brains of patients with schizophrenia also occur in patients with schizophreniform disorder. However, at present there is no consensus among scientists regarding whether or not ventricular enlargement, which is a poor prognostic factor in schizophrenia, has any prognostic value in patients with schizophreniform disorder. According to the American Psychiatric Association, approximately two-thirds of patients diagnosed with "provisional" schizophreniform disorder are subsequently diagnosed with schizophrenia; the remaining keep a diagnosis of schizophreniform disorder. Epidemiology Schizophreniform disorder is equally prevalent among men and women. The most common ages of onset are 18–24 for men and 18–35 for women. While the symptoms of schizophrenia often develop gradually over a period of years, the diagnostic criteria for schizophreniform disorder require a much more rapid onset.Available evidence suggests variations in incidence across sociocultural settings. In the United States and other developed countries, the incidence is low, possibly fivefold less than that of schizophrenia. In developing countries, the incidence is substantially higher, especially for the subtype "With Good Prognostic Features". In some of these settings schizophreniform disorder may be as common as schizophrenia. References External links Strakowski SM (June 1994). "Diagnostic validity of schizophreniform disorder". Am J Psychiatry. 151 (6): 815–24. doi:10.1176/ajp.151.6.815. PMID 8184991. Clinical Trials in Schizophrenia, Schizoaffective, or Schizophreniform Disorder Schizophreniform Disorder Patient information
Primary effusion lymphoma	Primary effusion lymphoma (PEL) is classified as a diffuse large B cell lymphoma. It is a rare malignancy of plasmablastic cells that occurs in individuals that are infected with the Kaposis sarcoma-associated herpesvirus (i.e. KSHV/HHV8). Plasmablasts are immature plasma cells, i.e. lymphocytes of the B-cell type that have differentiated into plasmablasts but because of their malignant nature do not differentiate into mature plasma cells but rather proliferate excessively and thereby cause life-threatening disease. In PEL, the proliferating plasmablastoid cells commonly accumulate within body cavities to produce effusions (i.e. accumulations of fluid), primarily in the pleural, pericardial, or peritoneal cavities, without forming a contiguous tumor mass. In rare cases of these cavitary forms of PEL, the effusions develop in joints, the epidural space surrounding the brain and spinal cord, and underneath the capsule (i.e. tightly woven collagen fibers) which forms around breast implants. Less frequently, individuals present with extracavitary primary effusion lymphomas, i.e., solid tumor masses not accompanied by effusions. The extracavitary tumors may develop in lymph nodes, bone, bone marrow, the gastrointestinal tract, skin, spleen, liver, lungs, central nervous system, testes, paranasal sinuses, muscle, and, rarely, inside the vasculature and sinuses of lymph nodes. As their disease progresses, however, individuals with the classical effusion-form of PEL may develop extracavitary tumors and individuals with extracavitary PEL may develop cavitary effusions.PEL typically occurs in individuals who are immunocompromised, i.e., individuals whose immune system is weakened and therefore less able to fight infectious agents and cancers. This weakening is ascribed to KSHV/HHV8 infection that is commonly further promoted by concurrent human immunodeficiency virus (i.e. HIV) infection, prior organ transplantation, the decline in immunity that develops with aging, and/or cirrhosis of the liver due to hepatitis B or C virus. The plasmacytoid cells in PEL are also commonly infected with the Epstein-Barr virus (i.e. EBV). EBV is a known cause of various Epstein-Barr virus-associated lymphoproliferative diseases including various B-cell lymphomas. However, the role of this virus in the development of PEL is not clear, although some studies suggest that EBV infection cooperates with KSHV/HHV8 infection to promote the development and/or progression of this disease.Formally, PEL is defined by the World Health Organization, 2016 as a KSHV/HHV8-positive and KSHV/HHV8-driven large B-cell lymphoma. This lymphoma also belongs to a group of lymphoid neoplasms with plasmablastic differentiation that involve malignant plasmablasts but differ from PEL in the types of tissues where they accumulate, the gene abnormalities they carry, and/or the predisposing conditions involved in their development. More than 50, 30, and 60% of all PEL cases, respectively, develop in individuals who already have KSHV/HHV8-positive Kaposis sarcoma, human herpesvirus 8-associated multicentric Castleman disease, and/or (especially in HIV-positive individuals) evidence of bearing EBV-infected plasmablasts.Primary effussion lymphoma is an extremely aggressive cancer that is highly resistant to various chemotherapy treatments. It has carried a median survival time of ~5 months, with overall survival rates at 1, 3, and 5 year of only 30, 18, and 17%, respectively. In many cases, however, this high mortality reflects, at least in part, the lethality of its underlying predisposing diseases, particularly HIV/AIDS in HIV-infected individuals. New treatment strategies, including those directed at its underlying predisposing diseases, may improve the prognosis of PEL. Presentation Individuals diagnosed with PEL most commonly (>33% of all cases) present with advanced Stage III or IV disease. They are predominately males with a median age of 42 years if they are infected with HIV and 73 years if they are not so infected. Some one-third to one-half of these individuals have a history of Karposis sarcoma, less commonly of multicentric Castleman disease, and/or rarely of immune deficiency due to organ transplantation, hepatitis complicated by cirrhosis caused by hepatitis B or C viral infection, or of old age. PEL occurring in the elderly generally occurs in EBV-negative individuals residing in the Mediterranean region. Individuals with the cavitary form of PEL present with symptoms due to effusions in the pleural cavity (e.g. shortness of breath), pericardium (e.g. chest pain/discomfort, hypotension, shortness of breath), peritoneal cavity (e.g. abdominal swelling), or, much less often, joints (e.g. swelling), the epidural space (e.g. central nervous system symptoms), or breast implants (e.g. breast swelling/pain/malformation). While most cases of classical PEL involve one cavitary site, some individuals present with two or more sites of cavitary involvement. Individuals with extracavitary PEL present with lesions in the lung, central nervous system, gastrointestinal tract, and/or lymph nodes. Gastrointestinal track lesions often occur as multiple lymphoid polyps in the large intestine. At diagnosis, more than 50% of individuals afflicted with either cavitary or extracavitary PEL have or report a history of B symptoms (i.e. fever, weight loss, night sweat). Laboratory examination in all PEL cases often show anemia, low blood levels of platelets, high serum levels of IL6, and high levels of circulating KSHV/HHV8. Pathophysiology PEL develops in patients that have predisposing diseases that reduce the immune systems ability to attack precancerous and cancerous cells. Initially, KSHV/HHV8 viruses infect plasmablasts to establish a latency state in which the viruses express malignancy-promoting genes (see KSHV/HHV8 genes). Products of these viral genes include: 1) LANA-1, which inhibits host cells p53 protein thereby reducing these cells apoptosis (i.e. programmed cell death) response to injury, and also inhibits the activity of host cells retinoblastoma protein thereby increasing these cells proliferation; 2) vcylin, an analog of host cell cyclin, which binds RB to increase these cells proliferation; 3) vFLIP, which inhibits host cells apoptosis and activates these cells NF-κB signaling pathway to prolong their survival; 4) various protein isoforms of kaposin which stimulate host cells to release cytokines (e.g., GM-CSF and IL-6) that act back on these cells to stimulate their growth; 5) vIL6, a viral analog of host cells IL-6 which, while not often expressed, induces these cells to produce VEGF, a cytokine that feeds back on these cells to inhibit their apoptosis and to increase the permeability of nearby blood vessels thereby promoting the formation of effusions; 6) K1 protein which promotes the malignancy of host cells; 7) G-protein coupled receptor protein which promotes host cells proliferation and survival; and 8) several viral microRNAs that promote host cells to proliferate, inhibit these cells apoptosis, and stimulate the vascularization of nearby small blood vessel to promote effusions. While HIV/AIDS is associated with a wide range of cancers, including those involving B-cells such as plasmablastic lymphoma, the development of these cancers is commonly attributed to co-infection with oncogenic viruses (e.g. KSHV/HHV8, EBV): the direct role of HIV/AIDS in promoting PEL is unclear. Finally, some studies suggest that EBV cooperates with KSHV/HHV8 to cause PEL, perhaps by enhancing the ability of KSHV/HHV8 to establish their pro-malignant latency phase in infected cells.As a probable result of their excessive proliferation, prolonged survival, and ability to avoid attack by a weakened immune system, the malignant cells in PEL exhibit a high degree of genomic instability, i.e. alterations in the structure and/or expression of their genetic material which are associated with the development and/or progression of PEL. These alterations include mutations (i.e. changes in nucleic acid sequences), chromosomal rearrangements (i.e. deletions, duplications, inversions, translocations), aneuploidy (i.e. increases or decreases in the number of chromosomes), and the abnormal expression of genes that may or may not be a result of the preceding structural gene changes. Potentially important examples include: 1) overexpression of the APOBEC3B gene whose protein product (termed "probable DNA dC->dU-editing enzyme APOBEC-3B") contributes to the regulation of cell growth; 2) missense mutations in the IRAK1 gene which causes overactivation of its product protein, interleukin-1 receptor-associated kinase 1, and thereby overactivation of the NF-κB signaling pathway that regulates cell proliferation and survival; 3) overexpression of the AQP3 gene whose protein product, aquaporin 3, is a water channel that when overexpressed is thought to promote the progression and spread of various types of cancers; 4) overexpression of the P-selectin glycoprotein ligand-1 gene whose protein product promotes cell attachment to vascular endothelium; 5) overexpressin of the MUC1 gene whose product, the Mucin 1, cell surface associated protein, binds with P53 to inhibit cell death and interacts with beta-catenin to promote the tissue-invasiveness of cancer cells; and 6) overexpression of the MYC gene, whose product, c-Myc, is the cancer-causing MYC proto-oncogene although this overexpression, unlike the c-Myc overexpression occurring in other B-cell lymphomas, is usually not associated with structural abnormalities in its gene but rather is often overexpressed due to the action of the LANA-1 protein made by KSHV/HHV8. The identification of these changes in tissue samples can assist in making the diagnosis of PEL. Diagnosis In classical cavitary cases, the diagnosis of PEL may be suspected based on its presentation as effusions in one or more bodily cavities in individuals with a history of the immunodeficiencies cited above. The diagnosis is supported by microscopic examination of cytologic smears taken from these effusions. These smears typically show plasmablasts and, in some cases, other malignant cells that have the morphology of anaplastic cells (i.e., large pleomorphic cells) or the Reed-Sternberg cells associated with Hodgkin disease. As detected by immunostaining methods, the malignant cells typically express molecular marker proteins such as CD45 (which is not expressed on mature plasma cells) as well as activation and plasma cell marker proteins such as CD30, MUC1, CD38, syndecan 1, and IRF4/MUM1; they do not express B-cell molecular marker proteins such as PAX5, CD19, CD29, or CD79a. The cells may also express many of the structural and non-structural gene abnormalities cited in the Pathophysiology section. By definition, individuals with PEL are infected by Kaposis sarcoma-associated herpesvirus (HHV-8 or KSHV/HHV8) and therefore evidence malignant cells that express products of this virus such as LANA1. In most cases, these individuals are also infected with EBV and therefore evidence malignant cells that express products of this virus such as EBER1/2 nuclear RNAs. Cases associated with HIV/AIDS test positive for antibodies directed against this virus. (PEL occurs in the absence of HHV-8 and HIV, although this is rare.) Individuals with PEL that is associated with cirrosis due to hepatitis evidence positive serum tests for the hepatitis virus B antigen (HBsAg) or one of the various tests for hepatitis C antigen. Extracavitary PEL is diagnosed based on findings that their mass lesions contain the same or very similar types of malignant cells and the same set of blood and serum findings as those that are found in cavitary PEL. KSHV/HHV8-negative primary effusion lymphoma Effusion-based lymphoma, KSHV/HHV8-negative (also termed Type II PEL) has been described by some researchers. These cases closely resemble KSHV/HHV8-positive (also termed Type I PEL) but have yet to be defined by the World Health Organization (2017). Compared to Type I PEL, Type II PEL occurs more often in older individuals, is less often associated with EBV, and more often afflicts individuals who lack evidence of being immunocompromised. That is, the majority of HHV-8-negative EBL cases do not evidence a potentially PEL causative agent, such as HIV, EBV, HCV, or iatrogenic immunodeficiency, except for old age and, in 20% to 40% of cases, the presence of hepatitis C virus infection. Type II PEL also tends to involve malignant plasmablasts, anaplastic cells, and/or Reed-Sternberg-like cells that have somewhat different expression patters of protein markers (e.g. the malignant cells in Type II PEL frequently express CD20 but often do not express CD30) and gene abnormalities (e.g. the malignant cells in Type II PEL more commonly evidence rearrangements in their Myc, BCL2, and BCL6 genes) than the malignant cells in Type I PEL. The response to treatment and prognosis of Type II PEL is poor but may be somewhat better than the treatment-responsiveness and prognosis of Type I PEL. One factor that appears to improve the treatment of Type II PEL is the addition of rituximab (a monoclonal antibody directed against and killing CD20-bearing cell) to the intensive chemotherapy regimens used to treat Type I PEL: the malignant cells in Type II PEL commonly express CD20 whereas the malignant cells in Type I PEL rarely express this cell surface marker. However, there are several cases of KSHV/HHV8-negative EBL that presented with pericardial effusions without evidence of more extensive disease that have experienced complete responses and favorable prognoses without chemotherapy or other cancer treatment (including rituximab) after simple drainage of the effusion. These cases suggest that, in addition to the presence of rituximab-sensitive CD20-bearing malignant cells, Type II PEL may be a less severe disease than Type I PEL, at lease in certain cases. Treatment PEL is generally resistant to cancer chemotherapy drugs that are active against other B-cell lymphomas and therefore carries a poor prognosis. Overall median and 1 year survival rates in a series of 28 patients treated with chemotherapy for PEL were 6.2 months and 39.3%, respectively. In this study, the complete response rate (presumed to be temporary) to a standard CHOP chemotherapeutic regimen (i.e. cyclophosphamide doxorubicin, vincristine, and prednisone) was only 10% whereas a more intensive CHO chemotherapy regimen which included high dose methotrexate and bleomycin achieved a compete response rate (presumed temporary) of 70%. A second study using CHOP-like regimens or one of these regimens plus methotrexate also produced better results with the latter regimens: 5 year survival rates for the CHOP-like and CHOP-like plus methotrexate regimens were 34.4% and 45.7%, respectively. A review of 105 PEL cases reported median survival times, 1 year, 3 year, and 5 year survival rates of 4.8 months, 30%, 18%, and 17%, respectively. In this study, patients with advanced Ann Arbor Stage III or IV disease had a particularly poor survival rate at 1 year of 25%; this compared to a rate of 42% for patients with stage I or II disease.Anti-viral drugs directed against Cytomegalovirus (i.e. cidofovir, ganciclovir, and valganciclovir) have been reported to produce complete presumed temporary responses in individual cases of PEL while drugs directed against HIV in patients with HIV+ PEL have achieved presumed temporary median response and 5 year survival rates of 0.7 months and 28%, respectively. The National Comprehensive Cancer Network (NCCN) guideline recommends treating HIV/AIDS-related PEL with antiviral therapy in combination with aggressive chemotherapy regimens such as DA-EPOCH, cyclophosphamide, doxorubicin, and etoposide, or CHOP. Rituximab, a monoclonal antibody directed against and killing CD20-expressing cells, appears to improve the efficacy of chemotherapy regimens in treating cases of PEL that evidence CD20-positive malignant cells such as Type II PEL. It has been suggested that regimens that include rituximab might improve the treatment of not only CD+ Type II PEL but also the uncommon cases of CD20+ Type I PEL and all cases of CD- PEL. The efficacy of rituximab in CD- PEL may be due to the ability of this antibody to kill non-malignant CD+ 20 lymphocytes and thereby their potential to promote the disease. A National Cancer Institute-sponsored clinical study is in its recruiting phase to study the efficacy of DA-EPOCH (which includes rituximab) plus lenalidomide in treating PEL. Current studies are also examining the effects of drug-based inhibition of the signaling pathways that are overactive in the malignant plasmablasts in PEL (see Pathophysiology section) for their therapeutic effectiveness. History PEL was first described in 1989 as a malignant B cell-derived non-Hodgkin lymphoma that developed in three individuals afflicted with HIV/AIDS. In 1995, a group of researchers found DNA sequences that identified KSHV/HHV8 sequences in 8 lymphomas in the malignant cells of patients infected with the HIV; all 8 patients had effusions containing malignant cells in their pleural, pericardial, or peritoneal spaces and had malignant cells in their effusions that evidenced the Epstein-Barr viral genome. Nadir and colleagues termed this syndrome of findings pulmonary effusion lymphoma in 1996. During the years following these initial reports, several cases of PEL were found to be KSHV/HHV8-negative, i.e. occurring in individuals with no evidence of being infected with KSHV/HHV8, or to be manifested by solid tumors that were not associated with effusions, i.e. cases of extracavitary PEL. See also List of hematologic conditions References == External links ==
The Bends	"The bends" is a colloquialism for decompression sickness. The Bends may also refer to: The Bends (album), a 1995 studio album by Radiohead "The Bends" (song), a 1995 song by Radiohead "The Bends", a song by Mr. Bungle from the 1995 album Disco Volante "The Bends", a song by Earl Sweatshirt from the 2018 album Some Rap Songs See also Bends (film), a 2013 British film All pages with titles containing The Bends Bend (disambiguation) Bending (disambiguation)
Fetal rhabdomyoma	Rhabdomyoma is a benign mesenchymal tumor of skeletal muscle, separated into two major categories based on site: Cardiac and extracardiac. They are further separated by histology: fetal (myxoid and cellular), juvenile (intermediate), and adult types. Genital types are recognized, but are often part of either the fetal or juvenile types. The fetal type is thought to recapitulate immature skeletal muscle at about week six to ten of gestational development. Signs and symptoms Most fetal rhabdomyomas are tumors that develop in the head and neck or in the genital region. There are a number of cases which have been seen in association with Gorlin syndrome. However, cardiac myxomas are known to be associated with tuberous sclerosis. Pathophysiology Gross pathology The tumor may be seen within the subcutaneous tissues (below the skin), mucosal surfaces or in soft tissue. Within the head and neck, the posterior ear region, skin of the face, and the tongue are the most commonly affected sites (about a 2:1 ratio of soft tissue to mucosa). The tumors are well defined, non-specific usually solitary masses, but when seen in the head and neck (or genital region), they may be polypoid. Tumors range in dimension from a few millimeters up to 12.5 cm, with a mean of about 3.0 cm. Although there are isolated case reports, multifocality is very rare. Microscopic pathology Fetal rhabdomyoma are separated into two histologic types: Myxoid and cellular. However, irrespective of histologic type, these tumors almost never show necrosis or increased mitoses. However, a cambium layer, abnormal mitoses and nuclear pleomorphism is not seen. Cellular fetal rhabdomyomas are composed of bland, primitive spindled cells. The spindle cells are haphazardly arranged primitive, elongated skeletal muscle cells. The cells are set within a well-developed fibromyxoid stroma. A different pattern (intermediate type) is predominantly composed of cells with better differentiation towards skeletal muscle. There are often large ganglion cell-like rhabdomyoblasts showing prominent nucleoli within nuclei that show vesicular chromatin distribution. Another population includes strap-like rhabdomyoblasts with darkly staining pink cytoplasm. Nearly all tumors show short to more sweeping fascicles of spindled rhabdomyoblasts. The tumor cells may infiltrate into adjacent skeletal muscle or fat. It is not uncommon to see peri-neural association, although not perineural infiltration. Diagnosis These tumors may be detected prenatally by ultrasound and MRI. Additionally, preoperative fine needle aspiration can be used to diagnose the tumor. Ancillary testing A phosphotungstic acid hematoxylin stain may be used to highlight cross striations in the cytoplasm of the tumor cells. PAS with diastase will highlight the presence of glycogen in the tumor cells cytoplasm. Immunohistochemistry will yield a positive reaction with a variety of myoid markers, including desmin, myoglobin, myogenin, MYOD1 and muscle specific actin. They may also be positive with vimentin, smooth muscle actin, and Leu-7. However, the tumor cells are almost always negative with glial fibrillary acidic protein, S100 protein, cytokeratin, epithelial membrane antigen, CD68, FLI1, CD99 and CD56. Although not used as frequently now, electron microscopy will show thick and thin myofilaments, Z-bands: these are features of sarcometric differentiation. Differential diagnosis The differential diagnosis histologically includes rhabdomyosarcoma, granular cell tumor, alveolar soft part sarcoma, hibernoma, oncocytoma, and crystal storing histiocytosis, among others. Management Surgical excision is the treatment of choice. Recurrences are reported, but this is usually due to incomplete removal initially. There is no role for chemotherapy or radiation therapy. Epidemiology They present over a wide age range (birth to about 65 years), but within the head and neck region, about 50% of cases develop in patients younger than 15 years of age. Within the head and neck, males are affected about 2–3 times more often than females. == References ==
Pyknoachondrogenesis	Pyknoachondrogenesis is a very rare, fatal, presumably autosomal recessive genetic disorder characterized by symptoms similar to those shown by patients with achondrogenesis alongside severely osteoclerotic bones and early death. The findings that can be seen in patients with this condition include hydrops fetalis, palpebral edemas, low-set ears, abdomen prominence, short neck, large head, depressed nasal bridge, shortening and widening of the trunk, severe short-limbed dwarfism, craniofacial hyperostosis, agenesis of the pubic bones, hypoplasia of the pelvic bones and ischium, poor (sometimes absent) ossification of the vertebrae and sacrum, webbing of the neck, and shortening of a long bone and the ribs. Pregnancies of babies with this condition generally arent compatible with life and they end up in miscarriage, stillbirth, or in neonatal death (that is, death soon after birth). Only 5 cases from Italy and the United States, respectively, have been described in medical literature. == References ==
Dentinogenesis imperfecta	Dentinogenesis imperfecta (DI) is a genetic disorder of tooth development. It is inherited in an autosomal dominant pattern, as a result of mutations on chromosome 4q21, in the dentine sialophosphoprotein gene (DSPP). It is one of the most frequently occurring autosomal dominant features in humans. Dentinogenesis imperfecta affects an estimated 1 in 6,000-8,000 people.This condition can cause teeth to be discolored (most often a blue-gray or yellow-brown color) and translucent, giving teeth an opalescent sheen. Teeth are also weaker than normal, making them prone to rapid wear, breakage, and loss. These problems can affect baby (primary/deciduous) teeth alone, or both baby teeth and adult (permanent) teeth, with the baby teeth usually more severely affected.Although genetic factors are the main contributor for the disease, any environmental or systemic upset that impedes calcification or metabolisation of calcium can also result in anomalous dentine. Classification Shield classification (1973) This is the most widely used classification for dentinogenesis imperfecta, and sub-divides the condition into 3 types: Type I DI associated with Osteogenesis Imperfecta (OI). Type of DI with similar dental abnormalities usually an autosomal dominant trait with variable expressivity but can be recessive if the associated osteogenesis imperfecta is of recessive type.Recent genetic studies have identified that mutations in the genes coding for the collagen type 1 proteins, COL1A1 and COL1A2, are associated with this type of DI.Not all individuals with OI have dentinogenesis imperfecta, and the prevalence of DI varies depending on the sub-type of OI: Higher prevalence of DI among individuals with OI type III and IV at 43-82% and 37-100%, respectively Lower prevalence of DI among individuals with OI type I at 8-40% No data available for other OI sub-types Type II DI not associated with OI. Occurs in people without other inherited disorders (i.e. Osteogenesis imperfecta). It is an autosomal dominant trait. A few families with type II have progressive hearing loss in addition to dental abnormalities. Also called hereditary opalescent dentin. Type III Brandywine isolate. This type is rare with occurrences only in the secluded populations in Maryland, USA. Similar to DI type II, this type is also not associated with OI. Its predominant characteristic is bell-shaped crowns, especially in the permanent dentition. Unlike Types I and II, it involves teeth with shell-like appearance and multiple pulp exposures.Mutations in the gene coding for the dentine sialophosphoprotein (DSPP) are associated with DI type II and III. DSPP is a polypeptide which gives rise to 3 proteins; dentine sialoprotein (DSP), dentine glycoprotein (DGP), and dentine phosphoprotein (DPP). The DPP protein is thought to contribute to hydroxyapatite crystal formation and growth, a fundamental crystal which is widely distributed in mineralised dentine and enamel. The function of the DGP and DSP proteins is not well understood.Genetic studies have shown that type II and III may be the same sub-type of dentinogenesis imperfecta, differing only by the severity. de La Dure-Molla, Foruner and Berdal (2015) de La Dure-Molla, Foruner and Berdal (2015) have proposed a new classification to supersede the Shield Classification (1973). This new classification is designed to overcome the shortcomings of its predecessor, mainly the clinical difficulty in using the Shield classification due to the overlapping signs & symptoms between the sub-types.In this classification, the authors propose that the DSPP (dentine sialophosphoprotein) diseases, that is dentinogenesis imperfecta and dentine dysplasia, are jointly named "Dentinogenesis imperfecta", and sub-types are determined according to the severity of the condition. There are a few exceptions: Shields Dentine Dysplasia type I - this condition is unique in that it only affects root development, and is separately termed "radicular dentin dysplasia" in the new classification. Shields Dentinogenesis Imperfecta type I - this sub-type is not acknowledged in this new classification as the authors deem it a different disease since it is a syndrome of osteogenesis imperfecta Mild type Primary (baby) teeth are moderately affected. Permanent (adult) teeth are not discoloured, or the discolouration is mild (grey colour). Little or no attrition (tooth wear) is evident. The crown of the teeth may be bulbous and markedly constricted at the cemento-enamel junction (CEJ). Radiographically, evidence of partial pulp obliteration with a "thistle-shaped appearance". Moderate type Teeth are moderately discoloured (blue, grey or amber opalescent). More attrition is evident with shortening of crown height. Crowns may appear bulbous with prominent constriction at the CEJ. Radiographically, the pulp is small or is totally obliterated. Roots appear thinner and shorter than average. There may be periapical pathology. Severe type Teeth are markedly discoloured (brown opalescent). The crowns are very short due to severe attrition. Crowns may appear bulbous with prominent constriction at the CEJ. Radiographically, pulp appears large and the dentine layer is thin ("shell teeth" as described in Presentation section). Roots are thin and short. There may be multiple periapical pathologies. Radicular dentin dysplasia This sub-type is used in place of Shields dentine dysplasia type I, in which only the roots of the teeth are affected. Both primary and permanent teeth are affected. The teeth appear normal clinically. Radiographically, the roots are shorter and fused together with a rounded apex. Presentation Clinical presentation Clinical features include: Discoloured teeth - teeth may be amber, brown, blue or opalescent Bulbous shape to the tooth crown due to cervical constriction Tooth wear/Non-carious tooth surface loss (NCTSL) - due to the poorly mineralised dentine, the enamel of the tooth is unsupported and subsequently shears or chips off as it is subjected to biting forces. This exposes the underlying poorly mineralised dentine which is less resistant to wear. Therefore, features of abrasion and attrition may become apparent. Reduction in occlusal vertical dimension (OVD) - this is secondary to the tooth wear/NCTSL. A reduced OVD can lead to craniofacial dysgnathia, poor tooth aesthetics, and disorders during chewing, swallowing, speaking and eating.The baby (primary) teeth are usually more severely affected than adult (permanent) teeth.Enamel is usually lost early because it is further inclined to attrition due to loss of scalloping at the dentinoenamel junction (DEJ). It was suggested that the scalloping is beneficial for the mechanical properties of teeth as it reinforces the anchor between enamel and dentine. However, the teeth are not more susceptible to dental caries than normal ones. Periodontal disease, or gum disease, is a common finding amongst individuals with dentinogenesis imperfecta despite no clinical findings of tooth decay (dental caries). The reason for this is currently not well understood.Certain patients with dentinogenesis imperfecta will suffer from multiple periapical abscesses apparently resulting from pulpal strangulation secondary to pulpal obliteration or from pulp exposure due to extensive coronal wear. They may need apical surgery to save the involved teeth.Note that, although dentine exposure is a common clinical finding, individuals with dentinogenesis imperfecta usually do not experience tooth sensitivity as the exposed dentine is typically sclerosed (hardened), thereby appearing glassy/shiny. Radiographic presentation Radiographic features include: Bulbous shape of tooth crown with pronounced cervical constriction Small pulp, or total pulp obliteration Small or obliterated root canal Presence of pulp stones Narrow and small roots Periapical radiolucency without any evidence of clinical pathology such as tooth decay (dental caries) Presentation by sub-type of Dentinogenesis Imperfecta Clinical and radiographic features can be categorised by the sub-type of dentinogenesis imperfecta (see Shields Classification in the Classification section): Type I Clinically, both the baby (primary) and adult (permanent) teeth often appear amber coloured and translucent, and show signs of severe attrition. Primary teeth have a more obvious appearance as they have a thinner layer of enamel overlying dentine, hence the abnormal color of dentine is more noticeable.Radiographically, affected teeth have short and narrow roots, and obliterated pulps due to dentine hypertrophy before or shortly after tooth eruption.The severity of these features is variable, with some teeth presenting with total obliteration of the pulp, while other teeth appear to have normal, healthy dentine.Some type I cases present with no clinical findings, with only radiographic abnormalities. Type II Type II has a similar clinical and radiographic appearance to type I with some distinguishing features: Bulbous crowns are common with pronounced cervical constriction All teeth in the mouth are affected, with severe abnormalities present in both the baby (primary) and adult (permanent) teeth. This is in contrast to type I where the presentation is more variable Rarely, individuals exhibit sensorineural hearing loss. It is proposed this hearing loss is a secondary feature to attrition; this type of tooth wear can cause jaw overclosure with subsequent changes to the shape of the inner ear, thus causing hearing loss. However, the true cause remains unknown. Type III Similar clinical and radiographic features to that of type I and II are apparent for the adult (permanent) teeth. The main distinguishing feature is "shell teeth", a term used to describe the unique appearance of the baby (primary) teeth; the primary teeth have multiple pulp exposures and radiographically appear hollow as the dentine layer is thin (dentine hypotrophy) and the pulp chamber is very large. Histology The enamel has a regular structure, however, there are abnormalities in the structure of dentine and at the amelo-dentinal junction. These abnormalities include: Fewer dentinal tubules Dentinal tubules may be of smaller diameter, irregular in shape, and may also be obliterated Abnormal morphology of apatite crystals Higher water and collagen content in the organic component of dentine (see Structure section on dentin page to learn more) Diagnosis To determine if the condition has been inherited, it is suggested to ask if any other family member has Dentinogenesis imperfecta. A lack of family history may indicate that the condition was acquired.It is suggested that the dental/medical professional establish if the condition is a syndrome of another inherited condition such as: Osteogenesis imperfecta - indicates Type I Dentinogenesis Imperfecta (see Shields Classification in Classification section) Ehlers Danlos syndrome Goldblatt syndrome Schimke immune-osseus dysplasia Brachio-skeleto-genital syndrome Osteodysplastic and primordial short stature with severe microdontia Opalescent teeth Rootless molars[This is not a comprehensive list] It can be useful to enquire about symptoms of osteogenesis imperfecta, as Type I Dentinogenesis Imperfecta (Shields Classification) is associated with osteogenesis imperfecta. Notable information includes: History of bone fracture caused by minimal trauma Short stature Blue sclera Hearing lossCommon dental features of osteogenesis imperfecta include: Hypodontia Oligodontia Taurodontism Unerupted permanent 2nd molars, with no obstruction in the path of eruption Retrognathic maxilla Differential diagnosis Hypocalcified forms of amelogenesis imperfecta Congenital erythropoietic porphyria Conditions that can cause early loss of teeth e.g. Kostmanns disease, cyclic neutropenia, Chediak-Hegashi syndrome, histiocytosis X, Papillon-Lefevre syndrome Permanent tooth discolouration caused by medications such as tetracyclines, or medical conditions such as rickets Treatment Preventive and restorative care are important as well as esthetics as a consideration. This ensures preservation of the patients vertical face height between their upper and lower teeth when they bite together. The basis of treatment is standard throughout the different types of DI where prevention, preservation of occlusal face height, maintenance of function, and aesthetic needs are priority. Preventive efforts can limit pathology occurring within the pulp, which may render future endodontic procedures less challenging, with better outcomes. Challenges are associated with root canal treatment of teeth affected by DI due to pulp chamber and root canal obliteration, or narrowing of such spaces. If root canal treatment is indicated, it should be done in a similar way like with any other tooth. Further consideration is given for restoring the root-treated tooth as it has weaker dentine which may not withstand the restoration.Preservation of occlusal face height may be tackled by use of stainless steel crowns which are advocated for primary teeth where occlusal face height may be hugely compromised due to loss of tooth tissue as a result of attrition, erosion of enamel.In most cases, full-coverage crowns or veneers (composite/porcelain) are needed for aesthetic appearance, as well as to prevent further attrition. Another treatment option is bonding, putting lighter enamel on the weakened enamel of the teeth and with many treatments of this bonding, the teeth appear whiter to the eye, but the teeth on the inside and under that cover are still the same. Due to the weakened condition of the teeth, many common cosmetic procedures such as braces and bridges are inappropriate for patients with Dentinogenesis imperfecta and are likely to cause even more damage than the situation they were intended to correct. Dental whitening (bleaching) is contraindicated although it has been reported to lighten the color of DI teeth with some success; however, because the discoloration is caused primarily by the underlying yellow-brown dentin, this alone is unlikely to produce normal appearance in cases of significant discoloration.If there is considerable attrition, overdentures may be prescribed to prevent further attrition of remaining teeth and for preserving the occlusal face height. Management of DI associated with OI Bisphosphonates have recently been introduced to treat several bone disorders, which include osteogenesis imperfecta.A recognized risk of this drug relevant to dental treatments is bisphosphonate-associated osteonecrosis of the jaw (BRONJ). Occurrences of this risk is associated with dental surgical procedures such as extractions. Dental professionals should therefore proceed with caution when carrying out any dental procedures in patients who have Type 2 DI who may be on bisphosphonate drug therapy. See also Dentin Dentinogenesis Tooth development Osteogenesis imperfecta References This article incorporates public domain text from The U.S. National Library of Medicine == External links ==
Chloroform	Chloroform, or trichloromethane, is an organic compound with formula CHCl3 and is a common organic solvent. It is a colorless, strong-smelling, dense liquid produced on a large scale as a precursor to PTFE. It is also a precursor to various refrigerants. It is one of the four chloromethanes and a trihalomethane. It is a powerful anesthetic, euphoriant, anxiolytic, and sedative when inhaled or ingested. Structure The molecule adopts a tetrahedral molecular geometry with C3v symmetry. Natural occurrence The total global flux of chloroform through the environment is approximately 660000 tonnes per year, and about 90% of emissions are natural in origin. Many kinds of seaweed produce chloroform, and fungi are believed to produce chloroform in soil. Abiotic processes are also believed to contribute to natural chloroform productions in soils although the mechanism is still unclear.Chloroform volatilizes readily from soil and surface water and undergoes degradation in air to produce phosgene, dichloromethane, formyl chloride, carbon monoxide, carbon dioxide, and hydrogen chloride. Its half-life in air ranges from 55 to 620 days. Biodegradation in water and soil is slow. Chloroform does not significantly bioaccumulate in aquatic organisms. History Chloroform was synthesized independently by several investigators circa 1831: Moldenhawer, a German pharmacist from Frankfurt an der Oder, appears to have produced chloroform in 1830 by mixing chlorinated lime with ethanol; he mistook it for Chloräther (chloric ether, 1,2-dichloroethane), however. Samuel Guthrie, a U.S. physician from Sackets Harbor, New York, also appears to have produced chloroform in 1831 by reacting chlorinated lime with ethanol, as well as noting its anaesthetic properties; he also believed that he had prepared chloric ether, however. Justus von Liebig carried out the alkaline cleavage of chloral. Eugène Soubeiran obtained the compound by the action of chlorine bleach on both ethanol and acetone. In 1834, French chemist Jean-Baptiste Dumas determined chloroforms empirical formula and named it. In 1835, Dumas prepared the substance by the alkaline cleavage of trichloroacetic acid. Regnault prepared chloroform by chlorination of chloromethane. In 1842, Robert Mortimer Glover in London discovered the anaesthetic qualities of chloroform on laboratory animals. In 1847, Scottish obstetrician James Y. Simpson was the first to demonstrate the anaesthetic properties of chloroform on humans, provided by local pharmacist William Flockhart of Duncan, Flockhart and company, and helped to popularise the drug for use in medicine. By the 1850s, chloroform was being produced on a commercial basis, in Britain about 750,000 doses a week by 1895, by using the Liebig procedure, which retained its importance until the 1960s. Today, chloroform – along with dichloromethane – is prepared exclusively and on a massive scale by the chlorination of methane and chloromethane. Production In industry production, chloroform is produced by heating a mixture of chlorine and either chloromethane (CH3Cl) or methane (CH4). At 400–500 °C, a free radical halogenation occurs, converting these precursors to progressively more chlorinated compounds: CH4 + Cl2 → CH3Cl + HCl CH3Cl + Cl2 → CH2Cl2 + HCl CH2Cl2 + Cl2 → CHCl3 + HClChloroform undergoes further chlorination to yield carbon tetrachloride (CCl4): CHCl3 + Cl2 → CCl4 + HClThe output of this process is a mixture of the four chloromethanes (chloromethane, dichloromethane, chloroform, and carbon tetrachloride), which can then be separated by distillation.Chloroform may also be produced on a small scale via the haloform reaction between acetone and sodium hypochlorite: 3 NaClO + (CH3)2CO → CHCl3 + 2 NaOH + CH3COONa Deuterochloroform Deuterated chloroform is an isotopologue of chloroform with a single deuterium atom. CDCl3 is a common solvent used in NMR spectroscopy. Deuterochloroform is produced by the haloform reaction, the reaction of acetone (or ethanol) with sodium hypochlorite or calcium hypochlorite. The haloform process is now obsolete for the production of ordinary chloroform. Deuterochloroform can be prepared by the reaction of sodium deuteroxide with chloral hydrate. Inadvertent formation of chloroform The haloform reaction can also occur inadvertently in domestic settings. Bleaching with hypochlorite generates halogenated compounds in side reactions; chloroform is the main byproduct. Sodium hypochlorite solution (chlorine bleach) mixed with common household liquids such as acetone, methyl ethyl ketone, ethanol, or isopropyl alcohol can produce some chloroform, in addition to other compounds such as chloroacetone or dichloroacetone. Uses In terms of scale, the most important reaction of chloroform is with hydrogen fluoride to give monochlorodifluoromethane (CFC-22), a precursor in the production of polytetrafluoroethylene (Teflon): CHCl3 + 2 HF → CHClF2 + 2 HClThe reaction is conducted in the presence of a catalytic amount of mixed antimony halides. Chlorodifluoromethane is then converted into tetrafluoroethylene, the main precursor to Teflon. Before the Montreal Protocol, chlorodifluoromethane (designated as R-22) was also a popular refrigerant. Solvent The hydrogen attached to carbon in chloroform participates in hydrogen bonding. Worldwide, chloroform is also used in pesticide formulations, as a solvent for fats, oils, rubber, alkaloids, waxes, gutta-percha, and resins, as a cleansing agent, grain fumigant, in fire extinguishers, and in the rubber industry. CDCl3 is a common solvent used in NMR spectroscopy. Lewis acid In solvents such as CCl4 and alkanes, chloroform hydrogen bonds to a variety of Lewis bases. HCCl3 is classified as a hard acid and the ECW model lists its acid parameters as EA = 1.56 and CA = 0.44. Reagent As a reagent, chloroform serves as a source of the dichlorocarbene :CCl2 group. It reacts with aqueous sodium hydroxide usually in the presence of a phase transfer catalyst to produce dichlorocarbene, :CCl2. This reagent effects ortho-formylation of activated aromatic rings such as phenols, producing aryl aldehydes in a reaction known as the Reimer–Tiemann reaction. Alternatively, the carbene can be trapped by an alkene to form a cyclopropane derivative. In the Kharasch addition, chloroform forms the CHCl2 free radical in addition to alkenes. Anaesthetic The anaesthetic qualities of chloroform were first described in 1842 in a thesis by Robert Mortimer Glover, which won the Gold Medal of the Harveian Society for that year. Glover also undertook practical experiments on dogs to prove his theories. Glover further refined his theories and presented them in the thesis for his doctorate at the University of Edinburgh in the summer of 1847. The Scottish obstetrician James Young Simpson was one of the persons required to read the thesis, but later claimed to have never read the thesis and to have come to his conclusions independently.On 4 November 1847, Simpson first discovered the anesthetic qualities of chloroform on humans. He and two colleagues were entertaining themselves by trying the effects of various substances, and thus revealed the potential for chloroform in medical procedures.A few days later, during the course of a dental procedure in Edinburgh, Francis Brodie Imlach became the first person to use chloroform on a patient in a clinical context. In May 1848, Robert Halliday Gunning made a presentation to the Medico-Chirurgical Society of Edinburgh following a series of laboratory experiments on rabbits that confirmed Glovers findings and also refuted Simpsons claims of originality. A knighthood for Simpson, and massive media coverage of the wonders of chloroform, ensured that Simpsons reputation remained high. In contrast, the laboratory experiments proving the dangers of chloroform were largely ignored. Gunning, who became one of the richest persons in Britain, endowed some 13 university scholarships under the names of other scientists rather than his own name. He considered Simpson a charlatan, but one of these prizes is named the Simpson Prize for Obstetrics. It is, however, probably a strange reverse compliment, as arguably any Simpson prize in the wider public eye should be a prize for anaesthesia. By not calling it this he effectively snubbed Simpson whilst at the same time appearing to honour him.The use of chloroform during surgery expanded rapidly thereafter in Europe. In the 1850s, chloroform was used by the physician John Snow during the birth of Queen Victorias last two children. In the United States, chloroform began to replace ether as an anesthetic at the beginning of the 20th century; it was quickly abandoned in favor of ether upon discovery of its toxicity, however, especially its tendency to cause fatal cardiac arrhythmia analogous to what is now termed "sudden sniffers death". Some people used chloroform as a recreational drug or to attempt suicide. One possible mechanism of action for chloroform is that it increases movement of potassium ions through certain types of potassium channels in nerve cells. Chloroform could also be mixed with other anesthetic agents such as ether to make C.E. mixture, or ether and alcohol to make A.C.E. mixture.In 1848, Hannah Greener, a 15-year-old girl who was having an infected toenail removed, died after being given the anesthetic. Her autopsy establishing the cause of death was undertaken by John Fife assisted by Robert Mortimer Glover. A number of physically fit patients died after inhaling it. In 1848, however, John Snow developed an inhaler that regulated the dosage and so successfully reduced the number of deaths.The opponents and supporters of chloroform were mainly at odds with the question of whether the complications were solely due to respiratory disturbance or whether chloroform had a specific effect on the heart. Between 1864 and 1910, numerous commissions in Britain studied chloroform but failed to come to any clear conclusions. It was only in 1911 that Levy proved in experiments with animals that chloroform can cause cardiac fibrillation. The reservations about chloroform could not halt its soaring popularity. Between 1865 and 1920, chloroform was used in 80 to 95% of all narcoses performed in the UK and German-speaking countries. In the United States, however, there was less enthusiasm for chloroform narcosis. In Germany, the first comprehensive surveys of the fatality rate during anesthesia were made by Gurlt between 1890 and 1897. In 1934, Killian gathered all the statistics compiled until then and found that the chances of suffering fatal complications under ether were between 1:14,000 and 1:28,000, whereas under chloroform the chances were between 1:3,000 and 1:6,000. The rise of gas anesthesia using nitrous oxide, improved equipment for administering anesthetics and the discovery of hexobarbital in 1932 led to the gradual decline of chloroform narcosis. Criminal use Chloroform has reputedly been used by criminals to knock out, daze, or even murder victims. Joseph Harris was charged in 1894 with using chloroform to rob people. Serial killer H. H. Holmes used chloroform overdoses to kill his female victims. In September 1900, chloroform was implicated in the murder of the U.S. businessman William Marsh Rice, the namesake of the institution now known as Rice University. Chloroform was deemed a factor in the alleged murder of a woman in 1991 when she was asphyxiated while sleeping. In 2002, 13-year-old Kacie Woody was sedated with chloroform when she was abducted by David Fuller and during the time that he had her, before he shot and killed her. In a 2007 plea bargain, a man confessed to using stun guns and chloroform to sexually assault minors.Use of chloroform as an incapacitating agent has become widely recognized, bordering on clichéd, due to the popularity of crime fiction authors having criminals use chloroform-soaked rags to render victims unconscious. Nonetheless, it is nearly impossible to incapacitate someone using chloroform in this manner. It takes at least five minutes of inhaling an item soaked in chloroform to render a person unconscious. Most criminal cases involving chloroform also involve another drug being co-administered, such as alcohol or diazepam, or the victim being found to have been complicit in its administration. After a person has lost consciousness due to chloroform inhalation, a continuous volume must be administered, and the chin must be supported to keep the tongue from obstructing the airway, a difficult procedure typically requiring the skills of an anesthesiologist. In 1865 as a direct result of the criminal reputation chloroform had gained, the medical journal The Lancet offered a "permanent scientific reputation" to anyone who could demonstrate "instantaneous insensibility", i.e. losing consciousness instantaneously, using chloroform. Safety Exposure Chloroform is known to form as a by-product of water chlorination along with a range of other disinfection by-products and as such is commonly present in municipal tap water and swimming pools. Reported ranges vary considerably but are generally below the current health standard for total trihalomethanes of 100μg/L. Nonetheless, the presence of chloroform in drinking water at any concentration is considered controversial by some.Historically, chloroform exposure may well have been higher due to its common use as an anesthetic, as an ingredient in cough syrups, and as a constituent of tobacco smoke where DDT had previously been used as a fumigant. Pharmacology It is well absorbed, metabolized, and eliminated rapidly by mammals after oral, inhalation, or dermal exposure. Accidental splashing into the eyes has caused irritation. Prolonged dermal exposure can result in the development of sores as a result of defatting. Elimination is primarily through the lungs in the form of chloroform and carbon dioxide; less than 1% is excreted in the urine.Chloroform is metabolized in the liver by the cytochrome P-450 enzymes, by oxidation to chloromethanol and by reduction to the dichloromethyl free radical. Other metabolites of chloroform include hydrochloric acid and digluathionyl dithiocarbonate, with carbon dioxide as the predominant end product of metabolism.Like most other general anesthetics and sedative-hypnotic drugs, chloroform is a positive allosteric modulator for the GABAA receptor. Chloroform causes depression of the central nervous system (CNS), ultimately producing deep coma and respiratory center depression. When ingested, chloroform caused symptoms similar to those seen following inhalation. Serious illness has followed ingestion of 7.5 g (0.26 oz). The mean lethal oral dose for an adult is estimated at 45 g (1.6 oz).The anesthetic use of chloroform has been discontinued because it caused deaths due to respiratory failure and cardiac arrhythmias. Following chloroform-induced anesthesia, some patients suffered nausea, vomiting, hyperthermia, jaundice, and coma due to hepatic dysfunction. At autopsy, liver necrosis and degeneration have been observed.Chloroform has induced liver tumors in mice and kidney tumors in mice and rats. The hepatotoxicity and nephrotoxicity of chloroform is thought to be due largely to phosgene. Conversion to phosgene Chloroform converts slowly in air to the extremely poisonous phosgene (COCl2), releasing HCl in the process. 2 CHCl3 + O2 → 2 COCl2 + 2 HClTo prevent accidents, commercial chloroform is stabilized with ethanol or amylene, but samples that have been recovered or dried no longer contain any stabilizer. Amylene has been found ineffective, and the phosgene can affect analytes in samples, lipids, and nucleic acids dissolved in or extracted with chloroform. Phosgene and HCl can be removed from chloroform by washing with saturated aqueous carbonate solutions, such as sodium bicarbonate. This procedure is simple and results in harmless products. Phosgene reacts with water to form carbon dioxide and HCl, and the carbonate salt neutralizes the resulting acid.Suspected samples can be tested for phosgene using filter paper (treated with 5% diphenylamine, 5% dimethylaminobenzaldehyde in ethanol, and then dried), which turns yellow in phosgene vapor. There are several colorimetric and fluorometric reagents for phosgene, and it can also be quantified with mass spectrometry. Regulation Chloroform is suspected of causing cancer (i.e., possibly carcinogenic, IARC Group 2B) as per the International Agency for Research on Cancer (IARC) Monographs. [PDF] It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities. Bioremediation of chloroform Some anaerobic bacteria use chloroform for their respiration, termed organohalide respiration, converting it to dichloromethane. References External links Chloroform "The Molecular Lifesaver" An article at Oxford University providing facts about chloroform. Concise International Chemical Assessment Document 58 IARC Summaries & Evaluations: Vol. 1 (1972), Vol. 20 (1979), Suppl. 7 (1987), Vol. 73 (1999) International Chemical Safety Card 0027 NIOSH Pocket Guide to Chemical Hazards. "#0127". National Institute for Occupational Safety and Health (NIOSH). NIST Standard Reference Database
Anterior cutaneous nerve entrapment syndrome	Anterior cutaneous nerve entrapment syndrome (ACNES) is a nerve entrapment condition that causes chronic pain of the abdominal wall. It occurs when nerve endings of the lower thoracic intercostal nerves (7–12) are entrapped in abdominal muscles, causing a severe localized nerve (neuropathic) pain that is usually experienced at the front of the abdomen. ACNES is frequently overlooked and unrecognized, although the incidence is estimated to be 1:2000 patients.The relative unfamiliarity with this condition often leads to significant diagnostic delays and misdiagnoses, often resulting in unnecessary diagnostic interventions and futile procedures. Physicians often misdiagnose ACNES as irritable bowel syndrome or appendicitis as symptoms of the condition are not unique to this syndrome. Signs and symptoms Affected individuals typically experience limited relief from standard pain relieving medication, with the exception of some neuroleptic agents. Patients frequently experience pseudovisceral phenomena or symptoms of altered autonomic nervous system function including nausea, bloating, abdominal swelling, loss of appetite with consecutively lowered body weight or an altered defecation process.Pain is typically related to tensing the abdominal wall muscles, so any type of movement is prone to aggravate pain. Lying quietly can be the least painful position. Most patients report that they cannot sleep on the painful side. Diagnosis Once ACNES is considered based on the patients history, the diagnosis can be made via a thorough physical examination: looking for a painful spot, which worsens by tensing the abdominal muscles with lifting the head and straightened legs (Carnetts sign). Almost always, a small area of maximal pain is covered by a larger area of altered skin sensibility with somatosensory disturbances such as hypoesthesia as well as hyperesthesia or hyperalgesia and change of cool perception. Pinching the skin between thumb and index finger is extremely painful compared to the opposite non-involved side.Confirmation of a diagnosis of ACNES is warranted using an abdominal wall infiltration with a local anesthetic agent near the painful spot. Treatment Treatment consists of several such anesthetic injections, sometimes combined with corticosteroids. Such an approach yields persistent pain relief in two-thirds of patients. This beneficial effect on pain has been demonstrated in a prospective double blind trial. The physical volume of the injection may also break apart the adhesions or fibrosis responsible for the entrapment symptoms.Patients who do not respond to a stratagem of repetitive local trigger point injections can be offered a surgical approach. Terminal branches of an intercostal nerve are removed at the level of the anterior sheath of the rectus abdominal muscle (anterior neurectomy). Several larger series demonstrated a successful response in approximately two out of three patients, which was confirmed in another prospective double blind surgical trial: 73% of the patients who underwent a neurectomy were pain free, compared to 18% in the non-nerve resected group. Patients not responding to an anterior neurectomy, or those in whom the pain syndrome recurs after an initial pain free period (10%) may choose to undergo secondary surgery. This involves a repeated exploration combined with a posterior neurectomy. This procedure has been shown to be beneficial in 50% of cases. Epidemiology This syndrome is predominantly found in young women, but also occurs in children, teenagers and octogenarians. == References ==
Multisystem inflammatory syndrome in children	Multisystem inflammatory syndrome in children (MIS-C), or paediatric inflammatory multisystem syndrome (PIMS / PIMS-TS), or systemic inflammatory syndrome in COVID-19 (SISCoV), is a rare systemic illness involving persistent fever and extreme inflammation following exposure to SARS-CoV-2, the virus responsible for COVID-19. MIS-C is also recognized as a potential pediatric adverse event following COVID-19 vaccination. It can rapidly lead to medical emergencies such as insufficient blood flow around the body (a condition known as shock). Failure of one or more organs can occur. A warning sign is unexplained persistent fever with severe symptoms following exposure to COVID-19. Prompt referral to paediatric specialists is essential, and families need to seek urgent medical assistance. Most affected children will need intensive care.All affected children have persistent fever. Other clinical features vary. The first symptoms often include acute abdominal pain with diarrhoea or vomiting. Muscle pain and general tiredness are frequent, and low blood pressure is also common. Symptoms can also include pink eye, rashes, enlarged lymph nodes, swollen hands and feet, and "strawberry tongue". Various mental disturbances are possible. A cytokine storm may take place, in which the childs innate immune system stages an excessive and uncontrolled inflammatory response. Heart failure is common. Clinical complications can include damage to the heart muscle, respiratory distress, acute kidney injury, and increased blood coagulation. Coronary artery abnormalities can develop (ranging from dilatation to aneurysms).This life-threatening disease has proved fatal in under 2% of reported cases. Early recognition and prompt specialist attention are essential. Anti-inflammatory treatments have been used, with good responses being recorded for intravenous immunoglobulin (IVIG), with or without corticosteroids. Oxygen is often needed. Supportive care is key for treating clinical complications. Most children who receive expert hospital care survive.Knowledge of this newly described syndrome is evolving rapidly. Its clinical features may appear somewhat similar to Kawasaki disease, a rare disease of unknown origin that typically affects young children, in which blood vessels become inflamed throughout the body. It can also show features of other serious inflammatory conditions of childhood, including toxic shock and macrophage activation syndromes. Nevertheless, it appears to be a separate syndrome. Older children tend to be affected.This emerging condition has been defined slightly differently (using different names), by the World Health Organization (WHO), the Royal College of Paediatrics and Child Health (RCPCH), and the Centers for Disease Control and Prevention (CDC). Although the condition is thought to follow SARS-CoV-2 viral infection, antigen or antibody tests are not always positive. Exclusion of alternative causes, including bacterial and other infections, is essential for differential diagnosis. Some general clinical guidance has been provided by the RCPCH, the National Institutes of Health, the American College of Rheumatology, and the American Academy of Pediatrics.Clusters of new cases have been reported two to six weeks after local peaks in viral transmission. The disease is thought to be driven by a delayed biological mechanism in certain predisposed children. The European Centre for Disease Prevention and Control (ECDC) has rated risk to children in Europe as being low overall, based on a very low likelihood of a child developing this high impact disease. Regarding ethnicity, the condition seems to affect more children of African, Afro-Caribbean, and Hispanic descent, whereas Kawasaki disease affects more of East Asian ancestry. Initial reports regarded children in various parts of Europe and the United States, and it was unclear to what extent the condition had gone unrecognized elsewhere. Reports have since emerged of cases in various other countries around the world. In adults, a similar condition has occasionally been reported, which has been called multisystem inflammatory syndrome in adults (MIS-A). Name The disorder has been called by various names, including: Multisystem inflammatory syndrome in children (MIS-C) Multisystem inflammatory syndrome (MIS) in children and adolescents temporally related to COVID-19 Paediatric inflammatory multisystem syndrome (PIMS) Paediatric inflammatory multisystem syndrome, temporally associated with SARS-CoV-2 infection (PIMS-TS) Paediatric multisystem inflammatory syndrome (PMIS) Kawa-COVID-19 Systemic inflammatory syndrome in COVID-19 (SISCoV) Background Symptomatic cases of COVID-19 in children have been relatively uncommon, possibly because they generally experience milder disease. Early infection tends to be associated with mild or no symptoms, while the later pulmonary phase, which can be life-threatening in adults, is usually mild or absent. While cases of children with severe symptoms are exceptional, they can occasionally require intensive care. Fatalities have been rare.In April 2020, a small group of children with evidence of SARS-CoV-2 infection or exposure to COVID-19 were found to display clinical features corresponding to the diagnostic criteria of Kawasaki disease, sometimes accompanied by shock. Kawasaki disease is a rare syndrome which mainly affects young children (adult onset has occasionally been reported). It is a form of vasculitis, where blood vessels become inflamed throughout the body, and it results in a persistent fever. Recovery typically occurs spontaneously, though some children later develop mid-sized or giant coronary artery aneurysms in the heart – a potentially fatal complication. Symptoms of toxic shock (a syndrome caused by bacterial toxins) occasionally occur – an association sometimes referred to as Kawasaki shock syndrome, which is characterized by systolic hypotension or signs of poor perfusion. While the exact cause of Kawasaki disease is unknown, one plausible explanation is that it may stem from an infection triggering an autoimmune and/or autoinflammatory response in children who are genetically predisposed. No specific diagnostic test exists for Kawasaki disease, and its recognition is based on various combinations of clinical and laboratory findings (including persistent fever, widespread rashes, enlarged lymph nodes, conjunctivitis, changes to the mucous membranes, and swollen hands and feet). Characteristics MIS-C / PIMS-TS is a systemic disorder involving persistent fever, extreme inflammation (hyperinflammation), and organ dysfunction, which is temporally associated with exposure to COVID-19. Onset may be delayed or contemporary with ongoing SARS-CoV-2 infection, which may pass without symptoms. The time the syndrome takes to appear following the initial viral infection is debated, though it may develop between the first and second week. Epidemiological data suggest that recognition of the disease may typically be delayed by 2–6 weeks, and usually by 3–4 weeks. By the time of presention, children have often developed antibodies to SARS-CoV-2, but test negative for the virus at RT-PCR.The condition may match some or all of the diagnostic criteria for Kawasaki disease (i.e. the complete or incomplete/atypical subtypes), or for Kawasaki disease shock syndrome. It tends to affect all paediatric age groups, ranging from infancy to adolescence. It can also share clinical features with other paediatric inflammatory conditions, including toxic shock syndrome, and secondary haemophagocytic lymphohistiocytosis or macrophage activation syndrome. Coinfections with other pathogens have been recorded.Affected children always present with persistent fever. Other clinical features at presentation vary. In contrast to acute COVID-19, most children have gastrointestinal symptoms, such as diarrhoea, vomiting, and intense abdominal pain (sometimes severe enough to suggest appendicitis). Muscle pain and feelings of tiredness and general physical weakness are also very common. Some Kawasaki-like symptoms that may be present (especially in children under the age of 5) include mucosal changes around the mouth ("strawberry tongue", cracked lips, etc.), red eyes (conjunctivitis without pus), widespread rash (consistent with leukocytoclastic vasculitis), red or swollen hands and feet, and enlarged lymph nodes. Chest or neck pain may also be present. Severe headache and altered mental state have been reported, along with various neurological disturbances. Features of meningitis have been reported as well as septic encephalopathy, stroke, and Guillain-Barre Syndrome. Some patients present with very low blood pressure and shock, and they may require urgent admission to a paediatric intensive care unit.Cardiovascular involvement is very frequent. Acute heart failure is common in the form of left ventricular dysfunction, and a left ventricular ejection fraction under 60% is frequent. Shock is often of myocardial – mainly left ventricular – origin. Respiratory symptoms are less common, and are not usually a prominent feature. When present, breathing difficulties are often linked to shock, and are suggestive of heart failure. Some children display features of a cytokine storm, including extremely high serum interleukin-6 (IL-6) levels, and need inotropic support to maintain cardiac output. Coronary artery abnormalities, such as dilatation, are frequent. Some children have developed coronary artery aneurysms. Electrocardiographic (ECG) abnormalities are common. Other cardiological features sometimes include inflammation of the heart valves (valvulitis) and of the fibrous sac surrounding the heart (pericarditis). Echocardiographic features of myocarditis (inflammation of the heart muscle) have been recorded.Affected children consistently show laboratory evidence of hyperinflammation. Pronounced biological markers of inflammation generally include strongly raised erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), procalcitonin, ferritin, and IL6. Low platelet counts and impaired blood clotting (coagulopathy) are also common, with increased levels of D-dimer and fibrinogen. Other haematological features include raised numbers of white blood cells (leukocytosis), characterized by high numbers of neutrophils, with many immature forms, and low numbers of lymphocytes (lymphopaenia). Numbers of red blood cells and platelets may be either normal or decreased. Acute kidney injury and low albumin levels in the blood (hypoalbuminaemia) are common. Low blood sodium levels and raised liver enzymes have been reported. Accumulations of fluid in the lungs (pleural effusion), around the heart (pericardial effusion), and in the abdomen (ascites) have also been reported, consistent with generalized inflammation.Differences with respect to Kawasaki disease include frequent presentation with gastrointestinal symptoms such as vomiting, diarrhoea, and abdominal pain. Neurological involvement also appears to be relatively frequent. It often affects older children, whereas Kawasaki disease usually occurs before the age of five. Multiorgan disease appears to be more frequent. Myocarditis and cardiogenic shock seem to be relatively common. Myocarditis may be more evident in older children and adolescents. Preschool children tend to display more Kawasaki-like characteristics. Features of macrophage activation syndrome appear to be more frequent than in Kawasaki disease. Characteristic laboratory findings that are not usually encountered in Kawasaki disease include very high levels of ventricular natriuretic peptide (a marker of heart failure), as well as somewhat lower platelet counts, lower absolute lymphocyte counts, and higher CRP levels. Very high troponin levels (suggestive of myocardial damage) are also common. Clinical course Clinical course tends to be more severe than with Kawasaki disease. A childs condition can deteriorate rapidly, even in the presence of reassuring laboratory findings. Many children develop shock and heart failure. Most require paediatric intensive care. Supplemental oxygen is often needed, and mechanical ventilation is sometimes used. Most children who receive expert multidisciplinary care survive. In addition to respiratory distress, major complications that may need aggressive supportive care can include myocardial damage, acute kidney injury, and coagulopathy (thrombophilia). In some cases, sustained cardiac arrhythmias have led to haemodynamic collapse and need for extracorporeal membrane oxygenation (ECMO). Deaths have been recorded in a small minority (under 2%) of the cases reported. Occasionally, fatalities have followed complications of ECMO. Some children exposed to COVID-19 also appear to have a less severe Kawasaki-like disease. Ventricular function often recovers before discharge from hospital (often after 6–10 days). Coronary artery aneurysms can develop even in the absence of Kawasaki-like features. Their frequency and severity is uncertain. So far, they have been recorded in 7% of reported cases. Long-term prognosis is unclear. Diagnosis Diagnosis is by specialist clinical evaluation. Diagnostic suspicion may be raised by unexplained persistent fever and clinically concerning symptoms following exposure to COVID-19. Families need to seek immediate medical care, as the childs condition can deteriorate rapidly. Paediatricians first involvement is often in the emergency department. Early recognition and multidisciplinary referral to paediatric specialists (in intensive care, infectious diseases, cardiology, haematology, rheumatology, etc.) is essential. Examinations may include blood tests, chest x-ray, heart ultrasound (echocardiography), and abdominal ultrasound. Clinicians worldwide have been urged to consider this condition in children who display some or all the features of Kawasaki disease or toxic shock syndrome. Case definitions and guidance A universally accepted case definition for this newly described syndrome has still not been agreed. In the meantime, different names and provisional case definitions are being used around the world. The initial case definitions released by the World Health Organization (WHO), the Royal College of Paediatrics and Child Health (RCPCH) and Centers for Disease Control and Prevention (CDC) all include involvement of more than one organ system, along with fever and elevated inflammatory markers. Criteria that vary among these three definitions include the ways in which involvement of different organs is defined, the duration of fever, and how exposure to COVID-19 is assessed. The preliminary WHO case definition is for "multisystem inflammatory syndrome (MIS) in children and adolescents temporally related to COVID-19" (box). The WHO has established a platform for standardized, anonymized clinical data, along with a dedicated case report form, and underlines the "urgent need for collection of standardized data describing clinical presentations, severity, outcomes, and epidemiology." Diagnostic guidance by the RCPCH proposes a broader case definition (for PIMS-TS), which was also endorsed by an expert panel convened by the American College of Cardiology. Key clinical criteria set out in the RCPHC case definition are: persistent fever, inflammation (indicated by neutrophilia, high CRP levels and low lymphocyte count), and evidence of organ dysfunction (shock; cardiac, respiratory, renal, gastrointestinal, or neurological disorder), coupled with additional clinical features, including laboratory, imaging and ECG findings. Coronary artery abnormalities, such as dilatation, may be apparent at echocardiography and ECG (or contrast CT of the chest). Biomarkers supporting the diagnosis include abnormal fibrinogen levels, high D-dimers (possible coagulopathy), high troponin, low albumin, and high ferritin. According to the RCPCH definition, the child may test positive or negative for SARS-CoV-2, but other possible microbial causes need to be excluded. The CDC case definition for MIS-C comprises individuals "aged <21 years presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological)." It also requires that there should either be a positive antigen/antibody SARS-CoV-2 test or COVID-19 exposure in the 4 weeks before onset of symptoms, along with exclusion of other plausible diagnoses. This case definition is quite broad (it overlaps not only with Kawasaki disease, but also with juvenile rheumatoid arthritis, and various infectious/inflammatory conditions of childhood, including other viral diseases), but not as broad as the RCPCH definition. The CDC advises health providers in the United States to inform their public health authorities of suspected cases, even if they also meet full or partial criteria for Kawasaki disease, and to consider MIS-C after any childhood fatality in which there is evidence of SARS-CoV-2 infection.Further case definitions have been formulated by the British Paediatric Surveillance Unit (BPSU) and the Canadian Paediatric Surveillance Program (CPSP). Some provisional diagnostic guidance has been provided by both the American College of Rheumatology and the American Academy of Pediatrics. In the UK, consensus has been reached for diagnostic investigation of children with suspected PIMS-TS. A clinical pathway for diagnostic evaluation of suspected MIS-C has also been proposed by the Childrens Hospital of Philadelphia. A set of guidelines proposed by Western New York recommends also evaluating children with clinical features that overlap with the MIS-C case definition, but who have been screened with mild illness and laboratory abnormalities, and who do not have an alternative diagnosis. Differential diagnosis It is essential to exclude alternative non-infectious and infectious causes of the inflammatory condition, including bacterial sepsis, staphylococcal and streptococcal shock, and infections associated with myocarditis, such as enterovirus. (Coinfection with additional pathogens, including human metapneumovirus and various other microbes, may sometimes occur.) Other potentially unrelated sources of abdominal pain include appendicitis and mesenteric adenitis.Differential diagnosis with Kawasaki disease can be challenging, given the lack of a diagnostic test for either condition. It is not currently known whether the newly described condition is superimposable with Kawasaki disease shock syndrome. Since prompt diagnosis and timely treatment of actual Kawasaki disease is important to prevent complications, a call has been made to "Keep a high suspicion for Kawasaki disease in all children with prolonged fever, but especially in those younger than 1 year of age." Treatment Due to the limited information available on this rare new diagnosis, clinical management has been largely based on expert opinion, including knowledge acquired from treating Kawasaki disease and other systemic inflammatory disorders of childhood, in addition to experience with COVID-19 in adults. Treatment is tailored for each individual child, with input from the various consulting specialists. Approaches vary. The RCPCH initially outlined a provisional approach to clinical management, including guidance on early medical management, monitoring and some general principles of treatment; for the UK, consensus has since been reached regarding a recommended pathway for clinical management (including access to registered clinical trials). The National Institutes of Health provides some general considerations. The American College of Rheumatology provides guidance for clinical management of MIS-C. The American Academy of Pediatrics has also provided some interim guidance. Other proposals have also been made. RCPCH guidance recommends that all affected children should be treated as having suspected COVID-19.Little specific information is available regarding therapeutic effectiveness. Most children who have been treated as for Kawasaki disease have recovered. Supportive care is a mainstay of therapy, and for mild or moderate disease it may be sufficient. Major complications may respond well to more aggressive supportive care. Cardiac and respiratory support may benefit children who present predominantly with shock.Strategies for clinical management tend to be broadly based on anti-inflammatory medications, treatment of shock, and prevention of thrombosis. Most children have received immunomodulatory treatment with intravenous immunoglobulin (IVIG). IVIG has been reported target IL-1β+ neutrophils and their activation in the affected children. Other anti-inflammatory treatments have been used, including corticosteroids at various doses. Good responses have been recorded for IVIG, with or without corticosteroids. Cases requiring steroids due to resistance to IVIG may be more common than in Kawasaki disease. In a minority of cases, cytokine blockers have been used as a supplemental therapy to inhibit production of IL-6 (tocilizumab) or IL-1 (anakinra); TNF-α-inhibitors (infliximab) have also been used. Inotropic or vasoactive agents are often used for children with cardiac dysfunction and hypotension. Anticoagulants have been used. Low-dose aspirin has been used as an antiplatelet drug.Treatment strategies are being considered to prevent serious long-term complications such as coronary artery aneurysms (the main complication of Kawasaki disease). Close outpatient follow-up by a paediatric cardiology team has been recommended. Causes While it has been hypothesized that the condition is related to COVID-19, it has also been emphasized that the potential link "is neither established nor well understood." A temporal association between SARS-CoV-2 infection and clinical presentation of the syndrome is plausible. A causality assessment found that temporality was among the five (out of nine) Bradford Hill criteria that supported a causal relationship between SARS-CoV-2 infection and the development of the syndrome. Further characterization of the syndrome is essential to identify risk factors and help understand causality. It is unclear to what extent this emerging syndrome has a similar aetiology to Kawasaki disease (a condition predating the emergence of SARS-CoV-2, which is currently thought to be triggered by a distinct viral agent). Although some cases resemble toxic shock syndrome, there is no evidence that staphylococcal or streptococcal toxins are involved. The role of comorbidities is unclear. Improved understanding will have potential implications for clinical management. Genome-wide association studies are expected to provide insights on susceptibility and potential biological mechanisms. Mechanism The pathogenesis is not completely known and could implicate several factors. SARS-CoV-2 could have one of several roles; it could act as an environmental trigger for the condition either directly or indirectly (by somehow paving the way for a different trigger).As with Kawasaki disease, antibody-dependent enhancement, whereby development of antibodies could facilitate viral entry into host cells, has been proposed as a potential mechanism. Epidemiological considerations make a post-infectious mechanism seem likely, possibly coinciding with the development of acquired immune responses to the virus. It has been suggested that the condition may be caused by the cytokine storms induced by COVID-19. The characteristic ability of coronaviruses to block type I and type III interferon responses could help explain a delayed cytokine storm in children whose immune systems struggle to control SARS-CoV-2 viral replication, or are overwhelmed by a high initial viral load. One plausible chain of events leading up to a hyperimmune response could involve early viral triggering of macrophage activation, followed by T helper cell stimulation, in turn leading to cytokine release, stimulation of macrophages, neutrophils, and monocytes, in conjunction with B cell and plasma cell activation, and autoantibody production.It is unknown to what extent the pathophysiology resembles that of other paediatric inflammatory syndromes that share similar clinical features. Clinical overlaps with syndromes that have different causes (Kawasaki disease, toxic shock, macrophage activation syndrome, and secondary haemophagocytic lymphohistiocytosis) may be explained by immunological activation and dysregulation of similar inflammatory pathways. In each of these syndromes, a cytokine storm leads to failure of multiple organs. They also share with MIS-C and severe cases of COVID-19 high levels both of ferritin (released by neutrophils) and of haemophagocytosis.The frequent gastrointestinal presentation and mesenteric lymph node inflammation are in keeping with the known liking of SARS-CoV-2 to replicate in enterocytes. Association of Kawasaki-like disease with COVID-19 could support the view that SARS-CoV-2 can cause systemic vasculitis by targeting endothelial tissue via angiotensin-converting enzyme 2 (ACE2), the protein which the virus uses to gain access to cells. While the initial infection is known to be capable of causing acute myocardial damage, occurrence of myocarditis could also plausibly be linked to systemic hyperinflammation triggered by a disorderly post-infectious immune response. It has been suggested that SARS-CoV-2 might lead to immune-mediated damage to the heart and coronary arteries via immune complexes or increased T-cell responses.Understanding the pathophysiology is a key research priority. Questions regarding the underlying molecular mechanisms that lead to the disorder following exposure to SARS-CoV-2 include identification of: any genetic predisposition factors; any associations with particular viral variant/s; any molecular patterns capable of triggering the autoimmune/autoinflammatory responses. Another key question is whether the molecular mechanisms that trigger autoimmune/autoinflammatory responses in children with PMIS and adults with severe COVID-19 (including the induction of high concentrations of IL-6) are similar or distinct.A potential link with Kawasaki disease is under discussion. It has been noted that a leading hypothesis for the pathogenesis of Kawasaki disease also involves a hyperinflammatory response to viral infection (such as by a novel RNA virus) in some genetically predisposed children, and that SARS-CoV-2 is now "added to the list" of implicated viral triggers. Hopes have been expressed that study of the new condition may help understand the hidden mechanisms behind Kawasaki disease. But current evidence suggest that MIS-C and Kawasaki disease represent two distinct disease entities Proposed role of the STING pathway A possible role of the stimulator of interferon genes known as STING has been proposed. SARS-CoV-2 is capable of upregulating the STING protein (encoded by TMEM173 transmembrane protein, and expressed in alveoli, endothelial cells, and the spleen), resulting in massive release of interferon-beta and cytokines derived from activation of NF-κB and IRF-3. In MIS-C, such a scenario could lead to a clinical picture similar to STING-associated vasculopathy with onset in infancy (also known as SAVI) – a condition characterized by fever, lung injury, vascular inflammation, myositis, skin lesions (occasionally acral necrosis), and arterial aneurysms. Variations in the presentation and severity of MIS-C might at least partially be explained by characteristic differences in polymorphisms of TMEM173 found in various populations. Epidemiology Epidemiological information is limited, and clinical statistics currently derive from review of case series. This emerging condition is considered rare. Its incidence is not known. Based on available reports, the fatality rate among diagnosed cases appears to have been about 1.7% (notably higher than the rate of 0.07% recorded among children with Kawasaki disease in Japan). A rapid risk assessment conducted by the European Centre for Disease Prevention and Control (ECDC) concluded that the overall risk to children in the European Union (EU), European Economic Area (EEA) and the UK "is considered low, based on a very low probability of [the disease] in children and a high impact of such disease."Clusters of cases of the newly described condition have been recorded 3–4 weeks after peaks in SARS-CoV-2 viral transmission through various local communities. Such observations have been seen to support the concept that SARS-CoV-2 infection may be capable of triggering a severe form of a Kawasaki-like disease. Frequent presentation without prominent respiratory symptoms in children who do not appear to have ongoing SARS-CoV-2 infection but who have already developed antibodies suggests that the disease may be driven by a delayed, post-infectious mechanism.The median age of onset appears to be at least 7 years (compared with 2 years for Kawasaki disease, which primarily affects children under the age of 5). Male children seem to be more frequently affected (broadly in line with Kawasaki disease, where the male to female ratio is about 1.5 to 1). Many affected children appear not to have underlying health conditions, such as asthma or autoimmune disorders, and there have been relatively few reports of known congenital heart disease or preexisting cardiovascular disease. Over half (52%) the children with available information had no recorded underlying health condition, including being overweight or obese (among those who did have some comorbidity, 51% were either overweight or obese).Regarding ethnicity, reports from France and the UK raised the possibility that children of Afro-Caribbean descent may be at greater risk, plausibly due to a genetic predisposition. In the US (as of mid-July), the majority of cases were classified as Hispanic/Latino (38%) or non-Hispanic Black (33%) people. Based on reports confined to Europe and the US, the condition seems to affect more children of African, Afro-Caribbean, and Hispanic descent, whereas Kawasaki disease affects more of East Asian and Pacific Islander ancestry. The role of socioeconomic and other environmental factors in such discrepancies is unclear.As regards geographical distribution, there has been uncertainty as to whether the initial reports of cases in Europe and North America reflected a true pattern, or whether the condition had gone unrecognized elsewhere. In Japan and other Southeast and East Asian countries where Kawasaki disease is usually much more prevalent than in Europe, no case of Kawasaki-like disease linked to COVID-19 had been reported during the first wave of transmission. Reports of confirmed or suspected cases have since emerged in many different countries around the world.None
Multisystem inflammatory syndrome in children	of the three main provisional case-definitions of the emerging entity is diagnostically specific. Concerns have been raised regarding the potential for missed or delayed diagnosis of Kawasaki disease due to heightened diagnostic suspicion for the new entity. Misclassification of cases of Kawasaki disease and of other inflammatory and infectious diseases of childhood whose case definitions overlap with MIS-C could skew understanding of the new entity, such as the frequency of coronary artery aneurysms. Another concern is that clinically less severe cases of the new entity may be missed, and that the actual spectrum of disease severity could be broader, especially given the reliance on early observations of severe disease for provisional case definition. Some statistical modeling has been used to explore possible subdivision of cases satisfying the CDCs case definition into three distinct subgroups based on underlying clinical similarities: Class 1, characterized by pronounced multiorgan involvement, with little overlap with Kawasaki disease or acute COVID-19; Class 2, more predominantly characterized by respiratory symptoms typical of acute COVID-19; Class 3, a clinically less severe grouping, where rashes and mucosal symptoms are prevalent, with less multiorgan involvement, and generally greater overlap with Kawasaki disease. A suggestion that research into the biology of the disease might benefit from considering cases of Kawasaki disease and of the provisionally defined entity in conjunction is debated. In adults There has been uncertainty as to whether the condition is confined to children, and the appropriateness of excluding adults from case definitions has been questioned. Sporadic reports exist of a similar life-threatening condition, denominated multisystem inflammatory syndrome in adults (MIS-A), which also usually requires intensive care. History Cases of Kawasaki disease with concurrent SARS-CoV-2 infection have been recorded among children in Europe and in the United States since 7 April 2020, when a report was published by the American Academy of Pediatrics regarding a case of classic Kawasaki disease in a six-month old girl who tested positive for COVID-19 in California. In this case, COVID-19 did not appear to have significant clinical implications.On 25 April, concerns were initially raised in the United Kingdom regarding a cluster of children of various ages presenting with a multisystem inflammatory state who required intensive care, and who all displayed "overlapping features of toxic shock syndrome and atypical Kawasaki disease with blood parameters consistent with severe COVID-19 in children." Details of the eight cases which helped trigger this alert (not all with confirmed exposure to COVID-19) were later reported in The Lancet, where the authors summarized the clinical picture as "a hyperinflammatory syndrome with multiorgan involvement similar to Kawasaki disease shock syndrome." Accounts of analogous cases – including some that appeared less clinically severe – were also being informally shared among clinicians around Europe. The EUs Early Warning and Response System flagged suspected cases in Austria, Germany and Portugal that had tested positive for SARS-CoV-2. In Bergamo, at the heart of the COVID-19 epidemic in Lombardy, a cluster of 20 cases of Kawasaki disease appeared to be roughly equivalent to the number commonly recorded there over the course of three years. In France, the government reported on 29 April that around 15 children were in hospital in Paris with symptoms of Kawasaki disease, an observation which prompted the organization of national surveillance programme for recent cases of Kawasaki-like disease.On 1 May, the RCPCH published a preliminary case definition based on review of the characteristics of the cases identified in the UK, accompanied by some clinical guidance. Two weeks later, on 15 May, two further preliminary case definitions were published separately by the WHO and by the CDC, while the ECDC released a rapid risk assessment of the condition on behalf of the European Union. In the following weeks, further clinical guidance was released by other medical organizations, including the NIH, the American College of Rheumatology, and the American Academy of Pediatrics. On 4 May, the New York City Department of Health and Mental Hygiene issued an alert to identify children with the condition in New York City hospitals, where 15 such cases were already being treated. On 9 May, the governor of New York, Andrew Cuomo announced a collaboration with the CDC to help develop national criteria for identifying and responding to the newly identified childhood disease.By 12 May, some 230 suspected cases had been reported across the EU and EEA, and in the UK (in the following days, sources were reporting up to 100 in the UK, over 135 in France, 20 in the Netherlands, 10 in Switzerland and 10 in Germany). In the United States, more than 200 cases were suspected by mid-May, including some 145 in New York; 186 confirmed cases were eventually diagnosed between 15 March and 20 May in 26 US states. As of 11 May 2020, five fatalities were reported (1 in France, 1 in the UK, 3 in the US). In peer-reviewed medical journals, case series and related studies of the new condition were rapidly reported from countries including the UK; Italy; Spain; France and Switzerland; France; and across the US, including New York. The emerging observations suggested somewhat greater variety in the severity of symptoms than was originally thought. The proposal of a new clinical entity during a pandemic also prompted scientific discussion about its possible distinction from Kawasaki disease, and the potential role of COVID-19.By 15 July, 342 confirmed MIS-C cases (including 6 deaths) had been recorded in the US across 36 states plus Washington DC. Most (71%) of the children were Hispanic/Latino or non-Hispanic Black people, and the CDC underlined the need to learn the reasons for such a preponderance. By 29 July, a total of 570 cases and 10 deaths had been reported across 40 states, Washington DC, and New York City.Until late May, no confirmed case had been documented outside the EU/EEA/UK and USA. No suspicious case had been observed in East Asia or Southeast Asia (or in Australia or New Zealand). The absence of documented cases in China and other Asian countries that had already experienced a COVID-19 epidemic led to conjectures regarding the possibility of a significant evolution of the virus, or variations in susceptibility in different populations. On 2 June, news emerged of a first case of MIS-C diagnosed in Peru. In Brazil, cases of MIS-C have been reported in São Paulo, and in the context of a prospective study in Pará; more children with severe late manifestations of COVID-19 were being admitted to paediatric intensive care units in the region. In Chile, 42 confirmed cases of MIS-C had been recorded nationally by June 28, including 27 in the capital, Santiago. In Russia, 13 children had been treated (5 with intensive care) by mid-June for a multisystem inflammatory syndrome at the Morozov Childrens Hospital in Moscow, including a 2-year-old girl with the COVID-19 infection who died on 23 May following an initial diagnosis of suspected Kawasaki disease. In Iran, a case report (first submitted in May) described severe MIS-C in a 5-year-old girl who had presented with shock and was initially diagnosed with Kawasaki disease, and further cases of the new syndrome have been recorded. In India, a case of suspected MIS-C was reported in late May regarding a child who had presented in a COVID-19 hotspot in Kerala. An editorial commentary urged clinicians to have a high level of diagnostic suspicion and follow WHO and CDC definitions to facilitate timely identification and treatment of cases.During July, suspected cases were being flagged and reported in Mumbai, in Delhi, Chennai, and elsewhere. In Pakistan, at least 24 children were said to have Kawasaki-like symptoms in Lahore, where 8 cases fulfilling WHO criteria were prospectively identified by 30 June. In Kazakhstan, 14 cases were confirmed by 20 August (among 2,357 children known to have been infected). Cases have been recorded in Israel, including one of a child who presented with severe central nervous system involvement and complement deficiency. In Turkey, four children with a Kawasaki-like disease probably associated with COVID-19 are reported to have been admitted to the childrens hospital of Hacettepe University in Ankara between 13 April and 11 July. In Algeria, a first case was recorded in June. In Egypt, on 10 July the authorities denied rumours of the existence of cases of Kawasaki-like disease in the country. In South Africa, the first 23 affected children were treated in Cape Town – the initial epicentre of the national COVID-19 epidemic – between 4 June and 24 July. In Ecuador, the Ministry of Health announced on 19 July the presence of 46 probable cases. In Costa Rica, a national public health organization announced towards the end of August that three children had been diagnosed with MIS-C. Cases of MIS-C had also been recorded in many other Latin American countries, including Argentina, Bolivia, Colombia, Cuba, the Dominican Republic, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Uruguay, and Venezuela, as well as in Puerto Rico. News of a first confirmed case of PIMS-TS in Australia emerged (from Victoria) on 4 September, along with news of other suspected cases under review. In South Korea, news of two confirmed cases broke on 5 October (and the existence of a case dating back to the end of April was reported in November). A similar condition began to be recognized in some adults. In June, an adult case of a Kawasaki-like multisystem inflammatory syndrome following SARS-CoV-2 infection was described in a 54-year-old woman from Israel with no history of autoimmune disease, who experienced uveitis in both eyes. (A further suspected adult case was covered in the Israeli national press.) A case involving a 36-year-old Hispanic American woman with clinical features otherwise consistent with MIS-C was reported from New York. A diagnosis consistent with PMIS was also reported in a UK-born, 21-year-old man of Somali origin. A case report published in The Lancet regarding a 45-year-old Hispanic man who presented in New York with features strongly resembling MIS-C called for awareness of "a potential MIS-C-like condition in adults." Further reports of multisystem inflammatory syndrome linked to COVID-19 exposure emerged in adults. In October, the CDC reported on the condition and named it multisystem inflammatory syndrome in adults (MIS-A). Questions have been raised regarding possible relationships between MIS-C and certain severe manifestations of COVID-19 in adults.Childrens neurological symptoms, as studied in London in mid-2020, often involved "both the central and peripheral nervous systems," according to a report by the American Academy of Neurology released on 13 April 2021.The official MIS-C Awareness Week is in December - Created by the non-profit organization CircumSTANCE. CircumSTANCE created the first ever Multisystem Inflammatory Syndrome Awareness campaign in 2020, they also created the official "MIS-C Awareness Ribbon". For more information on MIS-C awareness and advocacy, please visit their web site and social media pages. www.abovecircumstances.org Explanatory notes References External links Fact sheet for parents and Caregivers of Pre-School and School-Age Children released by New York Citys Health Department Information for parents provided by the Childrens Hospital Los Angeles Information for paediatric health care providers in the U.S.A. (from the CDC)
Small intestinal bacterial overgrowth	Small intestinal bacterial overgrowth (SIBO), also termed bacterial overgrowth, or small bowel bacterial overgrowth syndrome (SBBOS), is a disorder of excessive bacterial growth in the small intestine. Unlike the colon (or large bowel), which is rich with bacteria, the small bowel usually has fewer than 100,000 organisms per millilitre. Patients with bacterial overgrowth typically develop symptoms which may include nausea, bloating, vomiting, diarrhea, malnutrition, weight loss and malabsorption, which is caused by a number of mechanisms. The diagnosis of bacterial overgrowth is made by a number of techniques, with the gold standard being an aspirate from the jejunum that grows in excess of 105 bacteria per millilitre. Risk factors for the development of bacterial overgrowth include dysmotility; anatomical disturbances in the bowel, including fistulae, diverticula and blind loops created after surgery, and resection of the ileo-cecal valve; gastroenteritis-induced alterations to the small intestine; and the use of certain medications, including proton pump inhibitors. Small bowel bacterial overgrowth syndrome is treated with an elemental diet or antibiotics, which may be given in a cyclic fashion to prevent tolerance to the antibiotics, sometimes followed by prokinetic drugs to prevent recurrence if dysmotility is a suspected cause. Definition SIBO may be defined as an increased number of bacteria measured via exhaled hydrogen and/or methane gas following the ingestion of glucose, or via analysis of small bowel aspirate fluid. Nevertheless, as of 2020, the definition of SIBO as a clinical entity lacks precision and consistency; it is a term generally applied to a clinical disorder where symptoms, clinical signs, and/or laboratory abnormalities are attributed to changes in the numbers of bacteria or in the composition of the bacterial population in the small intestine. The main obstacle to accurately define SIBO is limited understanding of the normal intestinal microbial population. Future advances in sampling technology and techniques for counting bacterial populations and their metabolites should provide much-needed clarity. Methane-dominant SIBO The archaeon Methanobrevibacter smithii, has been associated with symptoms of SIBO which result in a positive methane breath test. In addition to the archaeon, a few bacteria can also produce methane, such as members of the Clostridium and Bacteroides genus. Production of methane therefore, may not be bacterial, nor limited to the small intestine, and it has been proposed that the condition should be classified as a separate intestinal methanogen overgrowth (IMO). Signs and symptoms Symptoms traditionally linked to SIBO include bloating, diarrhea, and abdominal pain/discomfort. Steatorrhea may be seen in more severe cases.Bacterial overgrowth can cause a variety of symptoms, many of which are also found in other conditions, making the diagnosis challenging at times. Many of the symptoms are due to malabsorption of nutrients due to the effects of bacteria which either metabolize nutrients or cause inflammation of the small bowel, impairing absorption. The symptoms of bacterial overgrowth include nausea, flatus, constipation, bloating, abdominal distension, abdominal pain or discomfort, diarrhea, fatigue, and weakness. SIBO also causes an increased permeability of the small intestine. Some patients may lose weight. Children with bacterial overgrowth may develop malnutrition and have difficulty attaining proper growth. Steatorrhea, a sticky type of diarrhea where fats are not properly absorbed and spill into the stool, may also occur.Patients with bacterial overgrowth that is longstanding can develop complications of their illness as a result of malabsorption of nutrients. Laboratory test results may include elevated folate, and, less commonly, vitamin B12 deficiency or other nutritional deficiencies. Anemia may occur from a variety of mechanisms, as many of the nutrients involved in production of red blood cells are absorbed in the affected small bowel. Iron is absorbed in the more proximal parts of the small bowel, the duodenum and jejunum, and patients with malabsorption of iron can develop a microcytic anemia, with small red blood cells. Vitamin B12 is absorbed in the last part of the small bowel, the ileum, and patients who malabsorb vitamin B12 can develop a megaloblastic anemia with large red blood cells. Related conditions In recent years, several proposed links between SIBO and other disorders have been made. However, the usual methodology of these studies involves the use of breath testing as an indirect investigation for SIBO. Breath testing has been criticized by some authors for being an imperfect test for SIBO, with multiple known false positives. Irritable bowel syndrome Some studies reported up to 80% of patients with irritable bowel syndrome (IBS) have SIBO (using the hydrogen breath test). IBS-D is associated with elevated hydrogen numbers on breath tests while IBS-C is associated with elevated methane numbers on breath tests. Subsequent studies demonstrated statistically significant reduction in IBS symptoms following therapy for SIBO.Various mechanisms are involved in the development of diarrhea and IBS-D in bacterial overgrowth. First, the excessive bacterial concentrations can cause direct inflammation of the small bowel cells, leading to an inflammatory diarrhea. The malabsorption of lipids, proteins and carbohydrates may cause poorly digestible products to enter into the colon. This can cause diarrhea by the osmotic drive of these molecules, but can also stimulate the secretory mechanisms of colonic cells, leading to a secretory diarrhea.There is a lack of consensus however, regarding the suggested link between IBS and SIBO. Other authors concluded that the abnormal breath results so common in IBS patients do not suggest SIBO, and state that "abnormal fermentation timing and dynamics of the breath test findings support a role for abnormal intestinal bacterial distribution in IBS." There is general consensus that breath tests are abnormal in IBS; however, the disagreement lies in whether this is representative of SIBO. Etiology and risk factors Certain people are more predisposed to the development of bacterial overgrowth because of certain risk factors. These factors can be grouped into four categories: (1) disordered motility or movement of the small bowel or anatomical changes that lead to stasis, (2) disorders in the immune system, (3) interference with the production of proteolytic enzymes, gastric acid, or bile, and (4) conditions that cause more bacteria from the colon to enter the small bowel. In some people, methanogens may reside in the oral cavity, as evidenced by reductions in breath methane levels following mouthwash with chlorhexidine. This may affect results from hydrogen-methane breath testing. Absence or impairment of the migrating motor complex (MMC), a cyclical motility pattern in the small intestine, and phase III of the MMC in particular, is associated with the development of SIBO. Problems with motility may either be diffuse, or localized to particular areas. MMC impairment may be a result of post-infectious irritable bowel syndrome, drug use, or intestinal pseudo-obstruction among other causes. There is an overlap in findings between tropical sprue, post-infectious irritable bowel syndrome and small intestinal bacterial overgrowth in the pathophysiology of the three conditions and also SIBO can similarly sometimes be triggered by an acute gastrointestinal infection. As of 2020, there is still controversy about the role of SIBO in the pathogenesis of common functional symptoms such as those considered to be components of irritable bowel syndrome. Diseases like scleroderma cause diffuse slowing of the bowel, leading to increased bacterial concentrations. More commonly, the small bowel may have anatomical problems, such as out-pouchings known as diverticula that can cause bacteria to accumulate. After surgery involving the stomach and duodenum (most commonly with Billroth II antrectomy), a blind loop may be formed, leading to stasis of flow of intestinal contents. This can cause overgrowth, and is termed blind loop syndrome.Systemic or metabolic disorders may lead to conditions allowing bacterial overgrowth as well. For example, diabetes can cause intestinal neuropathy, pancreatitis leading to pancreatic insufficiency can impair digestive enzyme production, and bile may be affected as part of cirrhosis of the liver. Proton pump inhibitors, a class of medication that are used to reduce stomach acid, is associated with an increased risk of developing SIBO.Finally, abnormal connections between the bacteria-rich colon and the small bowel can increase the bacterial load in the small bowel. Patients with Crohns disease or other diseases of the ileum may require surgery that removes the ileocecal valve connecting the small and large bowel; this leads to an increased reflux of bacteria into the small bowel. After bariatric surgery for obesity, connections between the stomach and the ileum can be formed, which may increase bacterial load in the small bowel. Diagnosis The diagnosis of bacterial overgrowth can be made by physicians in various ways. Malabsorption can be detected by a test called the D-xylose absorption test. Xylose is a sugar that does not require enzymes to be digested. The D-xylose test involves having a patient drink a certain quantity of D-xylose, and measuring levels in the urine and blood; if there is no evidence of D-xylose in the urine and blood, it suggests that the small bowel is not absorbing properly (as opposed to problems with enzymes required for digestion).The gold standard for detection of bacterial overgrowth is the aspiration of more than 105 bacteria per millilitre from the small bowel. The normal small bowel has less than 104 bacteria per millilitre. Some experts however, consider aspiration of more than 103 positive if the flora is predominately colonic type bacteria as these types of bacteria are considered pathological in excessive numbers in the small intestine. The reliability of aspiration in the diagnosis of SIBO has been questioned as SIBO can be patchy and the reproducibility can be as low as 38 percent. Breath tests have their own reliability problems with a high rate of false positive. Some doctors factor in a patients response to treatment as part of the diagnosis. Breath tests have been developed to test for bacterial overgrowth. These tests are either based on bacterial metabolism of carbohydrates to hydrogen, methane, or hydrogen sulfide, or based on the detection of by-products of digestion of carbohydrates that are not usually metabolized. The hydrogen breath test involves having the patient fast for a minimum of 12 hours then having them drink a substrate usually glucose or lactulose, then measuring expired hydrogen and methane concentrations typically over a period of several hours. It compares well to jejunal aspirates in making the diagnosis of bacterial overgrowth. Carbon-13 (13C) and carbon-14 (14C) based tests have also been developed based on the bacterial metabolism of D-xylose. Increased bacterial concentrations are also involved in the deconjugation of bile acids. The glycocholic acid breath test involves the administration of the bile acid 14C glycocholic acid, and the detection of 14CO2, which would be elevated in bacterial overgrowth.However, some physicians suggest that if the suspicion of bacterial overgrowth is high enough, the best diagnostic test is a trial of treatment. If the symptoms improve, an empiric diagnosis of bacterial overgrowth can be made.There is insufficient evidence to support the use of inflammatory markers, such as fecal calprotectin, to detect SIBO. Treatment Treatment strategies should focus on identifying and correcting the root causes, where possible, resolving nutritional deficiencies, and administering antibiotics. This is especially important for patients with indigestion and malabsorption. Although whether antibiotics should be a first line treatment is a matter of debate. Some experts recommend probiotics as first line therapy with antibiotics being reserved as a second line treatment for more severe cases of SIBO. Prokinetic drugs are other options but research in humans is limited. A variety of antibiotics, including tetracycline, amoxicillin-clavulanate, metronidazole, neomycin, cephalexin and trimethoprim-sulfamethoxazole have been used; however, the best evidence is for the use of rifaximin, a poorly-absorbed antibiotic. Although irritable bowel syndrome has been shown to respond to the treatment of poorly-absorbed antibiotics, there is limited evidence on the effectiveness of such treatment in cases of SIBO, and as of 2020, randomized controlled trials are still needed to further confirm the eradicating effect of such treatment in SIBO. A course of one week of antibiotics is usually sufficient to treat the condition. However, if the condition recurs, antibiotics can be given in a cyclical fashion in order to prevent tolerance. For example, antibiotics may be given for a week, followed by three weeks off antibiotics, followed by another week of treatment. Alternatively, the choice of antibiotic used can be cycled. There is still limited data to guide the clinician in developing antibiotic strategies for SIBO. Therapy remains, for the most part, empiric. However, concerns exist about the potential risks of long-term broad-spectrum antibiotic therapy.Probiotics are bacterial preparations that alter the bacterial flora in the bowel to cause a beneficial effect. Animal research has demonstrated that probiotics have barrier enhancing, antibacterial, immune modulating and anti-inflammatory effects which may have a positive effect in the management of SIBO in humans. Lactobacillus casei has been found to be effective in improving breath hydrogen scores after 6 weeks of treatment presumably by suppressing levels of a small intestinal bacterial overgrowth of fermenting bacteria. The multi-strain preparation VSL#3 was found to be effective in suppressing SIBO. Lactobacillus plantarum, Lactobacillus acidophilus, and Lactobacillus casei have all demonstrated effectiveness in the treatment and management of SIBO. Conversely, Lactobacillus fermentum and Saccharomyces boulardii have been found to be ineffective. A combination of Lactobacillus plantarum and Lactobacillus rhamnosus has been found to be effective in suppressing bacterial overgrowth of abnormal gas producing organisms in the small intestine.Probiotics are superior to antibiotics in the treatment of SIBO. A combination of probiotic strains has been found to produce better results than therapy with the antibiotic drug metronidazole.An elemental diet has been shown to be highly effective for eliminating SIBO with a two-week diet demonstrating 80% efficacy and a three-week diet demonstrating 85% efficacy. An elemental diet works via providing nutrition for the individual while depriving the bacteria of a food source. Additional treatment options include the use of prokinetic drugs such as 5-HT4 receptor agonists or motilin agonists to extend the SIBO free period after treatment with an elemental diet or antibiotics. A diet void of certain foods that feed the bacteria can help alleviate the symptoms. For example, if the symptoms are caused by bacterial overgrowth feeding on indigestible carbohydrate rich foods, following a FODMAP restriction diet may help. References == External links ==
Traumatic brain injury	A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity (ranging from mild traumatic brain injury [mTBI/concussion] to severe traumatic brain injury), mechanism (closed or penetrating head injury), or other features (e.g., occurring in a specific location or over a widespread area). Head injury is a broader category that may involve damage to other structures such as the scalp and skull. TBI can result in physical, cognitive, social, emotional and behavioral symptoms, and outcomes can range from complete recovery to permanent disability or death. Causes include falls, vehicle collisions and violence. Brain trauma occurs as a consequence of a sudden acceleration or deceleration within the cranium or by a complex combination of both movement and sudden impact. In addition to the damage caused at the moment of injury, a variety of events following the injury may result in further injury. These processes include alterations in cerebral blood flow and pressure within the skull. Some of the imaging techniques used for diagnosis include computed tomography (CT) and magnetic resonance imaging (MRIs). Prevention measures include use of seat belts and helmets, not drinking and driving, fall prevention efforts in older adults and safety measures for children. Depending on the injury, treatment required may be minimal or may include interventions such as medications, emergency surgery or surgery years later. Physical therapy, speech therapy, recreation therapy, occupational therapy and vision therapy may be employed for rehabilitation. Counseling, supported employment and community support services may also be useful. TBI is a major cause of death and disability worldwide, especially in children and young adults. Males sustain traumatic brain injuries around twice as often as females. The 20th century saw developments in diagnosis and treatment that decreased death rates and improved outcomes. Classification Traumatic brain injury is defined as damage to the brain resulting from external mechanical force, such as rapid acceleration or deceleration, impact, blast waves, or penetration by a projectile. Brain function is temporarily or permanently impaired and structural damage may or may not be detectable with current technology.TBI is one of two subsets of acquired brain injury (brain damage that occur after birth); the other subset is non-traumatic brain injury, which does not involve external mechanical force (examples include stroke and infection). All traumatic brain injuries are head injuries, but the latter term may also refer to injury to other parts of the head. However, the terms head injury and brain injury are often used interchangeably. Similarly, brain injuries fall under the classification of central nervous system injuries and neurotrauma. In neuropsychology research literature, in general the term "traumatic brain injury" is used to refer to non-penetrating traumatic brain injuries. TBI is usually classified based on severity, anatomical features of the injury, and the mechanism (the causative forces). Mechanism-related classification divides TBI into closed and penetrating head injury. A closed (also called nonpenetrating, or blunt) injury occurs when the brain is not exposed. A penetrating, or open, head injury occurs when an object pierces the skull and breaches the dura mater, the outermost membrane surrounding the brain. Severity Brain injuries can be classified into mild, moderate, and severe categories. The Glasgow Coma Scale (GCS), the most commonly used system for classifying TBI severity, grades a persons level of consciousness on a scale of 3–15 based on verbal, motor, and eye-opening reactions to stimuli. In general, it is agreed that a TBI with a GCS of 13 or above is mild, 9–12 is moderate, and 8 or below is severe. Similar systems exist for young children. However, the GCS grading system has limited ability to predict outcomes. Because of this, other classification systems such as the one shown in the table are also used to help determine severity. A current model developed by the Department of Defense and Department of Veterans Affairs uses all three criteria of GCS after resuscitation, duration of post-traumatic amnesia (PTA), and loss of consciousness (LOC). It also has been proposed to use changes that are visible on neuroimaging, such as swelling, focal lesions, or diffuse injury as method of classification. Grading scales also exist to classify the severity of mild TBI, commonly called concussion; these use duration of LOC, PTA, and other concussion symptoms. Pathological features Systems also exist to classify TBI by its pathological features. Lesions can be extra-axial, (occurring within the skull but outside of the brain) or intra-axial (occurring within the brain tissue). Damage from TBI can be focal or diffuse, confined to specific areas or distributed in a more general manner, respectively. However, it is common for both types of injury to exist in a given case.Diffuse injury manifests with little apparent damage in neuroimaging studies, but lesions can be seen with microscopy techniques post-mortem, and in the early 2000s, researchers discovered that diffusion tensor imaging (DTI), a way of processing MRI images that shows white matter tracts, was an effective tool for displaying the extent of diffuse axonal injury. Types of injuries considered diffuse include edema (swelling), concussion and diffuse axonal injury, which is widespread damage to axons including white matter tracts and projections to the cortex.Focal injuries often produce symptoms related to the functions of the damaged area. Research shows that the most common areas to have focal lesions in non-penetrating traumatic brain injury are the orbitofrontal cortex (the lower surface of the frontal lobes) and the anterior temporal lobes, areas that are involved in social behavior, emotion regulation, olfaction, and decision-making, hence the common social/emotional and judgment deficits following moderate-severe TBI. Symptoms such as hemiparesis or aphasia can also occur when less commonly affected areas such as motor or language areas are, respectively, damaged.One type of focal injury, cerebral laceration, occurs when the tissue is cut or torn. Such tearing is common in orbitofrontal cortex in particular, because of bony protrusions on the interior skull ridge above the eyes. In a similar injury, cerebral contusion (bruising of brain tissue), blood is mixed among tissue. In contrast, intracranial hemorrhage involves bleeding that is not mixed with tissue.Hematomas, also focal lesions, are collections of blood in or around the brain that can result from hemorrhage. Intracerebral hemorrhage, with bleeding in the brain tissue itself, is an intra-axial lesion. Extra-axial lesions include epidural hematoma, subdural hematoma, subarachnoid hemorrhage, and intraventricular hemorrhage. Epidural hematoma involves bleeding into the area between the skull and the dura mater, the outermost of the three membranes surrounding the brain. In subdural hematoma, bleeding occurs between the dura and the arachnoid mater. Subarachnoid hemorrhage involves bleeding into the space between the arachnoid membrane and the pia mater. Intraventricular hemorrhage occurs when there is bleeding in the ventricles. Signs and symptoms Symptoms are dependent on the type of TBI (diffuse or focal) and the part of the brain that is affected. Unconsciousness tends to last longer for people with injuries on the left side of the brain than for those with injuries on the right. Symptoms are also dependent on the injurys severity. With mild TBI, the patient may remain conscious or may lose consciousness for a few seconds or minutes. Other symptoms of mild TBI include headache, vomiting, nausea, lack of motor coordination, dizziness, difficulty balancing, lightheadedness, blurred vision or tired eyes, ringing in the ears, bad taste in the mouth, fatigue or lethargy, and changes in sleep patterns. Cognitive and emotional symptoms include behavioral or mood changes, confusion, and trouble with memory, concentration, attention, or thinking. Mild TBI symptoms may also be present in moderate and severe injuries.A person with a moderate or severe TBI may have a headache that does not go away, repeated vomiting or nausea, convulsions, an inability to awaken, dilation of one or both pupils, slurred speech, aphasia (word-finding difficulties), dysarthria (muscle weakness that causes disordered speech), weakness or numbness in the limbs, loss of coordination, confusion, restlessness, or agitation. Common long-term symptoms of moderate to severe TBI are changes in appropriate social behavior, deficits in social judgment, and cognitive changes, especially problems with sustained attention, processing speed, and executive functioning. Alexithymia, a deficiency in identifying, understanding, processing, and describing emotions occurs in 60.9% of individuals with TBI. Cognitive and social deficits have long-term consequences for the daily lives of people with moderate to severe TBI, but can be improved with appropriate rehabilitation.When the pressure within the skull (intracranial pressure, abbreviated ICP) rises too high, it can be deadly. Signs of increased ICP include decreasing level of consciousness, paralysis or weakness on one side of the body, and a blown pupil, one that fails to constrict in response to light or is slow to do so. Cushings triad, a slow heart rate with high blood pressure and respiratory depression is a classic manifestation of significantly raised ICP. Anisocoria, unequal pupil size, is another sign of serious TBI. Abnormal posturing, a characteristic positioning of the limbs caused by severe diffuse injury or high ICP, is an ominous sign.Small children with moderate to severe TBI may have some of these symptoms but have difficulty communicating them. Other signs seen in young children include persistent crying, inability to be consoled, listlessness, refusal to nurse or eat, and irritability. Causes The most common causes of TBI in the U.S. include violence, transportation accidents, construction site mishaps, and sports. Motor bikes are major causes, increasing in significance in developing countries as other causes reduce. The estimates that between 1.6 and 3.8 million traumatic brain injuries each year are a result of sports and recreation activities in the US. In children aged two to four, falls are the most common cause of TBI, while in older children traffic accidents compete with falls for this position. TBI is the third most common injury to result from child abuse. Abuse causes 19% of cases of pediatric brain trauma, and the death rate is higher among these cases. Although men are twice as likely to have a TBI. Domestic violence is another cause of TBI, as are work-related and industrial accidents. Firearms and blast injuries from explosions are other causes of TBI, which is the leading cause of death and disability in war zones. According to Representative Bill Pascrell (Democrat, NJ), TBI is "the signature injury of the wars in Iraq and Afghanistan." There is a promising technology called activation database-guided EEG biofeedback, which has been documented to return a TBIs auditory memory ability to above the control groups performance Mechanism Physical forces The type, direction, intensity, and duration of forces all contribute to the characteristics and severity TBI. Forces that may contribute to TBI include angular, rotational, shear, and translational forces.Even in the absence of an impact, significant acceleration or deceleration of the head can cause TBI; however in most cases, a combination of impact and acceleration is probably to blame. Forces involving the head striking or being struck by something, termed contact or impact loading, are the cause of most focal injuries, and movement of the brain within the skull, termed noncontact or inertial loading, usually causes diffuse injuries. The violent shaking of an infant that causes shaken baby syndrome commonly manifests as diffuse injury. In impact loading, the force sends shock waves through the skull and brain, resulting in tissue damage. Shock waves caused by penetrating injuries can also destroy tissue along the path of a projectile, compounding the damage caused by the missile itself.Damage may occur directly under the site of impact, or it may occur on the side opposite the impact (coup and contrecoup injury, respectively). When a moving object impacts the stationary head, coup injuries are typical, while contrecoup injuries are usually produced when the moving head strikes a stationary object. Primary and secondary injury A large percentage of the people killed by brain trauma do not die right away but rather days to weeks after the event; rather than improving after being hospitalized, some 40% of TBI patients deteriorate. Primary brain injury (the damage that occurs at the moment of trauma when tissues and blood vessels are stretched, compressed, and torn) is not adequate to explain this deterioration; rather, it is caused by secondary injury, a complex set of cellular processes and biochemical cascades that occur in the minutes to days following the trauma. These secondary processes can dramatically worsen the damage caused by primary injury and account for the greatest number of TBI deaths occurring in hospitals.Secondary injury events include damage to the blood–brain barrier, release of factors that cause inflammation, free radical overload, excessive release of the neurotransmitter glutamate (excitotoxicity), influx of calcium and sodium ions into neurons, and dysfunction of mitochondria. Injured axons in the brains white matter may separate from their cell bodies as a result of secondary injury, potentially killing those neurons. Other factors in secondary injury are changes in the blood flow to the brain; ischemia (insufficient blood flow); cerebral hypoxia (insufficient oxygen in the brain); cerebral edema (swelling of the brain); and raised intracranial pressure (the pressure within the skull). Intracranial pressure may rise due to swelling or a mass effect from a lesion, such as a hemorrhage. As a result, cerebral perfusion pressure (the pressure of blood flow in the brain) is reduced; ischemia results. When the pressure within the skull rises too high, it can cause brain death or brain herniation, in which parts of the brain are squeezed by structures in the skull. Diagnosis Diagnosis is suspected based on lesion circumstances and clinical evidence, most prominently a neurological examination, for example checking whether the pupils constrict normally in response to light and assigning a Glasgow Coma Score. Neuroimaging helps in determining the diagnosis and prognosis and in deciding what treatments to give. DSM-5 can be utilized to diagnose TBI and its psychiatric sequelae.The preferred radiologic test in the emergency setting is computed tomography (CT): it is quick, accurate, and widely available. Follow-up CT scans may be performed later to determine whether the injury has progressed.Magnetic resonance imaging (MRI) can show more detail than CT, and can add information about expected outcome in the long term. It is more useful than CT for detecting injury characteristics such as diffuse axonal injury in the longer term. However, MRI is not used in the emergency setting for reasons including its relative inefficacy in detecting bleeds and fractures, its lengthy acquisition of images, the inaccessibility of the patient in the machine, and its incompatibility with metal items used in emergency care. A variant of MRI since 2012 is High definition fiber tracking (HDFT).Other techniques may be used to confirm a particular diagnosis. X-rays are still used for head trauma, but evidence suggests they are not useful; head injuries are either so mild that they do not need imaging or severe enough to merit the more accurate CT. Angiography may be used to detect blood vessel pathology when risk factors such as penetrating head trauma are involved. Functional imaging can measure cerebral blood flow or metabolism, inferring neuronal activity in specific regions and potentially helping to predict outcome.Neuropsychological assessment can be performed to evaluate the long-term cognitive sequelae and to aid in the planning of the rehabilitation. Instruments range from short measures of general mental functioning to complete batteries formed of different domain-specific tests. Prevention Since a major cause of TBI are vehicle accidents, their prevention or the amelioration of their consequences can both reduce the incidence and gravity of TBI. In accidents, damage can be reduced by use of seat belts, child safety seats and motorcycle helmets, and presence of roll bars and airbags. Education programs exist to lower the number of crashes. In addition, changes to public policy and safety laws can be made; these include speed limits, seat belt and helmet laws, and road engineering practices.Changes to common practices in sports have also been discussed. An increase in use of helmets could reduce the incidence of TBI. Due to the possibility that repeatedly "heading" a ball practicing soccer could cause cumulative brain injury, the idea of introducing protective headgear for players has been proposed. Improved equipment design can enhance safety; softer baseballs reduce head injury risk. Rules against dangerous types of contact, such as "spear tackling" in American football, when one player tackles another head first, may also reduce head injury rates.Falls can be avoided by installing grab bars in bathrooms and handrails on stairways; removing tripping hazards such as throw rugs; or installing window guards and safety gates at the top and bottom of stairs around young children. Playgrounds with shock-absorbing surfaces such as mulch or sand also prevent head injuries. Child abuse prevention is another tactic; programs exist to prevent shaken baby syndrome by educating about the dangers of shaking children. Gun safety, including keeping guns unloaded and locked, is another preventative measure. Studies on the effect of laws that aim to control access to guns in the United States have been insufficient to determine their effectiveness preventing number of deaths or injuries. Treatment It is important to begin emergency treatment within the so-called "golden hour" following the injury. People with moderate to severe injuries are likely to receive treatment in an intensive care unit followed by a neurosurgical ward. Treatment depends on the recovery stage of the patient. In the acute stage, the primary aim is to stabilize the patient and focus on preventing further injury. This is done because the initial damage caused by trauma cannot be reversed. Rehabilitation is the main treatment for the subacute and chronic stages of recovery. International clinical guidelines have been proposed with the aim of guiding decisions in TBI treatment, as defined by an authoritative examination of current evidence. Acute stage Tranexamic acid within three hours of a head injury decreases the risk of death. Certain facilities are equipped to handle TBI better than others; initial measures include transporting patients to an appropriate treatment center. Both during transport and in hospital the primary concerns are ensuring proper oxygen supply, maintaining adequate blood flow to the brain, and controlling raised intracranial pressure (ICP), since high ICP deprives the brain of badly needed blood flow and can cause deadly brain herniation. Other methods to prevent damage include management of other injuries and prevention of seizures. Some data supports the use of hyperbaric oxygen therapy to improve outcomes. Further research is required to determine the effectiveness and clinical importance of positioning the head at different angles (degrees of head-of-bed elevation) while the person is being treated in intensive care.Neuroimaging is helpful but not flawless in detecting raised ICP. A more accurate way to measure ICP is to place a catheter into a ventricle of the brain, which has the added benefit of allowing cerebrospinal fluid to drain, releasing pressure in the skull. Treatment of raised ICP may be as simple as tilting the persons bed and straightening the head to promote blood flow through the veins of the neck. Sedatives, analgesics and paralytic agents are often used. Propofol and midazolam are equally effective as sedatives.Hypertonic saline can improve ICP by reducing the amount of cerebral water (swelling), though it is used with caution to avoid electrolyte imbalances or heart failure. Mannitol, an osmotic diuretic, appears to be as effective as hypertonic saline at reducing ICP. Some concerns, however, have been raised regarding some of the studies performed. Diuretics, drugs that increase urine output to reduce excessive fluid in the system, may be used to treat high intracranial pressures, but may cause hypovolemia (insufficient blood volume). Hyperventilation (larger and/or faster breaths) reduces carbon dioxide levels and causes blood vessels to constrict; this decreases blood flow to the brain and reduces ICP, but it potentially causes ischemia and is, therefore, used only in the short term.Giving corticosteroids is associated with an increased risk of death, and so their routine use is not recommended. There is no strong evidence that the following pharmaceutical interventions should be recommended to routinely treat TBI: magnesium, monoaminergic and dopamine agonists, progesterone, aminosteroids, excitatory amino acid reuptake inhibitors, beta-2 antagonists (bronchodilators), haemostatic and antifibrinolytic drugs.Endotracheal intubation and mechanical ventilation may be used to ensure proper oxygen supply and provide a secure airway. Hypotension (low blood pressure), which has a devastating outcome in TBI, can be prevented by giving intravenous fluids to maintain a normal blood pressure. Failing to maintain blood pressure can result in inadequate blood flow to the brain. Blood pressure may be kept at an artificially high level under controlled conditions by infusion of norepinephrine or similar drugs; this helps maintain cerebral perfusion. Body temperature is carefully regulated because increased temperature raises the brains metabolic needs, potentially depriving it of nutrients. Seizures are common. While they can be treated with benzodiazepines, these drugs are used carefully because they can depress breathing and lower blood pressure. Anti-convulsant medications have only been found to be useful for reducing the risk of an early seizure. Phenytoin and leviteracetam appear to have similar levels of effectiveness for preventing early seizures. People with TBI are more susceptible to side effects and may react adversely to some medications. During treatment monitoring continues for signs of deterioration such as a decreasing level of consciousness.Traumatic brain injury may cause a range of serious coincidental complications that include cardiac arrhythmias and neurogenic pulmonary edema. These conditions must be adequately treated and stabilised as part of the core care. Surgery can be performed on mass lesions or to eliminate objects that have penetrated the brain. Mass lesions such as contusions or hematomas causing a significant mass effect (shift of intracranial structures) are considered emergencies and are removed surgically. For intracranial hematomas, the collected blood may be removed using suction or forceps or it may be floated off with water. Surgeons look for hemorrhaging blood vessels and seek to control bleeding. In penetrating brain injury, damaged tissue is surgically debrided, and craniotomy may be needed. Craniotomy, in which part of the skull is removed, may be needed to remove pieces of fractured skull or objects embedded in the brain. Decompressive craniectomy (DC) is performed routinely in the very short period following TBI during operations to treat hematomas; part of the skull is removed temporarily (primary DC). DC performed hours or days after TBI in order to control persistently high intracranial pressures (secondary DC), although can reduce intracranial pressure and length of stay in ICU, but have worse Glasgow Coma Scale (GCS) scores, and high chances of death, vegetative state, or severe disability when compared to those receiving standard medical therapies. Chronic stage Once medically stable, people may be transferred to a subacute rehabilitation unit of the medical center or to an independent rehabilitation hospital. Rehabilitation aims to improve independent functioning at home and in society, and to help adapt to disabilities. Rehabilitation has demonstrated its general effectiveness when conducted by a team of health professionals who specialize in head trauma. As for any person with neurologic deficits, a multidisciplinary approach is key to optimizing outcome. Physiatrists or neurologists are likely to be the key medical staff involved, but depending on the person, doctors of other medical specialties may also be helpful. Allied health professions such as physiotherapy, speech and language therapy, cognitive rehabilitation therapy, and occupational therapy will be essential to assess function and design the rehabilitation activities for each person. Treatment of neuropsychiatric symptoms such as emotional distress and clinical depression may involve mental health professionals such as therapists, psychologists, and psychiatrists, while neuropsychologists can help to evaluate and manage cognitive deficits. Social workers, rehabilitation support personnel, nutritionists, therapeutic recreationists, and pharmacists are also important members of the TBI rehabilitation team. After discharge from the inpatient rehabilitation treatment unit, care may be given on an outpatient basis. Community-based rehabilitation will be required for a high proportion of people, including vocational rehabilitation; this supportive employment matches job demands to the workers abilities. People with TBI who cannot live independently or with family may require care in supported living facilities such as group homes. Respite care, including day centers and leisure facilities for disabled people, offers time off for caregivers, and activities for people with TBI.Pharmacological treatment can help to manage psychiatric or behavioral problems. Medication is also used to control post-traumatic epilepsy; however the preventive use of anti-epileptics is not recommended. In those cases where the person is bedridden due to a reduction of consciousness, has to remain in a wheelchair because of mobility problems, or has any other problem heavily impacting self-caring capacities, caregiving and nursing are critical. The most effective research documented intervention approach is the activation database guided EEG biofeedback approach, which has shown significant improvements in memory abilities of the TBI subject that are far superior than traditional approaches (strategies, computers, medication intervention). Gains of 2.61 standard deviations have been documented. The TBIs auditory memory ability was superior to the control group after the treatment. Effect on the gait pattern In patients who have developed paralysis of the legs in the form of spastic hemiplegia or diplegia as a result of the traumatic brain injury, various gait patterns can be observed, the exact extent of which can only be described with the help of complex gait analysis systems. In order to facilitate interdisciplinary communication in the interdisciplinary team between those affected, doctors, physiotherapists and orthotists, a simple description of the gait pattern is useful. J. Rodda and H. K. Graham already described in 2001 how gait patterns of CP patients can be more easily recognized and defined gait types which they compared in a classification. They also described that gait patterns can vary with age. Building on this, the Amsterdam Gait Classification was developed at the free university in Amsterdam, the VU medisch centrum. A special feature of this classification is that it makes different gait patterns very recognizable and can be used in patients in whom only one leg and both legs are affected. The Amsterdam Gait Classification was developed for viewing patients with cerebral palsy. However, it can be used just as well in patients with traumatic brain injuries. According to the Amsterdam Gait Classification, five gait types are described. To assess the gait pattern, the patient is viewed visually or via a video recording from the side of the leg to be assessed. At the point in time at which the leg to be viewed is in mid stance and the leg not to be viewed is in mid swing, the knee angle and the contact of the foot with the ground are assessed on the one hand.Classification of the gait pattern according to the Amsterdam Gait Classification: In gait type 1, the knee angle is normal and the foot contact is complete. In gait type 2, the knee angle is hyperextended and the foot contact is complete. In gait type 3, the knee angle is hyperextended and foot contact is incomplete (only on the forefoot). In gait type 4, the knee angle is bent and foot contact is incomplete (only on the forefoot). With gait type 5, the knee angle is bent and the foot contact is complete.Gait types 5 is also known as crouch gait. Orthotics To improve the gait pattern, orthotics can be included in the therapy concept. An Orthosis can support physiotherapeutic treatment in setting the right motor impulses in order to create new cerebral connections. The orthosis must meet the requirements of the medical prescription. In addition, the orthosis must be designed by the orthotist in such a way that it achieves the effectiveness of the necessary levers, matching the gait pattern, in order to support the proprioceptive approaches of physiotherapy. The orthotic concepts of the treatment are based on the concepts for the patients with cerebral palsy. The characteristics of the stiffness of the orthosis shells and the adjustable dynamics in the ankle joint are important elements of the orthosis to be considered. The orthotic concepts of the treatment are based on the concepts for the patients with cerebral palsy. Due to these requirements, the development of orthoses has changed significantly in
Traumatic brain injury	recent years, especially since around 2010. At about the same time, care concepts were developed that deal intensively with the orthotic treatment of the lower extremities in cerebral palsy. Modern materials and new functional elements enable the rigidity to be specifically adapted to the requirements that fits to the gait pattern of the patient. The adjustment of the stiffness has a decisive influence on the gait pattern and on the energy cost of walking. It is of great advantage if the stiffness of the orthosis can be adjusted separately from one another via resistances of the two functional elements in the two directions of movement, dorsiflexion and plantar flexion. Prognosis Prognosis worsens with the severity of injury. Most TBIs are mild and do not cause permanent or long-term disability; however, all severity levels of TBI have the potential to cause significant, long-lasting disability. Permanent disability is thought to occur in 10% of mild injuries, 66% of moderate injuries, and 100% of severe injuries. Most mild TBI is completely resolved within three weeks. Almost all people with mild TBI are able to live independently and return to the jobs they had before the injury, although a small portion have mild cognitive and social impairments. Over 90% of people with moderate TBI are able to live independently, although some require assistance in areas such as physical abilities, employment, and financial managing. Most people with severe closed head injury either die or recover enough to live independently; middle ground is less common. Coma, as it is closely related to severity, is a strong predictor of poor outcome.Prognosis differs depending on the severity and location of the lesion, and access to immediate, specialised acute management. Subarachnoid hemorrhage approximately doubles mortality. Subdural hematoma is associated with worse outcome and increased mortality, while people with epidural hematoma are expected to have a good outcome if they receive surgery quickly. Diffuse axonal injury may be associated with coma when severe, and poor outcome. Following the acute stage, prognosis is strongly influenced by the patients involvement in activity that promote recovery, which for most patients requires access to a specialised, intensive rehabilitation service. The Functional Independence Measure is a way to track progress and degree of independence throughout rehabilitation.Medical complications are associated with a bad prognosis. Examples of such complications include: hypotension (low blood pressure), hypoxia (low blood oxygen saturation), lower cerebral perfusion pressures, and longer times spent with high intracranial pressures. Patient characteristics also influence prognosis. Examples of factors thought to worsen it include: abuse of substances such as illicit drugs and alcohol and age over sixty or under two years (in children, younger age at time of injury may be associated with a slower recovery of some abilities). Other influences that may affect recovery include pre-injury intellectual ability, coping strategies, personality traits, family environment, social support systems and financial circumstances.Life satisfaction has been known to decrease for individuals with TBI immediately following the trauma, but evidence has shown that life roles, age, and depressive symptoms influence the trajectory of life satisfaction as time passes. Many people with traumatic brain injuries have poor physical fitness following their acute injury and this may result with difficulties in day-to-day activities and increased levels of fatigue. Complications Improvement of neurological function usually occurs for two or more years after the trauma. For many years it was believed that recovery was fastest during the first six months, but there is no evidence to support this. It may be related to services commonly being withdrawn after this period, rather than any physiological limitation to further progress. Children recover better in the immediate time frame and improve for longer periods.Complications are distinct medical problems that may arise as a result of the TBI. The results of traumatic brain injury vary widely in type and duration; they include physical, cognitive, emotional, and behavioral complications. TBI can cause prolonged or permanent effects on consciousness, such as coma, brain death, persistent vegetative state (in which patients are unable to achieve a state of alertness to interact with their surroundings), and minimally conscious state (in which patients show minimal signs of being aware of self or environment). Lying still for long periods can cause complications including pressure sores, pneumonia or other infections, progressive multiple organ failure, and deep venous thrombosis, which can cause pulmonary embolism. Infections that can follow skull fractures and penetrating injuries include meningitis and abscesses. Complications involving the blood vessels include vasospasm, in which vessels constrict and restrict blood flow, the formation of aneurysms, in which the side of a vessel weakens and balloons out, and stroke.Movement disorders that may develop after TBI include tremor, ataxia (uncoordinated muscle movements), spasticity (muscle contractions are overactive), myoclonus (shock-like contractions of muscles), and loss of movement range and control (in particular with a loss of movement repertoire). The risk of post-traumatic seizures increases with severity of trauma (image at right) and is particularly elevated with certain types of brain trauma such as cerebral contusions or hematomas. People with early seizures, those occurring within a week of injury, have an increased risk of post-traumatic epilepsy (recurrent seizures occurring more than a week after the initial trauma). People may lose or experience altered vision, hearing, or smell.Hormonal disturbances may occur secondary to hypopituitarism, occurring immediately or years after injury in 10 to 15% of TBI patients. Development of diabetes insipidus or an electrolyte abnormality acutely after injury indicate need for endocrinologic work up. Signs and symptoms of hypopituitarism may develop and be screened for in adults with moderate TBI and in mild TBI with imaging abnormalities. Children with moderate to severe head injury may also develop hypopituitarism. Screening should take place 3 to 6 months, and 12 months after injury, but problems may occur more remotely.Cognitive deficits that can follow TBI include impaired attention; disrupted insight, judgement, and thought; reduced processing speed; distractibility; and deficits in executive functions such as abstract reasoning, planning, problem-solving, and multitasking. Memory loss, the most common cognitive impairment among head-injured people, occurs in 20–79% of people with closed head trauma, depending on severity. People who have had TBI may also have difficulty with understanding or producing spoken or written language, or with more subtle aspects of communication such as body language. Post-concussion syndrome, a set of lasting symptoms experienced after mild TBI, can include physical, cognitive, emotional and behavioral problems such as headaches, dizziness, difficulty concentrating, and depression. Multiple TBIs may have a cumulative effect. A young person who receives a second concussion before symptoms from another one have healed may be at risk for developing a very rare but deadly condition called second-impact syndrome, in which the brain swells catastrophically after even a mild blow, with debilitating or deadly results. About one in five career boxers is affected by chronic traumatic brain injury (CTBI), which causes cognitive, behavioral, and physical impairments. Dementia pugilistica, the severe form of CTBI, affects primarily career boxers years after a boxing career. It commonly manifests as dementia, memory problems, and parkinsonism (tremors and lack of coordination).TBI may cause emotional, social, or behavioral problems and changes in personality. These may include emotional instability, depression, anxiety, hypomania, mania, apathy, irritability, problems with social judgment, and impaired conversational skills. TBI appears to predispose survivors to psychiatric disorders including obsessive compulsive disorder, substance abuse, dysthymia, clinical depression, bipolar disorder, and anxiety disorders. In patients who have depression after TBI, suicidal ideation is not uncommon; the suicide rate among these persons is increased 2- to 3-fold. Social and behavioral symptoms that can follow TBI include disinhibition, inability to control anger, impulsiveness, lack of initiative, inappropriate sexual activity, asociality and social withdrawal, and changes in personality.TBI also has a substantial impact on the functioning of family systems Caregiving family members and TBI survivors often significantly alter their familial roles and responsibilities following injury, creating significant change and strain on a family system. Typical challenges identified by families recovering from TBI include: frustration and impatience with one another, loss of former lives and relationships, difficulty setting reasonable goals, inability to effectively solve problems as a family, increased level of stress and household tension, changes in emotional dynamics, and overwhelming desire to return to pre-injury status. In addition, families may exhibit less effective functioning in areas including coping, problem solving and communication. Psychoeducation and counseling models have been demonstrated to be effective in minimizing family disruption. Epidemiology TBI is a leading cause of death and disability around the globe and presents a major worldwide social, economic, and health problem. It is the number one cause of coma, it plays the leading role in disability due to trauma, and is the leading cause of brain damage in children and young adults. In Europe it is responsible for more years of disability than any other cause. It also plays a significant role in half of trauma deaths.Findings on the frequency of each level of severity vary based on the definitions and methods used in studies. A World Health Organization study estimated that between 70 and 90% of head injuries that receive treatment are mild, and a US study found that moderate and severe injuries each account for 10% of TBIs, with the rest mild.The incidence of TBI varies by age, gender, region and other factors. Findings of incidence and prevalence in epidemiological studies vary based on such factors as which grades of severity are included, whether deaths are included, whether the study is restricted to hospitalized people, and the studys location. The annual incidence of mild TBI is difficult to determine but may be 100–600 people per 100,000. Mortality In the US, the case fatality rate is estimated to be 21% by 30 days after TBI. A study on Iraq War soldiers found that severe TBI carries a mortality of 30–50%. Deaths have declined due to improved treatments and systems for managing trauma in societies wealthy enough to provide modern emergency and neurosurgical services. The fraction of those who die after being hospitalized with TBI fell from almost half in the 1970s to about a quarter at the beginning of the 21st century. This decline in mortality has led to a concomitant increase in the number of people living with disabilities that result from TBI.Biological, clinical, and demographic factors contribute to the likelihood that an injury will be fatal. In addition, outcome depends heavily on the cause of head injury. In the US, patients with fall-related TBIs have an 89% survival rate, while only 9% of patients with firearm-related TBIs survive. In the US, firearms are the most common cause of fatal TBI, followed by vehicle accidents and then falls. Of deaths from firearms, 75% are considered to be suicides.The incidence of TBI is increasing globally, due largely to an increase in motor vehicle use in low- and middle-income countries. In developing countries, automobile use has increased faster than safety infrastructure could be introduced. In contrast, vehicle safety laws have decreased rates of TBI in high-income countries, which have seen decreases in traffic-related TBI since the 1970s. Each year in the United States, about two million people have a TBI, approximately 675,000 injuries are seen in the emergency department, and about 500,000 patients are hospitalized. The yearly incidence of TBI is estimated at 180–250 per 100,000 people in the US, 281 per 100,000 in France, 361 per 100,000 in South Africa, 322 per 100,000 in Australia, and 430 per 100,000 in England. In the European Union the yearly aggregate incidence of TBI hospitalizations and fatalities is estimated at 235 per 100,000. Demographics TBI is present in 85% of traumatically injured children, either alone or with other injuries. The greatest number of TBIs occur in people aged 15–24. Because TBI is more common in young people, its costs to society are high due to the loss of productive years to death and disability. The age groups most at risk for TBI are children ages five to nine and adults over age 80, and the highest rates of death and hospitalization due to TBI are in people over age 65. The incidence of fall-related TBI in First-World countries is increasing as the population ages; thus the median age of people with head injuries has increased.Regardless of age, TBI rates are higher in males. Men have twice as many TBIs as women do and have a fourfold risk of fatal head injury, and males account for two thirds of childhood and adolescent head trauma. However, when matched for severity of injury, women appear to fare more poorly than men.Socioeconomic status also appears to affect TBI rates; people with lower levels of education and employment and lower socioeconomic status are at greater risk. Approximately half of those incarcerated in prisons and jails in the United States have had TBIs. History Head injury is present in ancient myths that may date back before recorded history. Skulls found in battleground graves with holes drilled over fracture lines suggest that trepanation may have been used to treat TBI in ancient times. Ancient Mesopotamians knew of head injury and some of its effects, including seizures, paralysis, and loss of sight, hearing or speech. The Edwin Smith Papyrus, written around 1650–1550 BC, describes various head injuries and symptoms and classifies them based on their presentation and tractability. Ancient Greek physicians including Hippocrates understood the brain to be the center of thought, probably due to their experience observing the effects of head trauma.Medieval and Renaissance surgeons continued the practice of trepanation for head injury. In the Middle Ages, physicians further described head injury symptoms and the term concussion became more widespread. Concussion symptoms were first described systematically in the 16th century by Berengario da Carpi.It was first suggested in the 18th century that intracranial pressure rather than skull damage was the cause of pathology after TBI. This hypothesis was confirmed around the end of the 19th century, and opening the skull to relieve pressure was then proposed as a treatment.In the 19th century it was noted that TBI is related to the development of psychosis. At that time a debate arose around whether post-concussion syndrome was due to a disturbance of the brain tissue or psychological factors. The debate continues today. Perhaps the first reported case of personality change after brain injury is that of Phineas Gage, who survived an accident in which a large iron rod was driven through his head, destroying one or both of his frontal lobes; numerous cases of personality change after brain injury have been reported since.The 20th century saw the advancement of technologies that improved treatment and diagnosis such as the development of imaging tools including CT and MRI, and, in the 21st century, diffusion tensor imaging (DTI). The introduction of intracranial pressure monitoring in the 1950s has been credited with beginning the "modern era" of head injury. Until the 20th century, the mortality rate of TBI was high and rehabilitation was uncommon; improvements in care made during World War I reduced the death rate and made rehabilitation possible. Facilities dedicated to TBI rehabilitation were probably first established during World War I. Explosives used in World War I caused many blast injuries; the large number of TBIs that resulted allowed researchers to learn about localization of brain functions. Blast-related injuries are now common problems in returning veterans from Iraq & Afghanistan; research shows that the symptoms of such TBIs are largely the same as those of TBIs involving a physical blow to the head.In the 1970s, awareness of TBI as a public health problem grew, and a great deal of progress has been made since then in brain trauma research, such as the discovery of primary and secondary brain injury. The 1990s saw the development and dissemination of standardized guidelines for treatment of TBI, with protocols for a range of issues such as drugs and management of intracranial pressure. Research since the early 1990s has improved TBI survival; that decade was known as the "Decade of the Brain" for advances made in brain research. Research directions Diagnosis Quantitative EEG and EEG, which has no specific patterns in TBI is used in research settings to differentiate between mild TBI and no TBI. Medications No medication is approved to halt the progression of the initial injury to secondary injury. The variety of pathological events presents opportunities to find treatments that interfere with the damage processes. Neuroprotection methods to decrease secondary injury, have been the subject of interest follows TBI. However, trials to test agents that could halt these cellular mechanisms have met largely with failure. For example, interest existed in cooling the injured brain; however, a 2020 Cochrane review did not find enough evidence to see if it was useful or not. Maintaining a normal temperature in the immediate period after a TBI appeared useful. One review found a lower than normal temperature was useful in adults but not children. While two other reviews found it did not appear to be useful.Further research is necessary to determine if the vasoconstrictor indomethacin (indometacin) can be used to treat increased pressure in the skull following a TBI.In addition, drugs such as NMDA receptor antagonists to halt neurochemical cascades such as excitotoxicity showed promise in animal trials but failed in clinical trials. These failures could be due to factors including faults in the trials design or in the insufficiency of a single agent to prevent the array of injury processes involved in secondary injury.Other topics of research have included investigations into mannitol, dexamethasone, progesterone, xenon, barbiturates, magnesium (no strong evidence), calcium channel blockers, PPAR-γ agonists, curcuminoids, ethanol, NMDA antagonists, caffeine. Procedures In addition to traditional imaging modalities, there are several devices that help to monitor brain injury and facilitate research. Microdialysis allows ongoing sampling of extracellular fluid for analysis of metabolites that might indicate ischemia or brain metabolism, such as glucose, glycerol, and glutamate. Intraparenchymal brain tissue oxygen monitoring systems (either Licox or Neurovent-PTO) are used routinely in neurointensive care in the US. A non invasive model called CerOx is in development.Research is also planned to clarify factors correlated to outcome in TBI and to determine in which cases it is best to perform CT scans and surgical procedures.Hyperbaric oxygen therapy (HBO) has been evaluated as an add on treatment following TBI. The findings of a 2012 Cochrane systematic review does not justify the routine use of hyperbaric oxygen therapy to treat people recovering from a traumatic brain injury. This review also reported that only a small number of randomized controlled trials had been conducted at the time of the review, many of which had methodological problems and poor reporting. HBO for TBI is controversial with further evidence required to determine if it has a role. Psychological Further research is required to determine the effectiveness of non-pharmacological treatment approaches for treating depression in children/adolescents and adults with TBI.As of 2010, the use of predictive visual tracking measurement to identify mild traumatic brain injury was being studied. In visual tracking tests, a head-mounted display unit with eye-tracking capability shows an object moving in a regular pattern. People without brain injury are able to track the moving object with smooth pursuit eye movements and correct trajectory. The test requires both attention and working memory which are difficult functions for people with mild traumatic brain injury. The question being studied, is whether results for people with brain injury will show visual-tracking gaze errors relative to the moving target. Monitoring pressure Pressure reactivity index is used to correlate intracranial pressure with arterial blood pressure to give information about the state of cerebral perfusion, thus guiding treatment and prevent excessively high or low blood flow to the brain. However, such method of monitoring intracranial pressure of equal or less than 20 mmHg is no better than imaging and clinical examination that monitor the neurological status of the brain in prolonging the survival, preserving the mental or functional status of the subject. Sensory processing In animal models of TBI, sensory processing has been widely studied to show systematic defects arise and are slowly but likely only partially recovered. It is especially characterised by an initial period of decreased activity in upper cortical layers. This period of decreased activity has also been characterised as by specific timing effects in the patterns of cortical activity in these upper layers in response to regular sensory stimuli. References Cited texts The original version of this article contained text from the NINDS public domain pages on TBI Archived December 18, 2016, at the Wayback Machine External links Brain injury at Curlie The Brain Injury Hub – information and practical advice to parents and family members of children with acquired brain injury Archived October 5, 2020, at the Wayback Machine Defense and Veterans Brain Injury Center – U.S. Department of Defense Military Health System center for traumatic brain injury Archived October 12, 2019, at the Wayback Machine
Right atrial enlargement	Right atrial enlargement (RAE) is a form of cardiomegaly, or heart enlargement. It can broadly be classified as either right atrial hypertrophy (RAH), overgrowth, or dilation, like an expanding balloon. Common causes include pulmonary hypertension, which can be the primary defect leading to RAE, or pulmonary hypertension secondary to tricuspid stenosis; pulmonary stenosis or Tetralogy of Fallot i.e. congenital diseases; chronic lung disease, such as cor pulmonale. Other recognised causes are: right ventricular failure, tricuspid regurgitation, and atrial septal defect. Diagnosis It is characterized by a high P wave amplitude (P pulmonale), i.e. a height greater than 2.5 mm in inferior ECG leads (II, III, aVF); and greater than 1.5 mm in right sided precordial leads (V1, V2). Large "a" waves on the JVP waveform can also aid in diagnosis. == References ==

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