Promoter DNA Methylation in GWAS-Identified Genes as Potential Functional Elements for Blood Pressure: An Observational and Mendelian Randomization Study.
Genome-wide association studies have identified numerous genetic loci for blood pressure (BP). However, the relationships of functional elements inside these loci with BP are not fully understood. This study represented an effort to determine if promoter DNA methylations inside BP-associated loci were associated with BP.We conducted a cross-sectional study investigating the association between promoter DNA methylations of 10 candidate genes and BP in 1,241 Chinese individuals. Twenty-one genomic fragments in the CpG Islands were sequenced. The associations of methylation levels with BP and hypertension were assessed in regression models. Mendelian randomization (MR) analysis was then applied to find supporting evidence for the identified associations.A total of 413 DNA methylation sites were examined in an observational study. Methylation levels of 24 sites in PRDM6, IGFBP3, SYT7, PDE3A, TBX2 and C17orf82 were significantly associated with BP. Methylation levels of PRDM6 and SYT7 were significantly associated with hypertension. Methylation levels of five sites (including cg06713098) in IGFBP3 were significantly associated with DBP. MR analysis found associations between the methylation levels of six CpG sites (cg06713098, cg14228300, cg23193639, cg21268650, cg10677697 and cg04812164) around the IGFBP3 promoter and DBP. Methylation levels of cg14228300 and cg04812164 were associated with SBP. By further applying several MR methods we showed that the associations may not be due to pleiotropy. Association between IGFBP3 mRNA levels in blood cells and BP was also found in MR analysis. This study identified promoter methylation as potential functional element for BP. The identified methylations may be involved in the regulatory pathway linking genetic variants to BP.


Levels of complexity in phonological disorders: evidence from Cantonese.
Longitudinal data from ten phonologically disordered Cantonese-speaking boys were analysed for distinctive features (manner and place). The children labelled 95 pictures, attempting each initial Cantonese segment at least five times. The applicability of Dinnsen et al.'s implicational hierarchy to this data was examined. Categorization of each child's system according to an implicational hierarchy was successful for nine of the ten children when phonetic inventories were considered. In addition, a phonemic inventory based on Dinnsen et al.'s phonetic inventory captured the system of phonological contrasts used by eight of the ten children. The patterns of the children who did not match the hierarchy were considered deviant rather than delayed. The ability of the hierarchy to predict the route of development in this group of children was also examined. The hierarchies (both phonetic and phonemic) successfully predicted the route of change in these cases. Implications for the use of an implicational hierarchy in phonological assessment and treatment are discussed. Further research on feature-based phonological development, in both typically-developing and disordered phonological systems is required.


Association between serum ferritin and osteocalcin as a potential mechanism explaining the iron-induced insulin resistance.
Increased iron stores are associated with increased risk of type 2 diabetes, however, the mechanisms underlying these associations are poorly understood. Because a reduction of circulating osteocalcin levels after iron overload have been demonstrated in cell cultures, and osteocalcin is related to glucose and insulin metabolism, the iron-induced osteocalcin reductions could contribute to explain the role of iron metabolism in the development of type 2 diabetes mellitus. To analyzed the associations between serum total and uncarboxylated osteocalcin and adiponectin concentrations with serum ferritin and soluble transferrin receptor (sTfR) in elderly subjects. We evaluated a total of 423 subjects from the PREDIMED cohort in a population-based cross-sectional analysis. Extensive clinical, nutritional and laboratory measurements, including total and uncarboxylated osteocalcin, adiponectin, ferritin and sTfR were recorded. Serum ferritin was positively correlated with increased glucose and insulin circulating levels but also with HOMA-IR, and was inversely associated with total osteocalcin and adiponectin. A regression analysis revealed that serum ferritin and transferrin receptor levels were significantly associated with a decrease in total and uncarboxylated osteocalcin. Serum sTfR levels were associated with lower uncarboxylated osteocalcin levels in the whole-study subjects and remained significant only in the IFG (impaired fasting glucose) individuals. We described, for the first time, an inverse association between serum ferritin and sTfR with osteocalcin and extend previous results on adiponectin, thus supporting that factors related to iron metabolism could contribute to the insulin resistance and the development of type 2 diabetes mellitus. Controlled-Trials.com ISRCTN35739639 <http://www.controlled-trials.com/ISRCTN35739639>.


Digital Health Technologies Respond to the COVID-19 Pandemic In a Tertiary Hospital in China: Development and Usability Study.
The outbreak of COVID-19 has caused a continuing global pandemic. Hospitals are integral to the control and prevention of COVID-19; however, they are facing numerous challenges during the epidemic. Our study aimed to introduce the practical experience of the design and implementation of a web-based COVID-19 service platform at a tertiary hospital in China as well as the preliminary results of the implementation. The web-based COVID-19 service platform was deployed within the health care system of the Guangdong Second Provincial General Hospital and Internet Hospital; the function of the platform was to provide web-based medical services for both members of the public and lay health care workers. The focal functions of this system included automated COVID-19 screening, related symptom monitoring, web-based consultation, and psychological support; it also served as a COVID-19 knowledge hub. The design and process of each function are introduced. The usage data for the platform service were collected and are represented by three periods: the pre-epidemic period (December 22, 2019, to January 22, 2020, 32 days), the controlled period (January 23 to March 31, 2020, 69 days), and the postepidemic period (April 1 to June 30, 2020, 91 days). By the end of June 2020, 96,642 people had used the automated COVID-19 screening and symptom monitoring systems 161,884 and 7,795,194 times, respectively. The number of general web-based consultation services per day increased from 30 visits in the pre-epidemic period to 122 visits during the controlled period, then dropped to 73 visits in the postepidemic period. The psychological counseling program served 636 clients during the epidemic period. For people who used the automated COVID-19 screening service, 160,916 (99.40%) of the total users were classified in the no risk category. 464 (0.29%) of the people were categorized as medium to high risk, and 12 people (0.01%) were recommended for further COVID-19 testing and treatment. Among the 96,642 individuals who used the COVID-19 related symptoms monitoring service, 6696 (6.93%) were symptomatic at some point during the monitoring period. Fever was the most frequently reported symptom, with 2684/6696 symptomatic people (40.1%) having had this symptom. Cough and sore throat were also relatively frequently reported by the 6696 symptomatic users (1657 people, 24.7%, and 1622 people, 24.2%, respectively). The web-based COVID-19 service platform implemented at a tertiary hospital in China is exhibited to be a role model for using digital health technologies to respond to the COVID-19 pandemic. The digital solutions of automated COVID-19 screening, daily symptom monitoring, web-based care, and knowledge propagation have plausible acceptability and feasibility for complementing offline hospital services and facilitating disease control and prevention.


Diagnosis in young children: how a father's perceptions of mental health change.
This case study's purpose was to understand how diagnosing mental illness in a child affects a parent's perception of mental health, using Denzin's interpretive interactionism. Two interviews from a case study were analyzed. Emergent themes were alienation from peers, ambivalence, shifting orientation to mental illness, school system stigmatization and conflict with mental health care, and discovery of mental healthcare specialists and new peers. Perceptions were influenced by peers, education, and mental healthcare systems, and by the disease model paradigm of mental illness. Future research should explore the effect of the diagnostic process on parents of very young children, and expand on consequences of undergoing current diagnostic and treatment practices.


The effects of high fat feeding during one cycle of reproduction consisting of pregnancy, lactation and recovery on body composition and fat pad cellularity in the rat.
The changes in adipose depot weight, cell size, cell number and body composition during pregnancy, lactation and recovery were studied in Osborne-Mendel rats fed standard or high fat diets. Rats were killed on day 21 of pregnancy, after 21 days of lactation, and after 21 or 22 days of a postlactational recovery period. Nonpregnant control groups were killed at the beginning and at the conclusion of the experimental period. The high fat-fed, mated group was always fatter than similarly treated animals fed standard diets throughout pregnancy and lactation. However, by the end of the recovery period, carcass composition of the animals fed high fat or standard diets and the nonpregnant groups were not statistically different. The weight of the parametrial, retroperitoneal and subscapular depots was higher in the high fat-fed animals at the end of the recovery period, and in the latter two pads, this increase was statistically significant. Thus, despite the extensive lipid mobilization that occurs during lactation, the high fat-fed animals appear to be predisposed to postpartum obesity.


Does fluoride in the water close the dental caries gap between Indigenous and non-Indigenous children?
Indigenous children experience significantly more dental caries than non-Indigenous children. This study assessed if access to fluoride in the water closed the gap in dental caries between Indigenous and non-Indigenous children. Data from four states and two territories were sourced from the Child Dental Health Survey (CDHS) conducted in 2010. The outcomes were dental caries in the deciduous and permanent dentitions, and the explanatory variables were Indigenous status and access to fluoridated water (≥0.5 mg/L) prior to 2008. Dental caries prevalence and severity for Indigenous and non-Indigenous children, in both dentitions, was lower in fluoridated areas compared to non-fluoridated areas. Among non-Indigenous children, there was a 50.9% difference in mean dmft scores in fluoridated (1.70) compared to non-fluoridated (2.86) areas. The difference between Indigenous children in fluoridated (3.29) compared to non-fluoridated (4.16) areas was 23.4%. Among non-Indigenous children there was a 79.7% difference in the mean DMFT scores in fluoridated (0.68) compared to non-fluoridated (1.58) areas. The difference between Indigenous children in fluoridated (1.59) and non-fluoridated (2.23) areas was 33.5%. Water fluoridation is effective in reducing dental caries, but does not appear to close the gap between non-Indigenous children and Indigenous children.


Perspectives of Transgender Youth on Parental Support: Qualitative Findings From the Resilience and Transgender Youth Study.
Transgender youth are more likely than cisgender youth to report health risks related to violence victimization, substance use, mental health, and sexual health. Parental support may help foster resilience and better health outcomes among this population. However, limited research has characterized parental support among transgender youth. To address this gap, we conducted a thematic analysis of 33 in-depth interviews with transgender youth. We coded interviews using the dimensions of the social support framework (i.e., emotional, instrumental, appraisal, and informational) as well as inductive codes to identify emergent themes. Almost all participants described some form of general parental support (e.g., expressions of love, housing, advice, and affirmation). Parental support specific to gender identity was also noted (e.g., emotional support for coming out as transgender and chosen name and pronoun use) but was more limited. Parents may benefit from resources and programming to promote acceptance and gender-affirming behaviors.


Examining the relationship between head trauma and neurodegenerative disease: A review of epidemiology, pathology and neuroimaging techniques.
Traumatic brain injuries (TBI) are induced by sudden acceleration-deceleration and/or rotational forces acting on the brain. Diffuse axonal injury (DAI) has been identified as one of the chief underlying causes of morbidity and mortality in head trauma incidents. DAIs refer to microscopic white matter (WM) injuries as a result of shearing forces that induce pathological and anatomical changes within the brain, which potentially contribute to significant impairments later in life. These microscopic injuries are often unidentifiable by the conventional computed tomography (CT) and magnetic resonance (MR) scans employed by emergency departments to initially assess head trauma patients and, as a result, TBIs are incredibly difficult to diagnose. The impairments associated with TBI may be caused by secondary mechanisms that are initiated at the moment of injury, but often have delayed clinical presentations that are difficult to assess due to the initial misdiagnosis. As a result, the true consequences of these head injuries may go unnoticed at the time of injury and for many years thereafter. The purpose of this review is to investigate these consequences of TBI and their potential link to neurodegenerative disease (ND). This review will summarize the current epidemiological findings, the pathological similarities, and new neuroimaging techniques that may help delineate the relationship between TBI and ND. Lastly, this review will discuss future directions and propose new methods to overcome the limitations that are currently impeding research progress. It is imperative that improved techniques are developed to adequately and retrospectively assess TBI history in patients that may have been previously undiagnosed in order to increase the validity and reliability across future epidemiological studies. The authors introduce a new surveillance tool (Retrospective Screening of Traumatic Brain Injury Questionnaire, RESTBI) to address this concern.


Resuscitation fluids for the treatment of hemorrhagic shock in dogs: effects on myocardial blood flow and oxygen transport.
The efficacy of using colloids vs. crystalloids in the treatment of hemorrhagic shock remains controversial. An important aspect in the treatment of hemorrhagic shock is the reestablishment of normal myocardial blood flow after fluid resuscitation. This study, therefore, was designed to investigate the effect of resuscitation with different plasma substitutes on myocardial blood flow and oxygen transport after acute hemorrhage in dogs. Forty-three dogs were anesthetized and bled into a heparinized Wiggers' reservoir to a mean arterial pressure of 35 mm Hg. The animals were maintained at this level of hypotension for 90 mins, whereupon the animals were infused with one of five randomly selected fluids: a) succinylated gelatin (Gelofusine); b) urea-linked gelatin (Haemaccel); c) 6% hetastarch (Hespan); d) lactated Ringer's solution; or e) shed blood. Myocardial blood flow was measured using the radiolabeled microsphere technique. Resuscitation with succinylated gelatin, urea-linked gelatin, and hetastarch resulted in significant hemodilution. However, infusion of these fluids resulted in a compensatory hyperemia that increased myocardial blood flow and maintained oxygen transport at preshock values. No hyperemia was observed with reinfusion of shed blood. Resuscitation with lactated Ringer's solution produced significant hemodilution without hyperemia and, consequently, a significant decrease in oxygen transport. These results suggest that in lieu of blood, the artificial colloids are more effective than crystalloids in restoring myocardial blood flow and oxygen transport after acute experimental hemorrhage in dogs.


Diapeutic cancer-targeting alkylphosphocholine analogs may advance management of brain malignancies.
The following is a special report on alkylphosphocholine analogs as targeted imaging and therapy agents for cancer, and their potential role in diagnosis and treatment in glioblastoma and brain metastases. These novel cancer-targeting agents display impressive tumor avidity with low background in the normal brain, and multimodal diagnostic imaging and therapy capabilities. The use of these agents may significantly improve diagnosis, treatment and post-treatment follow-up in patients with brain malignancies.


On the importance of anion-π interactions in the mechanism of sulfide:quinone oxidoreductase.
Sulfide:quinone oxidoreductase (SQR) is a flavin-dependent enzyme that plays a physiological role in two important processes. First, it is responsible for sulfide detoxification by oxidizing sulfide ions (S(2-) and HS(-)) to elementary sulfur and the electrons are first transferred to flavin adenine dinucleotide (FAD), which in turn passes them to the quinone pool in the membrane. Second, in sulfidotrophic bacteria, SQRs play a key role in the sulfide-dependent respiration and anaerobic photosynthesis, deriving energy for their growth from reduced sulfur. Two mechanisms of action for SQR have been proposed: first, nucleophilic attack of a Cys residue on the C4 of FAD, and second, an alternate anionic radical mechanism by direct electron transfer from Cys to the isoalloxazine ring of FAD. Both mechanisms involve a common anionic intermediate that it is stabilized by a relevant anion-π interaction and its previous formation (from HS(-) and Cys-S-S-Cys) is also facilitated by reducing the transition-state barrier, owing to an interaction that involves the π system of FAD. By analyzing the X-ray structures of SQRs available in the Protein Data Bank (PDB) and using DFT calculations, we demonstrate the relevance of the anion-π interaction in the enzymatic mechanism.


Identification, cloning, and properties of cytosolic D-ribulose-5-phosphate 3-epimerase from higher plants.
Plant cells contain a complete oxidative pentose phosphate pathway in the chloroplasts, but an incomplete pathway was proposed to be present in the cytosol, with cytosolic (cyt) isoforms of ribulose-5-phosphate 3-epimerase (RPEase) and other non-oxidative branch enzymes being undetectable. Here we present for the first time the identification, cloning, and properties of a cyt-RPEase in rice (Oryza sativa) and presence of its homologues in other plant species. Recombinant cyt-RPEase is a homodimer of 24.3-kDa subunits such as in the case of the animal and yeast enzymes, whereas the chloroplast (chl) RPEase is a hexamer. Cytosolic and chloroplastic RPEases cannot be separated by anion exchange chromatography. Since plant cyt-RPEase is more closely related in its primary structure to homologous enzymes in animal and yeast cells than to the chloroplast RPEase, the plant nuclear genes coding for cytosolic and chloroplast RPEases were most likely derived from eubacteria and cyanobacteria, respectively. Accumulation of cyt-RPEase-mRNA and protein is high in root cells, lacking chl-RPEase, and lower in green tissue. These and other observations support the view that green and non-green plant cells possess a complete oxidative pentose phosphate pathway in the cytosol.


Overweight is not a comorbidity factor during childhood asthma: the GrowthOb study.
While being overweight is a risk factor for subsequent asthma in children, the importance of body mass index (BMI) as a comorbidity factor remains debated. The aim of this study was to assess the relationships between being overweight and the characteristics of childhood asthma. The BMI, BMI z-scores and International Obesity Task Force (IOTF) grades were evaluated in asthmatic children according to atopic status, symptoms during the past 3 months, exercise breathlessness, treatment and lung function in 6-15-yr-old children with confirmed asthma. 491 asthmatic children (mean ± SD age 10.8 ± 2.6 yrs; 179 females) were prospectively enrolled. There were 78 (15.5%) overweight (IOTF grade 1) and eight (1.6%) obese (grade 2) children. The children's BMI z-scores did not differ according to atopy, exacerbation, symptom-free days or treatment. The BMI z-score correlated positively with forced vital capacity and forced expiratory volume in 1 s in females, which could be related to earlier puberty in overweight females (growth spurt with increased volumes). Compared with normal weight children, overweight and obese children had reduced lung volume ratios (functional residual capacity/total lung capacity (TLC) and residual volume/TLC), no evidence of airflow limitation and similar symptoms. In conclusion, the observed functional relationships with BMI are not specific to asthma and being overweight is not associated with significant clinical impacts on asthma during childhood.


[Urticaria. Generalities].
This is an update article in urticaria. Its content try to summarize in few words all the practical knowledge that we have of these diseases "up to now". An exhaustive reference of the bibliography is avoided although the revision has been done indeed. We feel that if such is necessary in some papers, do difficult the reading in others like this, exclusively conceived for teaching.


Delayed Closure of Open Abdomen in Septic Patients Treated With Negative Pressure Vacuum Therapy and Dynamic Sutures: A 10-Years Follow-Up on Long-Term Complications.
Introduction: Patients with open abdomen after surgical interventions associated with the complication of secondary peritonitis are successfully treated with negative pressure wound therapy. The use of dynamic fascial sutures reduces fascial lateralization and increases successful delayed fascial closure after open abdomen treatment. Methods: In 2017 we published the follow-up results of 38 survivors out of 87 open abdomen patients treated with negative pressure wound therapy and dynamic fascial sutures between 2007 and 2012. In our current study we present the 10-years follow-up results regarding long-term complications with the focus on incisional hernias and pain. Since 2017 seven more patients have died, hence 31 patients were included in the current study. The patients were asked to answer questions about specific long-term complications of OA treatment including pain, the presence of incisional hernias and subsequent surgical interventions. Demographic data and data regarding fascial closure after open abdomen treatment were collected. All results were analyzed quantitatively. The follow-up period was 8-13 years. Results: The median age was 69 (30-90) years, and 15 (48.4%) were females. Twenty-four patients (77.4%) responded to the questionnaire: Three patients (12.5%) suffered from pain in the original operating field, all three at rest but not during exercise. None of the patients required analgesic treatment. Eleven patients (45.8%) were found to have incisional hernias. Five out of 11 hernias (45.5%) were treated by surgery and did not declare any pain in the operating field. Among the patients with incisional hernias lower MPI (Mannheimer Peritonitis Index) at the time of primary surgery but more reoperations and treatment days were found. The technique of fascial closure was heterogenic and no differences in the occurrence of incisional hernia could be detected. Conclusion: The incidence of incisional hernias after open abdomen treatment is still high, but are associated with little pain in the original operating field. Further studies are required to investigate methods for fascial closure techniques after OA treatment.


The Risk Factors of Hamstring Strain Injury Induced by High-Speed Running.
Hamstring strain injury is a multifactorial and complex problem involving interactions among various factors. Information about risk factors for this injury is inconsistent among studies because the strong effects of confounding factors and injury situations are often ignored. We investigated the relationship between hamstring strain induced by high-speed running and intrinsic risk factors, including hip muscle morphology and function, by excluding the influences of confounding factors. Sixty-one male track and field athletes (age, 19.6 ± 1.1 years; 95% confidence interval, 19.3-19.9) who often performed high-speed running were monitored throughout one season. Before the season, we measured hip and knee strength, muscle thickness of the gluteus maximus and biceps femoris, and hip and knee joint range of motion (ROM). We also obtained information about each athlete's history of hamstring injury by questionnaire. Eighteen athletes sustained hamstring strain injuries induced by high-speed running. Eighteen uninjured athletes who had the same profile of confounding factors as the injured athletes were selected as controls. Previously injured athletes had a significantly higher injury rate than uninjured athletes (p < .05; odds ratio, 2.85). No other measurements had a significant relationship with the occurrence of injury. However, passive hip ROM (flexion and extension) tended to be larger in the injured than control group. A history of hamstring strain was a strong risk factor for hamstring strain injury, and it may affect other factors. Therefore, the risk factors for hamstring strain injury should be investigated by eliminating the impact of a history of hamstring strain.


Surgical results in unusual cerebellopontine angle tumours.
Vestibular schwannomas account for 84% of cerebellopontine angle (CPA) lesions. The remaining CPA tumours comprise a fascinating group of lesions which may present in a similar fashion. Fortunately, advances in neuroradiology have increased our diagnostic accuracy of these lesions. This paper describes the surgical results of a series of 69 CPA lesions which were not vestibular schwannomas. The majority of these unusual CPA tumours were meningiomas, cholesteatomas and neuromas of other cranial nerves in the posterior fossa.


Misinterpreting growth and treatment outcome from serial cephalographs.
This communication addresses the issue of interpretation of serial cephalometric records. Angular measurements provide information that combines the vertical and sagittal components of a landmark's displacement. For example, a decrease in the SNA angle following orthodontic treatment with a headgear demonstrates maxillary retraction relative to nasion, an important assessment to depict a change closely related to the facial profile. Upon superimposition on the anterior cranial base, however, the vertical movement of point A may be the prevalent displacement, which would still account for the decrease in the SNA angle. The superposition allows the evaluation of the displacement in its vertical and sagittal components separately, relative to a structure that is relatively more stable than nasion. The superimposition enhanced the precision of the information regarding the actual displacement of the jaw. A patient's cephalometric records are presented, further demonstrating that the interpretation of changes during growth and treatment should be based not only on angular measurements, but also on regional superpositions. The frames of reference of both procedures are needed to fully understand the facial changes.


Outcomes of four-corner arthrodesis using the Hubcap circular plate.
We present results of four-corner carpal arthrodesis with the Acumed Hubcap circular plate performed at our unit. Eight patients underwent eight procedures over five years, for scapholunate advanced collapse (five wrists) and scaphoid non-union advanced collapse (three wrists). Outcomes included range of motion, quickDASH scores, and visual analogue scores for satisfaction. At final follow-up, mean flexion-extension arc was 56°, mean radial-ulnar deviation 29° and mean quickDASH score was 23/100. Mean score for satisfaction was 7.7/10 (77%). Seven out of eight (87.5%) patients said they would have it done again, and would also recommend it to others. Radiological union was achieved in all cases. One screw broke in one arthrodesis without causing symptoms. The functional outcomes with our use of the Hubcap are comparable to those reported in literature to date with other circular plates (e.g. Spider plate). There were no non-unions, which is the main reported complication with these plates.


Activity of the new triazole derivative albaconazole against Trypanosoma (Schizotrypanum) cruzi in dog hosts.
Albaconazole is an experimental triazole derivative with potent and broad-spectrum antifungal activity and a remarkably long half-life in dogs, monkeys, and humans. In the present work, we investigated the in vivo activity of this compound against two strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas' disease, using dogs as hosts. The T. cruzi strains used in the study were previously characterized (murine model) as susceptible (strain Berenice-78) and partially resistant (strain Y) to the drugs currently in clinical use, nifurtimox and benznidazole. Our results demonstrated that albaconazole is very effective in suppressing the proliferation of the parasite and preventing the death of infected animals. Furthermore, the parasitological, PCR, serological, and proliferative assay results indicated parasitological cure indices of 25 and 100% among animals inoculated with T. cruzi strain Y when they were treated with albaconazole at 1.5 mg/kg of body weight/day for 60 and 90 days, respectively. On the other hand, although albaconazole given at 1.5 mg/kg/day was very effective in suppressing the proliferation of the parasite in animals infected with the Berenice-78 T. cruzi strain, no parasitological cure was observed among them, even when a longer treatment period (150 doses) was used. In conclusion, our results demonstrate that albaconazole has trypanocidal activity in vivo and is capable of inducing radical parasitological cure, although natural resistance to this compound was also indicated. Furthermore, the compound can be used in long-term treatment schemes (60 to 150 days) with minimal toxicity and thus represents a potentially useful candidate for the treatment of human Chagas' disease.


Influence of Japanese consumer gender and age on sensory attributes and preference (a case study on deep-fried peanuts).
Detailed exploration of sensory perception as well as preference across gender and age for a certain food is very useful for developing a vendible food commodity related to physiological and psychological motivation for food preference. Sensory tests including color, sweetness, bitterness, fried peanut aroma, textural preference and overall liking of deep-fried peanuts with varying frying time (2, 4, 6, 9, 12 and 15 min) at 150 °C were carried out using 417 healthy Japanese consumers. To determine the influence of gender and age on sensory evaluation, systematic statistical analysis including one-way analysis of variance, polynomial regression analysis and multiple regression analysis was conducted using the collected data. The results indicated that females were more sensitive to bitterness than males. This may affect sensory preference; female subjects favored peanuts prepared with a shorter frying time more than male subjects did. With advancing age, textural preference played a more important role in overall preference. Older subjects liked deeper-fried peanuts, which are more brittle, more than younger subjects did. In the present study, systematic statistical analysis based on collected sensory evaluation data using deep-fried peanuts was conducted and the tendency of sensory perception and preference across gender and age was clarified. These results may be useful for engineering optimal strategies to target specific segments to gain greater acceptance in the market. © 2017 Society of Chemical Industry.


N-Acetylcysteine Mitigates Social Dysfunction in a Rat Model of Autism Normalizing Glutathione Imbalance and the Altered Expression of Genes Related to Synaptic Function in Specific Brain Areas.
Prenatal exposure to valproic acid (VPA) is a risk factor for autism spectrum disorder (ASD) in humans and it induces autistic-like behaviors in rodents. Imbalances between GABAergic and glutamatergic neurotransmission and increased oxidative stress together with altered glutathione (GSH) metabolism have been hypothesized to play a role in both VPA-induced embriotoxicity and in human ASD. N-acetylcysteine (NAC) is an antioxidant precursor of glutathione and a modulator of glutamatergic neurotransmission that has been tested in ASD, although the clinical studies currently available provided controversial results. Here, we explored the effects of repeated NAC (150 mg/kg) administration on core autistic-like features and altered brain GSH metabolism in the VPA (500 mg/kg) rat model of ASD. Furthermore, we measured the mRNA expression of genes encoding for scaffolding and transcription regulation proteins, as well as the subunits of NMDA and AMPA receptors and metabotropic glutamate receptors mGLUR1 and mGLUR5 in brain areas that are relevant to ASD. NAC administration ameliorated the social deficit displayed by VPA-exposed rats in the three-chamber test, but not their stereotypic behavior in the hole board test. Furthermore, NAC normalized the altered GSH levels displayed by these animals in the hippocampus and nucleus accumbens, and it partially rescued the altered expression of post-synaptic terminal network genes found in VPA-exposed rats, such as NR2a, MGLUR5, GLUR1, and GLUR2 in nucleus accumbens, and CAMK2, NR1, and GLUR2 in cerebellum. These data indicate that NAC treatment selectively mitigates the social dysfunction displayed by VPA-exposed rats normalizing GSH imbalance and reestablishing the expression of genes related to synaptic function in a brain region-specific manner. Taken together, these data contribute to clarify the behavioral impact of NAC in ASD and the molecular mechanisms that underlie its effects.


Characterization of autoantibodies from patients with Goodpasture's disease using a resonant mirror biosensor.
Goodpasture's disease is characterized by the binding of IgG autoantibodies to the glomerular basement membrane, leading to glomerular inflammation. The autoantigen has been identified as the noncollagenous domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1). We have used the IAsys resonant mirror biosensor to analyse the extent and affinity of binding of anti-GBM antibodies from sera of patients to purified alpha3(IV) NC1. alpha3(IV) NC1 monomers were immobilized to a carboxylate cuvette, with the simultaneous use of a control well. The binding of serum from patients with Goodpasture's disease (n = 12), normal controls (n = 14) and disease controls with vasculitis (n = 14) was analysed. Antibody binding was detected in sera from all patients with Goodpasture's disease but not from controls. IAsys measurements of binding correlated with antibody levels assessed by the standardized ELISA used for clinical assays. Both ELISA and biosensor measurements showed declining antibody levels in serial serum samples from treated patients; however, the biosensor detected antibody recrudescence when ELISA remained negative. Autoantibodies from patients' serum had average affinity constants (Kd) of 6.5 x 10-11M to 52.07 x 10-10M, as determined by an inhibition assay, indicating high affinity. Sips analysis showed that the antibody response was relatively homogeneous (values of 0.46-1). Biosensor techniques can therefore be used to detect and characterize anti-GBM antibodies in serum from patients, with high sensitivity and without need for antibody purification. This technique may be useful in diagnosis and monitoring of patients with Goodpasture's disease, and may be applicable to other autoantibody mediated diseases.


Native aortic valve pneumococcal endocarditis--fulminant presentation.
Pneumococcal endocarditis is a rare entity, corresponding to 1 to 3% of native valve endocarditis cases. It has a typically adverse prognosis, with high mortality. There is a reported predilection for the aortic valve; thus, a common presentation is acute left heart failure. We present a case of a 60-year-old woman with a history of sinusitis, who was admitted with the diagnosis of pneumonia. She rapidly deteriorated with signs of septic shock and was transferred to the critical care unit. The transesophageal echocardiogram revealed severe aortic regurgitation due to valve vegetations. Blood cultures were positive for Streptococcus pneumoniae. She underwent cardiac surgery and had multiple postoperative complications. Nonetheless, the patient made a slow and complete recovery. Infectious endocarditis should be ruled out if any suspicion arises, and echocardiography should be performed in an early stage in patients with poor response to vasopressors and inotropes. Patients with pneumococcal endocarditis benefit from an aggressive approach, with performance of early surgery.


[Neurologic complications in inflammatory bowel diseases].
Some inflammatory diseases of the gastrointestinal system are associated with neurological symptoms which, in rare cases, may precede the onset of the gastrointestinal manifestation of the disease. Celiac sprue is characterized by an intolerance to the wheat protein gluten. The typical neurological manifestation of celiac sprue is cerebellar ataxia. The ataxia as well as the gastrointestinal symptoms can be treated with a strictly gluten-free diet. The neurological symptoms of Whipple's disease, a disorder caused by gram-positive bacilli, are variable. Typical symptoms of cerebral Whipple's disease include dementia, ophthalmoplegia, movement disorders, and signs of hypothalamic dysfunction. Nowadays, the diagnosis of cerebral Whipple's disease is made by PCR detection of the bacilli in the CSF. Crohn's disease and ulcerative colitis are associated with neurological symptoms to a similar proportion. Various forms of polyneuropathies have been observed. The CNS manifestations of inflammatory bowel diseases include thromboembolic stroke, cerebral venous thrombosis, and cerebral vasculitis.


Ethical dilemmas in hyperbaric medicine.
Although hyperbaric oxygen therapy (HBO2T) is the primary or adjunctive treatment for a limited number of clinical conditions, off-label use is increasing as a result of public demand. Because of unusual research problems and limited regulatory mechanisms to ensure patient safety, physicians question whether it is ethical to provide HBO2T for an unproven indication. An ethical approach to the off-label use of HBO2T is proposed. This approach requires combining a physician's clinical judgment with guidelines written by recognized organizations in hyperbaric medicine and patient informed consent. Scientific guidelines can identify which off-label uses of HBO2T are not therapeutic, which are potentially therapeutic, and to what degree. Registries or a central repository for the systematic collection of data can promote research. Ethical guidelines should require patient informed consent for approved indications, for potentially therapeutic off-label indications, and for registry or research participation. The creation of a consortium of hyperbaric clinics may improve the validity of information disseminated to the general public and promote the ethical practice of HBO2T.


Critical Diamond-Blackfan anemia due to ribosomal protein S19 missense mutation.
Diamond-Blackfan anemia (DBA) is a rare congenital disorder characterized by pure erythrocyte aplasia, and approximately 70% of patients carry mutations in the genes encoding ribosomal proteins (RP). Here, we report the case of a male infant with DBA who presented with anemic crisis (hemoglobin [Hb] concentration 1.5 g/dL) at 58 days after birth. On admission, the infant was pale and had tachypnea, but recovered with intensive care, including red blood cell transfusions, and prednisolone. Based on the clinical diagnosis of DBA, the father of the infant had cyclosporine-A-dependent anemia. On analysis of RP genes when the infant was 6 months old, both the infant and the father, but not the mother, were found to harbor a mutation of RPS19 (c.167G > C, p. R56P). Therefore, genetic background search and early neonatal health check-ups are recommended for families with a history of inherited bone marrow failure syndromes.


Cocaine self-administration and naltrindole, a delta-selective opioid antagonist.
Recent reports from several laboratories have suggested a role for delta opioid receptors in expressing some of the biochemical and behavioral effects of cocaine. Here, this possibility has been further explored by evaluating the propensity of rats to self-administer i.v. cocaine in the absence or presence of naltrindole, a selective delta opioid antagonist. Following a number of days of stable cocaine intake, and before a day's session, naltrindole (3 or 10 mg kg-1) reduced pressing for cocaine, regardless of the schedule of reinforcement. These data further support the role of processes associated with delta opioid receptors in the ability of cocaine to reinforce its own use.


Engineered plant minichromosomes.
Minichromosomes offer an enormous potential for plant breeding and biotechnology, because they may simultaneously transfer and stably express multiple genes. Segregating independently of their host chromosomes, they provide a platform for accelerating plant breeding. Minichromosomes can be established from cloned components in vivo (bottom up) or via engineering of natural chromosomes (top down). When they possess functional centromeres and telomeres, they should be stably inherited, but their meiotic transmission rate is below that of endogenous chromosomes. To achieve the customized generation and control the regular transmission of minichromosomes are important challenges for applied research in chromosome biology. Here, construction and biology of plant minichromosomes are compared with data available for yeast and animal systems.


Atrial natriuretic peptide negatively modulates the stimulatory effects of angiotensin II on tuberoinfundibular dopaminergic neuronal activity. Neurochemical and electrophysiological studies.
The effects of angiotensin II (AII) and natriuretic peptide (ANP), alone or in combination, on tuberoinfundibular dopaminergic (TIDA) neuronal activity and on serum PRL levels were examined in this study. The TIDA neuronal activity was determined by measuring 3,4-dihydroxyphenylacetic acid (DOPAC) concentration in the median eminence using high-performance liquid chromatography plus electrochemical detection, and serum PRL levels were determined by radioimmunoassay. Intracerebroventricular injection of AII induced both time (5-60 min)- and dose (0.01-1 microg)-dependent effects by stimulating TIDA neuronal activity and inhibiting serum PRL levels in ovariectomized, estrogen-treated rats. ANP in 0.01-10 microg doses, on the other hand, had no significant effect on TIDA neurons, nor on serum PRL at 30 min. When ANP (in 0.1-10 microg doses) was co-administered with AII (1 microg dose), it dose-dependently attenuated the effects of AII on TIDA neuronal activity and on serum PRL levels. In a separate study using single-unit recording of neurons of the dorsomedial arcuate nucleus (dmARC) in brain slices, where most TIDA neurons reside, AII stimulated 68.0% of 72 units recorded. Few (5.6%) units were inhibited and the remaining ones were not responsive. ANP alone was mostly ineffective on dmARC neurons (63.0% of 54 units), and it stimulated and inhibited 22.2 and 14.8% of them, respectively. When ANP was co-administered with AII to AII-responsive units, however, it significantly attenuated the effects of AII in 81.5% of 27 units. Other neurons were unaffected. Thus, results from the in vivo study indicate that ANP can negatively modulate the stimulatory effect of AII on hypothalamic TIDA neurons and the inhibitory effect on serum PRL levels; and the in vitro electrophysiological data substantiates this observation by showing that ANP exerts a similar modulation on dmARC neurons.


The effect of thermosensitive hydrogel platelet-rich-plasma complex in the treatment of partial tear of anterior cruciate ligament in rat model.
The treatment of anterior cruciate ligament (ACL) partial tear is controversial. The reconstructive surgery is invasive while the prevalence of subsequent insufficiency after conservative treatment has been reported to range from 11% to 62%. Therefore, a new method that promotes tissue regeneration is needed. The aim of this study was to observe the healing of ACL partial tear biomechanically and histologically after the administration of a thermosensitive hydrogel platelet-rich-plasma (PRP) complex. The complex was prepared according to a previously published protocol. One hundred and fifty 12-week-old male Sprague-Dawley rats were included and they were allocated into 4 groups. Lesion control group (Group 1), treatment group (Group 2), gel-only group (Group 3) and intact group (Group 4). Biomechanical testing, histological analysis (H&E and immunohistochemical staining) and scoring was performed. On gross observation, the treatment group showed a continuous ACL with slightly thickened synovium or a partially healed ACL at 6-week follow up. In the biomechanical testing at 6 weeks after surgery, the failure load of the treatment group was significantly superior when compared with the lesion control group (52.7±10.8N vs. 41.6±7.8N, p<0.01), but the failure load was not restored to level of the intact group (52.7±10.8N vs. 61.5±9.1N, p=0.037). The maturity index of wound sites showed no significant inter-group differences at any timepoints. However, an increased expression of vascular endothelial growth factor (VEGF) and pro-collagen I was detected. The thermosensitive hydrogel-PRP was shown to be effective in enhancing the healing of ACL partial tear in the rat model, and potentially this complex can be used as a treatment for patients with ACL partial tear. The thermosensitive hydrogel-PRP is potentially translated to clinical use to treat patients with ACL partial tear by injection under arthroscopy or ultrasound guiding.


[Hepatic trauma (90 consecutive cases treated in 9 years].
90 consecutive hepatic traumatisms at the Hospital de Navarra are presented over a period of 9 years, excluding those which did not overcome the initial reanimation phase and those diagnosed as necropsy. The etiology is presented (76 closed and 14 open), the degree of lesion, associated intra and extra-abdominal lesions plus the results (12.2% mortality) and causes of death related to the degree of lesion and associated lesion. Finally, our casuistics and results are compared with those appearing in the existing bibliography on the subject.


Antitumor T-cell Immunity Contributes to Pancreatic Cancer Immune Resistance.
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Pancreatic tumors are minimally infiltrated by T cells and are largely refractory to immunotherapy. Accordingly, the role of T-cell immunity in pancreatic cancer has been somewhat overlooked. Here, we hypothesized that immune resistance in pancreatic cancer was induced in response to antitumor T-cell immune responses and that understanding how pancreatic tumors respond to immune attack may facilitate the development of more effective therapeutic strategies. We now provide evidence that T-cell-dependent host immune responses induce a PDAC-derived myeloid mimicry phenomenon and stimulate immune resistance. Three KPC mouse models of pancreatic cancer were used: the mT3-2D (Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre) subcutaneous and orthotopic models, as well as the KP1 (p48-CRE/LSL-Kras/Trp53 flox/flox ) subcutaneous model. KPC cancer cells were grown in immunocompetent and immunodeficient C57BL/6 mice and analyzed to determine the impact of adaptive immunity on malignant epithelial cells, as well as on whole tumors. We found that induced T-cell antitumor immunity, via signal transducer and activator of transcription 1 (STAT1), stimulated malignant epithelial pancreatic cells to induce the expression of genes typically expressed by myeloid cells and altered intratumoral immunosuppressive myeloid cell profiles. Targeting the Janus Kinase (JAK)/STAT signaling pathway using the FDA-approved drug ruxolitinib overcame these tumor-protective responses and improved anti-PD-1 therapeutic efficacy. These findings provide future directions for treatments that specifically disable this mechanism of resistance in PDAC.


In Silico Positional Analogue Scanning with Amber GPU-TI.
Positional analogue scanning (PAS) is an accepted strategy for multiparameter lead optimization (MPO) in drug discovery. Small structural changes as introduced by PAS can lead to 10-fold changes in binding potency in ∼10-20% of cases, a significant parameter shift irrespective of other MPO objectives. Sometimes performing a complete PAS is challenging due to resource and time constraints, building block availability, or difficulty in synthesis. Calculating relative binding free energies (RBFEs) for all positions can contribute to prioritizing the most promising analogues for synthesis. We tested a well-established RBFE calculation method, Amber GPU-TI, for 20 positional analogue scans in 14 test systems (cyclin-dependent kinase 8 (CDK8), hepatitis C virus nonstructural protein 5B (HCV NS5B), tankyrase, RAC-α serine/threonine-protein kinase (Akt), phosphodiesterase 1B (PDE1B), orexin/hypocretin receptor type 1 (OX1R), orexin/hypocretin receptor type 2 (OX2R), histone acetyltransferase K (lysine) acetyltransferase 6A (KAT6A), peroxisome proliferator-activated receptor γ (PPARγ), extracellular signal-regulated kinases (ERK1/2), coactivator-associated arginine methyltransferase 1 (PRMT4), αvβ6, bromodomain 1 (BD1), human immunodeficiency virus-1 (HIV-1) entry) involving nitrogen, methyl, halogen, methoxy, and hydroxyl scans with at least four analogues per set. Among the 66 analogue positions explored, we found that in 18 cases Amber GPU-TI calculations predicted a more than 10-fold change in potency. In all of these cases, the experimentally observed direction of potency changes agreed with the predictions. In 16 cases, more than 10-fold changes in experimental potency were observed. Again, in all of these cases, Amber GPU-TI predicted the direction of the potency changes correctly. In none of these cases would a decision made for or against synthesis based on a 10-fold change in potency have resulted in missing an important analogue. Therefore, in silico RBFE calculations using Amber GPU-TI can meaningfully contribute to the prioritization of positional analogues before synthesis.


Global shape and ligand binding efficiency of the HIV-1-neutralizing antibodies differ from those of antibodies that cannot neutralize HIV-1.
Asymmetric disposition of Fab arms in the structures solved for the broadly neutralizing monoclonal antibody (nmAb) IgG1 b12 raised the question of whether the unusual shape observed for b12 is common for all IgG1 mAbs or if there is a difference in the overall shape of nmAbs versus non-nmAbs. We compared small angle x-ray scattering (SAXS) data-based models and limited proteolysis profiles of some IgG1 mAbs known to be having and lacking HIV-1 neutralizing potency. In non-nmAbs, the Fab arms were found to be symmetrically disposed in space relative to central Fc, but in most nmAbs, the Fab arms were asymmetrically disposed, as seen for IgG1 b12. The only exceptions were 2G12 and 4E10, where both Fab arms were closed above Fc, suggesting some Fab-Fc and/or Fab-Fab interaction in the nmAbs that constrained extension of the Fab-Fc linker. Interestingly, these observations were correlated with differential proteolysis profiles of the mAbs by papain. Under conditions when papain could cut both Fab arms of non-nmAbs, only one Fab arm could be removed from neutralizing ones (except for 2G12 and 4E10). Chromatography and small angle x-ray scattering results of papain-digested products revealed that 1) the Fab-Fc or Fab-Fab interactions in unliganded mAbs are retained in digested products, and 2) whereas anti-gp120 non-nmAbs could bind two gp120 molecules, nmAbs could bind only one gp120. Additional experiments showed that except for 2G12 and 4E10, unopen shapes of nmAbs remain uninfluenced by ionic strength but can be reversibly opened by low pH of buffer accompanied by loss of ligand binding ability.


Progressive midbrain clefts after head trauma and decompressive surgery: a report of two patients.
This report describes two patients with acute-onset ptosis, oculomotor dysfunction, ataxia and drowsiness, referable to the midbrain tegmentum. Both patients had previously suffered severe closed head injuries requiring craniotomy for cerebral decompression. Serial brain scans in both cases revealed a newly developing cleft in the midbrain, with features suggestive of abnormal cerebrospinal fluid (CSF) flow across the aqueduct. A trial of acetazolamide was initiated to reduce CSF production, followed by a third ventriculostomy for CSF diversion in one patient, which resulted in arrested disease progression and partial recovery. There are only two previous reports in the literature of midbrain clefts that developed as remote sequelae of head trauma. We postulate that altered CSF flow dynamics in the aqueduct, possibly related to changes in brain compliance, may be contributory. Early recognition and treatment may prevent irreversible structural injury and possible death.


Electrochemical illumination of intramolecular communication in ferrocene-containing tris-β-diketonato aluminum(III) complexes; cytotoxicity of Al(FcCOCHCOCF3)3.
The series of ferrocene-containing tris-β-diketonato aluminum(III) complexes [Al(FcCOCHCOR)(3)] (R = CF(3), 1; CH(3), 2; C(6)H(5), 3; and Fc = ferrocenyl = Fe(η(5)-C(5)H(5))(η(5)-C(5)H(4)), 4) were synthesized and investigated structurally and electrochemically; complex 1 was subjected to cytotoxicity tests. (1)H NMR-spectroscopy distinguished between the mer and fac isomers of 2 and 3. Complex 1 existed only as the mer isomer. A single crystal X-ray crystallographic determination of the structure of a mer-isomer of Al(FcCOCHCOCF(3))(3), 1, (Z = 4, space group P2(1)2(1)2(1)) demonstrated extensive delocalization of all bonds which explained the pronounced electrochemically observed intramolecular communication between molecular fragments. In contrast to electrochemical studies in CH(2)Cl(2)/[N((n)Bu)(4)][PF(6)], the use of the supporting electrolyte [N((n)Bu)(4)][B(C(6)F(5))(4)] allowed identification of all Fc/Fc(+) electrochemical couples by cyclic and square wave voltammetry for 1-4. For R = Fc, formal reduction potentials of the six ferrocenyl groups were found to be E°' = 33, 123, 304, 432, 583, and 741 mV versus free ferrocene respectively. Complex 1 (IC(50) = 10.6 μmol dm(-3)) was less cytotoxic than the free FcCOCH(2)COCF(3) ligand having IC(50) = 6.8 μmol dm(-3) and approximately 2 orders of magnitude less toxic to human HeLa neoplastic cells than cisplatin (IC(50) = 0.19 μmol dm(-3)).


Histopathologic and microbiologic aspects of ventilator-associated pneumonia.
The relationship between microbiology and histology in patients with ventilator-associated pneumonia has been sparsely described. Twenty-five patients who died in the intensive care unit after their lungs had been mechanically ventilated for 72 h were studied. Twenty of the 25 died with clinical suspicion of pulmonary infection. A total of 375 immediate postmortem pulmonary biopsies were obtained after death and processed for quantitative microbiology and histology. Four evolutionary stages of pneumonia were defined: early, intermediate, advanced, and resolution. At least one specimen with histologic evidence of pneumonia was found in all but two patients (92%). Histologic pneumonia was a widespread and frequent process (46%) of biopsies examined) involving predominantly the lower lobes (55% of all biopsies with pneumonia) and showing different histopathologic stages of progression coexisting in the same lung lobes. Lung cultures were frequently polymicrobial (149 of 375, 40% of the pulmonary biopsy cultures, and 20 of 25, 80% of the cases) and not always yielding the same pathogen (19 microorganisms) when comparing one lung to the other. Histopathology and microbiologic biopsy cultures showed a weak relationship (28% and 49% of species had counts > or = 10(3) cfu/g in samples without pneumonia from patients with and without prior antibiotic treatment, respectively). Histopathologic evolutionary stages were not associated with any differences in quantitative culture results of pulmonary biopsies, independently of prior administration of antibiotics. Higher bacterial concentrations of biopsy cultures were associated with the absence of prior antibiotic treatment. Ventilator-associated pneumonia is a frequent diffuse and polymicrobial process showing different coexisting degrees of evolution and involving preferentially the lower lobes. Microbiology and histology can be dissociated even in the absence of prior antibiotic treatment. Lung histology appears more reliable than bacteriology as a diagnostic reference test.


Functionalized Antimicrobial Nanofibers: Design Criteria and Recent Advances.
The rise of antibiotic resistance has become a major threat to human health and it is spreading globally. It can cause common infectious diseases to be difficult to treat and leads to higher medical costs and increased mortality. Hence, multifunctional polymeric nanofibers with distinctive structures and unique physiochemical properties have emerged as a neo-tool to target biofilm and overcome deadly bacterial infections. This review emphasizes electrospun nanofibers' design criteria and properties that can be utilized to enhance their therapeutic activity for antimicrobial therapy. Also, we present recent progress in designing the surface functionalization of antimicrobial nanofibers with non-antibiotic agents for effective antibacterial therapy. Lastly, we discuss the future trends and remaining challenges for polymeric nanofibers.


[Diagnosis and treatment of familial hypercholesterolemia in children and adolescents].
The identification and management of hyperlipidemias in children are currently limited to persons regarded as being at very high risk, such as those with familial hypercholesterolemia. Universal screening of children is not recommended, but it is important to screen the subset of children and adolescents at highest risk, i.e. those with a family history of premature cardiovascular disease or familial hypercholesterolemia. Treatment of children and adolescents with hypercholesterolemia requires a multidisciplinary approach. Cholesterol-lowering medication may be required in addition to dietary therapy in children with a history of premature coronary heart disease among close relatives.


A combination-weighted Feldkamp-based reconstruction algorithm for cone-beam CT.
The combination-weighted Feldkamp algorithm (CW-FDK) was developed and tested in a phantom in order to reduce cone-beam artefacts and enhance cranio-caudal reconstruction coverage in an attempt to improve image quality when utilizing cone-beam computed tomography (CBCT). Using a 256-slice cone-beam CT (256CBCT), image quality (CT-number uniformity and geometrical accuracy) was quantitatively evaluated in phantom and clinical studies, and the results were compared to those obtained with the original Feldkamp algorithm. A clinical study was done in lung cancer patients under breath holding and free breathing. Image quality for the original Feldkamp algorithm is degraded at the edge of the scan region due to the missing volume, commensurate with the cranio-caudal distance between the reconstruction and central planes. The CW-FDK extended the reconstruction coverage to equal the scan coverage and improved reconstruction accuracy, unaffected by the cranio-caudal distance. The extended reconstruction coverage with good image quality provided by the CW-FDK will be clinically investigated for improving diagnostic and radiotherapy applications. In addition, this algorithm can also be adapted for use in relatively wide cone-angle CBCT such as with a flat-panel detector CBCT.


[Possible regulatory importance of cellular sulfhydryl groups and reduction metabolic pathways for the activation of human blood platelets].
The activation of the blood platelets is the prerequisite for their participation in physiological and pathological intravasal processes. An aimed influence on the distinct functions of the blood platelets presumes an exact knowledge about course and regulation of the activation of the platelets. Investigations on glucose-6-phosphate-dehydrogenase-deficient platelets and on the effect of glutathione-oxidizing substances on normal platelets showed references to a regulatory significance of the cellular thiol/disulphide state in the process of activation. In this case particularly the arachidonic acid balance and the SH/SS-state of platelet proteins seem to be in close connection with reductive ways of metabolism.


Neogambogic acid prevents silica-induced fibrosis via inhibition of high-mobility group box 1 and MCP-1-induced protein 1.
Silicosis is a systemic disease caused by inhaling silicon dioxide (SiO2); early stages are characterized by alveolar inflammation, and later stages are characterized by progressive lung fibrosis. Mounting evidence indicates that high-mobility group box 1 (HMGB1) is involved in pulmonary fibrosis. Whether neogambogic acid (NGA) inhibits macrophage and fibroblast activation induced by SiO2 by targeting HMGB1 remains unclear. Experiments using cultured mouse macrophages (RAW264.7 cells) demonstrated that SiO2 treatment induces the expression of HMGB1 in a time- and dose-dependent manner via mitogen-activated protein kinases (MAPKs) and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway; in turn, this expression causes macrophage apoptosis and fibroblast activation. Pretreating macrophages with NGA inhibited the HMGB1 expression induced by SiO2 and attenuated both macrophage apoptosis and fibroblast activation. Moreover, NGA directly inhibited MCP-1-induced protein 1 (MCPIP1) expression, as well as markers of fibroblast activation and migration induced by SiO2. Furthermore, the effects of NGA on macrophages and fibroblasts were confirmed in vivo by exposing mice to SiO2. NGA can prevent SiO2-induced macrophage activation and apoptosis via HMGB1 inhibition and SiO2-induced fibrosis via the MCPIP1 pathway. Targeting HMGB1 and MCPIP1 with NGA could provide insights into the potential development of a therapeutic approach for alleviating the inflammation and fibrosis induced by SiO2.


The Respiratory Chain of Plant Mitochondria: XVII. Flavoprotein-Cytochrome b(562) Interaction in Antimycin-treated Skunk Cabbage Mitochondria.
During the transition from the aerobic steady state with succinate as substrate to anaerobiosis, in suspensions of skunk cabbage (Symplocarpus foetidus) mitochondria treated with antimycin A, cytochrome b(562) becomes reoxidized to the extent of about 20%, synchronously with the reduction of cytochrome c(549). This reoxidation occurs in both the absence and presence of m-chlorobenzhydroxamic acid, a specific inhibitor for the alternate terminal oxidase of plant mitochondria. A flavoprotein component, amounting to 13% to 15% of the total nonfluorescent mitochondrial flavoprotein, undergoes reduction synchronously with the oxidation of cytochrome b(562) during the aerobic to anaerobic transition with succinate as substrate in the presence of both antimycin A and m-chlorobenzhydroxamic acid. This flavoprotein component remains reduced in the presence of cyanide. The half-time for reduction of the flavoprotein component and cytochrome c(549) and for oxidation of cytochrome b(562) during the aerobic to anaerobic transition with succinate as substrate in the presence of both antimycin A and m-chlorobenzhydroxamic acid is 2 seconds. The half-times for oxidation of cytochrome c(549) and the flavoprotein component are 2.1 and 170 milliseconds, respectively, during the anaerobic to aerobic transition induced by addition of 14 mum O(2) to the mitochondrial suspensions. The half-time for reduction of cytochrome b(562) under these conditions is 150 milliseconds, synchronous with the flavoprotein component. The synchrony of the flavoprotein oxidation and of the cytochrome b(562) reduction at a rate much slower than that of cytochrome c(549) oxidation implies that, in antimycin-treated plant mitochondria, the state of the cytochrome b(562)/antimycin complex is regulated by the redox state of this flavoprotein component, rather than by cytochrome c(549). It is tentatively suggested that these two components are not part of the main sequence of the respiratory chain, but may be part of a multienzyme complex active in the hydroxylation reactions required for ubiquinone biosynthesis in the inner mitochondrial membrane.


The psychopharmacological treatment of depression in primary care in the Royal Navy.
Depression is a common mental health condition in the UK Armed Forces. Although psychopharmacology is usually a second line intervention, there is a place for antidepressants in the management of depression in primary care. This article will examine the diagnosis of depression, the indications for starting antidepressants, the choice of anti-depressants and the occupational considerations in the Royal Navy. The aim is to equip General Practitioners (GPs) and General Duties Medical Officers (GDMOs) with the clinical information needed to initiate psychopharmacological treatment for depression where indicated.


Assessment of tetracycline, lead and cadmium residues in frozen chicken vended in Lagos and Ibadan, Nigeria.
This study determined the levels of tetracycline and heavy metals (lead and cadmium) levels in frozen chicken. One hundred frozen chicken muscle samples were sourced from major markets in Lagos and Ibadan (fifty samples each). The samples were analyzed using high power liquid chromatography (HPLC) for tetracycline residue determination while atomic absorption spectroscopy (AAS) was used to determine the levels of lead and cadmium residues in the samples. Mean concentrations of tetracycline residue levels in the frozen chicken sampled ranged from 1.1589-1.0463ppm which is higher than the maximum residue limit set by international food safety agencies. Pb contents were higher in chicken muscles sampled from markets in Ibadan (0.0227 +/- 0.0069 microg dL(-2)) than Lagos (0.0207 +/- 0.0082 microg dL(-1)), while Cd levels were 0.0013 microg dL(-1) higher than in the Lagos samples (0.0065 +/- 0.0026 microg dL(-1)). These values were within maximum residue limits. There were no significant differences (p < 0.05) in levels of tetracycline, lead and cadmium levels from the two market locations (Lagos and Ibadan) and parts (wings and thigh muscles). However, significant differences occurred in tetracycline and Pb levels in frozen chicken sourced from Cotonou. Though not significant, tetracycline contents in the thigh muscles of the frozen chicken samples was higher than that of the wings muscles and this was attributed to the site of administration of antibiotic injection and failure to observe the pre-slaughter withdrawal period by the farmers. This study is of public health importance as the presence of these residues above the maximum residue limit in frozen chicken predisposes consumers to drug resistance, allergic reactions and poisoning as a result of toxicity.


Considering the whole patient with hypertension: the ethos of pharmaceutical care.
From a pharmaceutical care perspective, this article will assess co-existing factors affecting the patient with hypertension. It will begin by defining pharmaceutical care, the components necessary for the provision of such, and how the provision of pharmaceutical care has already affected patient care. Then, it will explore those factors that influence the development of the therapeutic relationship, such as culture and ethnicity, socioeconomic status, age, gender, and functional status. Finally, this article will conclude with the rationale for and impact of providing pharmaceutical care to the patient with hypertension.


Replacement of cysteine-107 of Saccharomyces cerevisiae iso-1-cytochrome c with threonine: improved stability of the mutant protein.
Site-directed mutagenesis has been used to change the codon for cysteine-107 of Saccharomyces cerevisiae iso-1-cytochrome c to a threonine codon. The resulting protein is active in vivo, is methylated as in the wild-type protein and has optical properties indistinguishable from those of the wild-type protein. The threonine-107 iso-1-cytochrome c demonstrated fully reversible electrochemical behaviour and a mid-point reduction potential of 272 mV versus NHE. In addition, this mutant does not demonstrate a tendency to autoreduce or to dimerize as does the wild-type protein. These properties of the threonine-107 mutant establish that it will provide a useful background in which to make subsequent mutations for mechanistic and physical studies of yeast iso-1-cytochrome c.


In vitro studies of a photo-oxidized bovine articular cartilage.
Bovine articular cartilage was photo-oxidized and cultured with native articular bovine cartilage and synovial membrane to study the interaction between these tissues mimicking the physiological situation in the joint. The photo-oxidation was applied as a pretreatment of cartilage for future use in cartilage resurfacing procedures in joints. Properties of the transplant were assessed by testing the production of local mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2), and neutral metalloproteinase activities under normal conditions and after stimulation with various stimulants representative of inflammatory changes in pathophysiological conditions. Unlike normal cartilage photo-oxidized cartilage did not release significant amounts of NO and PGE2 and showed less gelatinolytic and caseinolytic activity compared to native bovine articular cartilage. Enzyme activity of the combined cultures was at a level intermediate between that of photo-oxidized cartilage and native cartilage cultures alone. In contrast to normal cartilage, living chondrocytes were not visible in photo-oxidized cartilage using live/dead staining. These results indicate, that the photo-oxidized cartilage may have a beneficial effect on adjacent native host cartilage and therefore be a suitable transplant for use in in vivo experiments.


Adaptive evolution of sexual systems in pedunculate barnacles.
How and why diverse sexual systems evolve are fascinating evolutionary questions, but few empirical studies have dealt with these questions in animals. Pedunculate (gooseneck) barnacles show such diversity, including simultaneous hermaphroditism, coexistence of dwarf males and hermaphrodites (androdioecy), and coexistence of dwarf males and females (dioecy). Here, we report the first phylogenetically controlled test of the hypothesis that the ultimate cause of the diverse sexual systems and presence of dwarf males in this group is limited mating opportunities for non-dwarf individuals, owing to mating in small groups. Within the pedunculate barnacle phylogeny, dwarf males and females have evolved repeatedly. Females are more likely to evolve in androdioecious than hermaphroditic populations, suggesting that evolution of dwarf males has preceded that of females in pedunculates. Both dwarf males and females are associated with a higher proportion of solitary individuals in the population, corroborating the hypothesis that limited mating opportunities have favoured evolution of these diverse sexual systems, which have puzzled biologists since Darwin.


Solid-Cystic Hypoglossal Nerve Schwannoma with Fluid-Fluid Level: A Rare Case Report.
Schwannomas (neurinoma, neurilemmoma) are benign slow-growing encapsulated tumours originating from well-differentiated myelin-producing Schwann cells or nerve fiber sheet cells at the glial-Schwann cell junction. Hypoglossal nerve schwannoma mostly develops in the intracranial and extra-cranial segment or in both intracranial and extra-cranial segment forming a dumbbell shape tumour. The peripheral hypoglossal schwannomas are very rare. We present a case of right hypoglossal nerve schwannoma in a 46-year-old female who presented with headache and neck pain since 2 weeks with deviation of tongue to right side since 1 week. Patient was investigated with Computed Tomography (CT) scan of head and Magnetic Resonance Imaging (MRI) of brain, which showed a dumb-bell shaped solid-cystic mass lesion with fluid-fluid level in right cerebello-pontine angle cistern.


Faculty development and mentorship using selected online asynchronous teaching strategies.
The use of distance learning continues to improve accessibility to nursing education programs, yet online teaching remains an intimidating experience for novice educators. An emerging role in professional faculty development is the online educator, who serves as a mentor for novice faculty. This article presents the necessary elements to plan, organize, and manage asynchronous online courses, especially for novice educators and online faculty mentors. Course engagement and faculty-student online communication strategies are explored using examples. Threaded discussion strategies for engaging students in active, collaborative learning are discussed using specific examples. A threaded discussion grading rubric is included. Strategies to sustain interactive learning and evaluate student learning using examples are offered.


Pneumocystis colonization in asthmatic patients not receiving oral corticosteroid therapy.
Pneumocystis jirovecii can colonize patients with chronic obstructive pulmonary disease. To determine if colonization occurs in asthma patients, sputum samples from 10 patients with mild asthma, who were not receiving oral corticosteroids, were evaluated by a sensitive real-time PCR assay that targets a multicopy gene of P. jirovecii. 2 patients (20%) had Pneumocystis DNA detected; 1 patient had 3 positive samples over an 11-day period. Thus, Pneumocystis colonization occurs in asthma patients, and further studies are warranted to evaluate its role in airways disease. NCT01113034.


Shedding of Mycobacterium caprae by wild red deer (Cervus elaphus) in the Bavarian alpine regions, Germany.
The number of natural infections with Mycobacterium caprae in wildlife and in cattle in the Bavarian and Austrian alpine regions has increased over the last decade. Red deer (Cervus elaphus) have been recognized as maintenance reservoir; however, the transmission routes of M. caprae among and from naturally infected red deer are unknown. The unexpected high prevalence in some hot spot regions might suggest an effective indirect transmission of infection. Therefore, this study was undertaken to diagnose the occurrence of M. caprae in faeces and secretions of red deer in their natural habitat. A total of 2,806 red deer hunted in this region during 2014-2016 were included in this study. After pathological examination, organs (lymph nodes, lung, heart), excretions and secretions (faeces, urine, saliva and tonsil swabs) were further investigated by qPCR specific for Mycobacterium tuberculosis complex (MTC), M. bovis and M. caprae. Samples tested positive by qPCR were processed for culturing of mycobacteria. In total, 55 (2.0%) animals were confirmed positive for M. caprae by pathological examination, PCR and culturing of the affected organ material. With the exception of one sample, all of the secretion and excretion samples were negative for mycobacteria of the Mycobacterium tuberculosis complex (MTC). From one red deer, M. caprae could be isolated from the heart sac as well as from the faeces. Whole-genome sequencing confirmed that both strains were clonally related. This is the first confirmation that M. caprae can be shed with the faeces of a naturally infected red deer. However, further studies focusing on a higher number of infected animals, sample standardization and coordinated multiple sampling are necessary to improve the understanding of transmission routes under natural conditions.


Arsenic(II) sulfide quantum dots prepared by a wet process from its bulk.
Arsenic(II) sulfide nanocrystals were fabricated by a wet process from its bulk through cluster-mediate transformation. The bulk arsenic(II) sulfide can be easily dissolved in ethylenediamine to form a solution-like cluster (As4S4-NH2C2H4NH2)). The cluster can be transformed to nanocrystals assisted by consumption of ethylenediamine in protic polar solvents with mild thermal treatment. The nanocrystals show size-dependent fluorescence ranging from UV to the blue, two photon fluorescence as well as cytotoxic effects on cancer cells.


Nurses' knowledge, attitudes, and beliefs regarding organ and tissue donation and transplantation.
The acute shortage of human organs and tissues for transplantation has been attributed in part to health professionals, including nurses, for their reluctance to recognize and refer suitable candidates for donation. In 1988, nurses' knowledge, attitudes, and beliefs regarding organ and tissue donation and transplantation were assessed using a 70-item questionnaire. Respondents included 1,683 nurses employed in 62 rural and urban hospitals in the Midwest. Only 365 respondents (21.7 percent) reported having requested tissue donations and 243 (14.4 percent) reported having requested organ donations. However, of those who requested tissue or organ donations, 270 (74 percent) obtained consents for tissues and 150 (61.7 percent) obtained consent for organ donations. Respondents were knowledgeable about organ and tissue donation (mean score of 7.5 on a 0 to 10 knowledge scale with 10 as highest) and reported attitudes and beliefs were moderately positive. Factors that were significantly correlated with the number of requests made for organs and tissues and the number of consents obtained included nurses' knowledge, attitudes, and beliefs about donation; nurses' perception of their own confidence in their ability to request tissues and organs; being a supervisor; and working in an emergency department.


Voltage- and use-dependent modulation of calcium channel current in guinea pig ventricular cells by amiodarone and des-oxo-amiodarone.
Amiodarone is an effective antiarrhythmic drug handicapped by serious side effects. The mechanism of its antiarrhythmic activity is not known but is presumed to involve inhibition of current flowing through ion channels. Des-oxo-amiodarone, a close structural analogue of amiodarone, was synthesized based on the hypothesis that the toxic and therapeutic properties reside in different parts of the molecule and that chemical modification could result in a less toxic agent that yet preserved amiodarone's antiarrhythmic efficacy. We compared the effects of amiodarone and des-oxo-amiodarone on Ca current in enzymatically dispersed guinea pig ventricular myocytes using the whole-cell patch-clamp method. Amiodarone caused both a tonic and a phasic (use-dependent) reduction of the Ca current. The relationship between membrane potential and the availability for channel opening upon depolarization (inactivation curve) was shifted toward more negative membrane potentials by amiodarone (delta - 10.6 +/- 2.2 mV, n = 7). The use-dependent reduction of the Ca current was also dependent on the frequency of the voltage clamp steps (0.5 Hz, 40.2 +/- 7.9%; 1.0 Hz, 50.0 +/- 6.7%). Dex-oxo-amiodarone had a dual effect on the Ca current: After maintaining the membrane potential for several seconds at negative membrane potentials (less than -45 mV), the Ca current was increased by des-oxo-amiodarone. Des-oxo-amiodarone also shifted the Ca channel inactivation curve to more negative membrane potentials up to 16 mV. Consequently, Ca current could be increased or decreased depending on the experimental conditions. Enhancement of Ca current by des-oxo-amiodarone was transient and was supplanted entirely by the antagonistic effects of the drug after approximately 5 min. The antagonistic effects of des-oxo-amiodarone on Ca current were also use- and frequency-dependent.


The possibility of angiogenesis inhibition in cutaneous melanoma by bevacizumab-loaded lipid-chitosan nanoparticles.
Cutaneous malignant melanoma is fastest-growing cancer in white populations with a large majority of dermal cancer death. The activity of vascular endothelial growth factors (VEGFs) results in the signaling of a variety of downstream intracellular pathways that ultimately leads to cell activation, proliferation, migration, and angiogenesis. VEGF inhibitors such as bevacizumab are widely used in chemotherapy with systemic administration, which in many cases is associated with a variety of side effects. Here, we designed and synthesized a lipid-polymer nanoparticle for local administration of bevacizumab. Drug release, dermal absorption, and the effects of synthesized nanoparticles containing bevacizumab on cell proliferation and in vitro and in vivo angiogenesis were investigated. Encapsulating bevacizumab in the synthesized nanoparticles resulted in a significant increase in its dermal absorption compared to free bevacizumab. Also, the suppressor effects of bevacizumab encapsulated in the synthesized nanoparticle on cell proliferation and angiogenesis were significantly more than those of free bevacizumab. Our findings indicate the remarkable effects of lipid-polymer nanoparticles in dermal absorption and in maintaining bevacizumab bioactivity, suggesting therapeutic benefits of local bevacizumab administration for angiogenesis-related disorders such as cutaneous melanoma. Chitosan nanoparticles containing bevacizumab antibody were synthesized by ion exchange method, and finally, these nanoparticles were coated with lipid (Lip-Chi-Bev NPs). In this study, the effect of synthesized nanoparticles on dermal absorption of bevacizumab was evaluated and its potential in inhibiting angiogenesis was evaluated by in vitro and in vivo models.


The influence of consanguinity on fertility and infant mortality in Sanabria (Zamora, Spain).
"The effects of consanguinity on fertility and infant mortality are studied in the population of the Sanabria Valley (Zamora province, Spain). The sample is made up of 965 complete families, 100 couples being first cousins (FC), 172 second cousins (SC) and 693 non-related (NR). There appears little difference in the fertility of consanguineous and unrelated couples but infant mortality rates (endogenous and exogenous) are higher among the offspring of consanguineous couples."


Knowledge and use of folic acid among women of reproductive age--Michigan, 1998.
Neural tube defects (NTDs), which include spina bifida and anencephaly, are serious malformations that occur in the developing fetus during the first 17-30 days after conception. Consumption of supplements containing folic acid can reduce NTDs 50%-70%. In the United States, approximately 4000 pregnancies are affected by NTDs each year, including approximately 140 infants in Michigan. In 1992, the U.S. Public Health Service recommended that all women of childbearing age consume at least 400 microg of folic acid daily. In 1998, the Institute of Medicine reaffirmed that recommendation and added that women capable of becoming pregnant take 400 microg of synthetic folic acid daily from fortified foods and/or supplements and consume a balanced, healthy diet of folate-rich foods. This report summarizes findings from the 1998 Behavioral Risk Factor Surveillance System (BRFSS) about multivitamin use and folic acid knowledge among women of reproductive age in Michigan. The findings suggest that public health campaigns that promote the consumption of folic acid should target women who are young, unmarried, obese, smoke, eat few fruits and vegetables, and have a low level of education.