Bridging the gap: a five stage approach for developing specialty-specific entrustable professional activities.
Entrustable Professional Activities (EPAs) are increasingly used as a focus for assessment in graduate medical education (GME). However, a consistent approach to guide EPA design is currently lacking, in particular concerning the actual content (knowledge, skills and attitude required for specific tasks) for EPAs. This paper describes a comprehensive five stage approach, which was used to develop two specialty-specific EPAs in emergency medicine focused on the first year of GME. The five stage approach was used to gain consensus on the task, content and entrustment scale for two specialty-specific EPAs in emergency medicine. The participants consisted of twelve clinical supervisors working in the emergency department. The five stages were: 1) Selecting the EPA topic; 2) Developing the EPA content by collecting data from participants using focus group and individual interviews; 3) Drafting the EPAs based on analysis of collected data; 4) Seeking feedback on the draft EPAs from the participants and other stakeholders; 5) Refining and finalising the EPAs based on feedback. Two specialty-specific EPAs were developed using the five stage approach. The participants reached consensus on the specific tasks and criteria for performance for the two EPAs. They also agreed that both day-to-day (ad hoc) and formal (summative) entrustment decisions were put into practice through the intensity of supervision provided to PGY1 doctors. As a result, a three level entrustment and supervision scale consisting of direct active, indirect active, passive was developed reflecting the shift in the intensity of supervision from close supervision to minimal supervision. The five stage approach described in this paper was used successfully to develop two specialty-specific EPAs in emergency medicine along with a three level entrustment scale.We propose that the five stage approach is transferable to a range of medical training contexts to design specialty-specific EPAs.


[Paroxysmal disorders during sleep as the debut of epilepsy in children].
The authors examined 100 children aged 3 to 14 years with paroxysmal disturbances during sleep, which were the first manifestations of epilepsy. On the basis of a long-term follow up these disturbances were differentiated clinically from similar disorders of non-epileptic nature. The most typical epileptic disturbances occurring during sleep (psychomotor paroxysms, crying, laughter, night fears, nightmarish dreams, psychosensory disorders) had some characteristics in common, namely changes in consciousness, appearance almost at the same time, stereotyry of the manifestations, attendant autonomic disorders, nocturnal enuresis followed by the development of the typical epileptic forms of attacks. The treatment of paroxysmal disturbances was conducted with regard to their clinical structure and the localization of the epileptic focus.


A chemical and mineralogical reconstruction of Zn-smelter emissions in the Kempen region (Belgium), based on organic pool sediment cores.
The atmospheric pollution history of a former Belgian Zn-smelter complex is preserved in organic sediments of a nearby peat bog pool. The stratigraphy of trace metals, Pb-isotope ratios and mineralogy indicate extreme heavy metal pollution in recent sediments. In the pollutant trend, extremes coincide with maxima in 20th century metal production, minima during major war conflicts and the final shutdown of the smelter. Peak pollution concentrations measure up to 4.7 wt.% Zn, 1.1 wt.% Pb and 0.1 wt.% Cd, which correspond to calculated atmospheric deposition rates of 9.0, 1.6 and 0.16 g m(-2) yr(-1), respectively. 206Pb/207Pb isotope ratios show higher values in the polluted interval (1.135-1.162) relative to local geogenic values deeper down-core (1.194-1.215). Within the polluted interval, three significantly different 208Pb/206Pb plateaus are recognized and suggested to indicate changes in the origins of processed ores. Microprobe analyses on sediment thin sections show extensive in situ FeS2 and ZnS precipitation, which suggests that anoxic processes are responsible for the immobilization of the atmospheric metal inputs. The occurrence of oxidized smelter dusts in an independent surface soil sample indicates a rapid diagenetic transformation of metal oxides into sulfides. Morphology and chemical characteristics allow the distinction between smelter related and diagenetic mineral deposits, and give evidence for dust from open-air ore repositories, as well as smelter operation without dust filters.


Orthodontic treatment in periodontally compromised patients: 12-year report.
This work describes the therapeutic protocol of combined orthodontic-periodontal treatment and evaluates the effectiveness of surgical and nonsurgical periodontal therapy in the maintenance of a healthy periodontal status after the orthodontic treatment. Surgical periodontal treatment was performed in 267 patients affected by severe periodontal disease, and 128 patients had nonsurgical treatment. For each patient the mean value of probing depth (mPPD) and the rate of positive bleeding on probing (%BoP) of the teeth involved in the orthodontic movement were registered before the start of the periodontal treatment, at the end of the orthodontic treatment, and 2, 4, 6, 10, and 12 years after the end of the orthodontic treatment. Comparison between pretreatment and posttreatment values and between pretreatment and follow-up values showed a decrease in mPPD and %BoP that was of statistical significance. The difference between posttreatment and follow-up values was not statistically significant. These results suggest that orthodontic treatment is no longer a contraindication in the therapy of severe adult periodontitis. In these cases orthodontics improve the possibilities of saving and restoring a deteriorated dentition.


The better prognosis in secondary infertility is associated with a higher proportion of ovulation disorders.
To determine the reason for the higher pregnancy rate in couples with secondary infertility, the authors compared 237 infertile couples who had a previous pregnancy in the current partnership (secondary infertility) with 135 infertile couples in whom the woman had been pregnant only in a previous partnership and 925 couples with primary infertility. Couples with secondary infertility had the highest proportion of ovulation disorders (36%); these couples with secondary infertility and an ovulation disorder had the shortest duration of infertility (26 months). Cumulative pregnancy rates at 36 months were 56% in secondary fertility, 44% in primary infertility, and 42% in pregnancy in a previous partnership (P = 0.001). In this study, the better prognosis in secondary infertility may be related to the higher proportion of couples with ovulation disorders, who had a shorter duration of infertility. Abortion rates in the earlier pregnancies with current or previous partners were 37% and 30%, respectively; after the period of infertility, the abortion rates were 14% and 12%, respectively.


Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency.
UbiA prenyltransferase domain-containing protein-1 (UBIAD1) synthesizes the vitamin K subtype menaquinone-4 (MK-4). Previous studies in cultured cells (Schumacher et al., 2015) revealed that UBIAD1 also inhibits endoplasmic reticulum (ER)-associated degradation (ERAD) of ubiquitinated HMG CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway that produces cholesterol and essential nonsterol isoprenoids. Gene knockout studies were previously attempted to explore the function of UBIAD1 in mice; however, homozygous germ-line elimination of the Ubiad1 gene caused embryonic lethality. We now report that homozygous deletion of Ubiad1 is produced in knockin mice expressing ubiquitination/ERAD-resistant HMGCR. Thus, embryonic lethality of Ubiad1 deficiency results from depletion of mevalonate-derived products owing to enhanced ERAD of HMGCR rather than from reduced synthesis of MK-4. These findings provide genetic evidence for the significance of UBIAD1 in regulation of cholesterol synthesis and offer the opportunity in future studies for the discovery of new physiological roles of MK-4.


Comparing GIS-based methods of measuring spatial accessibility to health services.
The inequitable geographic distribution of health care resources has long been recognized as a problem in the United States. Traditional measures, such as a simple ratio of supply to demand in an area or distance to the closest provider, are easy measures for spatial accessibility. However the former one does not consider interactions between patients and providers across administrative borders and the latter does not account for the demand side, that is, the competition for the supply. With advancements in GIS, however, better measures of geographic accessibility, variants of a gravity model, have been applied. Among them are (1) a two-step floating catchment area (2SFCA) method and (2) a kernel density (KD) method. This microscopic study compared these two GIS-based measures of accessibility in our case study of dialysis service centers in Chicago. Our comparison study found a significant mismatch of the accessibility ratios between the two methods. Overall, the 2SFCA method produced better accessibility ratios. There is room for further improvement of the 2SFCA method-varying the radius of service area according to the type of provider or the type of neighborhood and determining the appropriate weight equation form-still warrant further study.


Nuclear assembly of polyomavirus capsids in insect cells expressing the major capsid protein VP1.
Polyomavirus normally assembles in the nucleus of infected mouse cells. Sf9 insect cells expressing the polyomavirus major capsid protein VP1 were examined by electron microscopy. Capsidlike particles of apparently uniform size were found in the nucleus. Immunogold electron microscopy demonstrated abundant VP1 in the cytoplasm which was not assembled into any recognizable higher-order structure. Cytoplasmic VP1 assembled after the cells were treated with the calcium ionophore ionomycin. Purified VP1 aggregates were shown by negative staining and cryoelectron microscopy to consist predominantly of particles similar to the empty T = 7 viral capsid. Thus, polyomavirus VP1 can assemble in vivo into capsids independent of other viral proteins or DNA. Nuclear assembly may result from increased available calcium in this subcellular compartment.


Combined metabolome and transcriptome analysis reveals a critical role of lignin biosynthesis and lignification in stem-like pneumatophore development of the mangrove Avicennia marina.
Transcriptional and metabolic regulation of lignin biosynthesis and lignification plays crucial roles in Avicennia marina pneumatophore development, facilitating its adaptation to coastal habitats. Avicennia marina is a pioneer mangrove species in coastal wetland. To cope with the periodic intertidal flooding and hypoxia environment, this species has developed a complex and extensive root system, with its most unique feature being a pneumatophore with a distinct above- and below-ground morphology and vascular structure. However, the characteristics of pneumatophore lignification remain unknown. Studies comparing the anatomy among above-ground pneumatophore, below-ground pneumatophore, and feeding root have suggested that vascular structure development in the pneumatophore is more like the development of a stem than of a root. Metabolome and transcriptome analysis illustrated that the accumulation of syringyl (S) and guaiacyl (G) units in the pneumatophore plays a critical role in lignification of the stem-like structure. Fourteen differentially accumulated metabolites (DAMs) and 10 differentially expressed genes involved in the lignin biosynthesis pathway were targeted. To identify genes significantly associated with lignification, we analyzed the correlation between 14 genes and 8 metabolites and further built a co-expression network between 10 transcription factors (TFs), including 5 for each of MYB and NAC, and 23 enzyme-coding genes involved in lignin biosynthesis. 4-Coumarate-CoA ligase, shikimate/quinate hydroxycinnamoyl transferase, cinnamyl alcohol dehydrogenase, caffeic acid 3-O-methyltransferase, phenylalanine ammonia-lyase, and peroxidase were identified to be strongly correlated with these TFs. Finally, we examined 9 key candidate genes through quantitative real-time PCR to validate the reliability of transcriptome data. Together, our metabolome and transcriptome findings reveal that lignin biosynthesis and lignification regulate pneumatophore development in the mangrove species A. marina and facilitate its adaptation to coastal habitats.


Twisting and Turning the Sulfonamide Bond: A Synthetic, Quantum Chemical, and Crystallographic Study.
Structural restriction of the sulfonamide bond was used to design sultams with abnormal geometric parameters. Based on analysis of tertiary aliphatic sulfonamides published in the Cambridge crystallographic database, Paquette's sultams (i.e., bridged bicyclic sultams with a bridgehead nitrogen atom) were outlined, and a number of these compounds (including the novel smallest representative, 2-thia-1-azabicyclo[2.1.1]hexane 2,2-dioxide) were synthesized by cyclization of the corresponding amino sulfonyl fluorides. A series of tertiary aliphatic sulfonamides was studied by crystallographic and quantum chemical methods. It was found that the s-character of the nitrogen lone pair is the most important factor defining properties of the S-N bond. Thus, going from the sp3-hybrid lone pair in common sulfonamides to the sp-like lone pair in the smallest Paquette's sultam resulted in an increase in S-N bond length by ca. 0.06 Å. The strain energy of ca. 30 kcal/mol was predicted for the latter compound, which was higher than for any existing sulfonamides studied.


[Insular modifications in glycerophosphate dehydrogenase in diabetes].
In the model of non-insulin-dependent diabetes found in adult rats injected with streptozotocin during the neonatal period, the activity of the mitochondrial glycerophosphate dehydrogenase is severely reduced in pancreatic islets. This coincides with a decreased contribution of aerobic to total glycolysis in intact islets and could account for the preferential impairment of the insulin secretory response to glucose.


Enhancement of novel Endo-polygalacturonase expression in Rhodotorula mucilaginosa PY18: insights from mutagenesis and molecular docking.
Pectinase is a particular type of enzyme that can break down pectin compounds and is extensively utilised in the agricultural field. In this study, twenty yeast isolates were isolated and assayed for pectinase activity. Molecular identification by PCR amplification and sequencing of internal transcribed spacer (ITS) regions of isolate no. 18 had the highest pectinase activity of 46.35 U/mg, was identified as Rhodotorula mucilaginosa PY18, and was submitted under accession no. (OM275426) in NCBI. Rhodotorula mucilaginosa PY18 was further enhanced through sequential mutagenesis, resulting in a mutant designated as Rhodotorula mucilaginosa E54 with a specific activity of 114.2 U/mg. Using Response Surface Methodology (RSM), the best culture conditions for the pectinase-producing yeast mutant Rhodotorula mucilaginosa E54 were pH 5, 72-h incubation, 2.5% xylose, and 2.5% malt extract, with a pectinase-specific activity of 156.55 U/mg. Then, the obtained sequences of the endo-polygalacturonase PGI gene from Rhodotorula mucilaginosa PY18 and mutant Rhodotorula mucilaginosa E54 were isolated for the first time, sequenced, and submitted to NCBI accession numbers OQ283005 and OQ283006, respectively. The modelled 3D structure of the endo-PGI enzyme (485 residues) was validated using Ramachandran's plot, which showed 87.71, 85.56, and 91.57% in the most favourable region for template Rhodotorula mucilaginosa KR, strain Rhodotorula mucilaginosa PY18, and mutant Rhodotorula mucilaginosa E54, respectively. In molecular docking studies, the results of template Rhodotorula mucilaginosa KR endo-PG1 showed an interaction with an affinity score of - 6.0, - 5.9, and - 5.6 kcal/mol for active sites 1, 2, and 3, respectively. Rhodotorula mucilaginosa PY18 endo-PG1 showed an interaction affinity with a score of - 5.8, - 6.0, and - 5.0 kcal/mol for active sites 1, 2, and 3, respectively. Mutant Rhodotorula mucilaginosa E54 endo-PG1 showed an interaction affinity of - 5.6, - 5.5, - 5.5 and - 5.4 kcal/mol for active sites 1, 2, and 3, respectively. The endo-PGI genes of both the yeast strain Rhodotorula mucilaginosa PY18 and mutant Rhodotorula mucilaginosa E54 were successfully cloned and expressed in E. coli DH5α, showing significantly higher endo-PG1 activity, which recorded 94.57 and 153.10 U/mg for recombinant Rhodotorula mucilaginosa pGEM-PGI-PY18 and recombinant mutant Rhotorula pGEM-PGI-E54, respectively.


Word Repetition Paired With Startling Stimuli Decreases Aphasia and Apraxia Severity in Severe-to-Moderate Stroke: A Stratified, Single-Blind, Randomized, Phase 1 Clinical Trial.
This prospective, single-blinded, parallel, stratified, randomized clinical trial via telehealth aimed to investigate the impact of Startle Adjuvant Rehabilitation Therapy (START) on aphasia, apraxia of speech (AOS), and quality of life in individuals with chronic stroke. The study hypothesized that START would have a greater effect on AOS-related measures and more severe individuals. Forty-two participants with poststroke aphasia, AOS, or both were randomly assigned to the START or control group. Both groups received 77-dB GET READY and GO cues during a word repetition task for three 1-hr sessions on consecutive days. The START group additionally received 105-dB white noise GO cues during one third of trials. The Western Aphasia Battery-Revised, Apraxia Battery for Adults, Stroke Impact Scale, and Communication Outcomes After Stroke scale were administered at Day 1, Day 5, and 1-month follow-up. START improved performance on some subtests of the Western Aphasia Battery (Comprehension, Repetition, Reading) and measures of AOS (Diadochokinetic Rate, Increasing Word Length) in individuals with moderate/severe aphasia, whereas moderate/severe controls saw no changes. Individuals with mild aphasia receiving START had improved Reading, whereas mild controls saw improved Comprehension. The START group had increased mood and perceived communication recovery by Day 5, whereas controls saw no changes in quality of life. This study is the first to evaluate the impact of training with startling acoustic stimuli on clinical measures of aphasia and AOS. Our findings suggest START can enhance both nontrained speech production and receptive speech tasks in moderate/severe aphasia, possibly by reducing poststroke cortical inhibition. Our findings should be considered carefully, as our limitations include small effect sizes, within-group variability, and low completion rates for quality-of-life assessments and follow-up visits. Future studies should explore a mechanism of action, conduct larger and longer Phase 2 clinical trials, and evaluate long-term retention. https://doi.org/10.23641/asha.24093519.


Pathways: a school-based, randomized controlled trial for the prevention of obesity in American Indian schoolchildren.
Childhood obesity is a major public health problem in the United States, particularly among American Indian communities. The objective was to evaluate the effectiveness of a school-based, multicomponent intervention for reducing percentage body fat in American Indian schoolchildren. This study was a randomized, controlled, school-based trial involving 1704 children in 41 schools and was conducted over 3 consecutive years, from 3rd to 5th grades, in schools serving American Indian communities in Arizona, New Mexico, and South Dakota. The intervention had 4 components: 1) change in dietary intake, 2) increase in physical activity, 3) a classroom curriculum focused on healthy eating and lifestyle, and 4) a family-involvement program. The main outcome was percentage body fat; other outcomes included dietary intake, physical activity, and knowledge, attitudes, and behaviors. The intervention resulted in no significant reduction in percentage body fat. However, a significant reduction in the percentage of energy from fat was observed in the intervention schools. Total energy intake (by 24-h dietary recall) was significantly reduced in the intervention schools but energy intake (by direct observation) was not. Motion sensor data showed similar activity levels in both the intervention and control schools. Several components of knowledge, attitudes, and behaviors were also positively and significantly changed by the intervention. These results document the feasibility of implementing a multicomponent program for obesity prevention in elementary schools serving American Indian communities. The program produced significant positive changes in fat intake and in food- and health-related knowledge and behaviors. More intense or longer interventions may be needed to significantly reduce adiposity in this population.


Phytochemical and Pharmacological Activity Profile of Crataegus oxyacantha L. (Hawthorn) - A Cardiotonic Herb.
Crataegus oxyacantha L. (syn. C. rhipidophylla Gand.) (Rosac-eae) is one of the two medicinally recognized hawthorn species in European Pharmacopeia. Standardization of the extract prepared from the berry and flowers of the plant is required according to its oligomeric procyanidins. C. oxyacantha is well-known for its use in the treatment of various heart problems particularly, including heart failure in cases of declining cardiac performance equivalent to stages I and II of the New York Heart Association classification, angina pectoris, hypertension with myocardial insufficiency, mild alterations of cardiac rhythm, and atherosclerosis. C. oxyacantha has been reported to exert several other pharmacological activities such as hypotensive, antihyperlipidemic, antihyperglycemic, anxiolytic, immunomodulatory, and antimutagenic. Oligomeric procyanidins and flavone/flavonol types of flavonoids, which are considered to be the chief groups of active substances, phenolic acids, triterpenes, fatty acids, and sterols are present in the plant. The present review aims mainly to outline cardiotonic effect of C. oxyacantha as well as its brief phytochemistry. Numerous experiments and clinical studies have underlined cardiovascular efficacy of the plant through various mechanisms including positive inotropic and negative chronotropic effects, escalation in coronary blood flow and exercise tolerance, inhibition of the enzymes such as angiotensinconverting enzyme (ACE) and phosphodiesterase, anti-inflammatory and antihyperlipidemic effects, improving status of antioxidant enzymes, etc., which support its cardioactive efficacy. The plant possesses several other bioactivities for human health usually concomitant to its rich polyphenolic content.


Preclinical studies on neurobehavioral and neuromuscular effects of cocaine hydrolase gene therapy in mice.
Cocaine hydrolase gene transfer of mutated human butyrylcholinesterase (BChE) is evolving as a promising therapy for cocaine addiction. BChE levels after gene transfer can be 1,500-fold above those in untreated mice, making this enzyme the second most abundant plasma protein. Because mutated BChE is approximately 70 % as efficient in hydrolyzing acetylcholine as wild-type enzyme, it is important to examine the impact on cholinergic function. Here, we focused on memory and cognition (Stone T-maze), basic neuromuscular function (treadmill endurance and grip strength), and coordination (Rotarod). BALB/c mice were given adeno-associated virus vector or helper-dependent adenoviral vector encoding mouse or human BChE optimized for cocaine. Age-matched controls received saline or luciferase vector. Despite high doses (up to 10(13) particles per mouse) and high transgene expression (1,000-fold above baseline), no deleterious effects of vector treatment were seen in neurobehavioral functions. The vector-treated mice performed as saline-treated and luciferase controls in maze studies and strength tests, and their Rotarod and treadmill performance decreased less with age. Thus, neither the viral vectors nor the large excess of BChE caused observable toxic effects on the motor and cognitive systems investigated. This outcome justifies further steps toward an eventual clinical trial of vector-based gene transfer for cocaine abuse.


Safety, efficacy and patient satisfaction with continuous daily administration of levonorgestrel/ethinylestradiol oral contraceptives.
The progestational steroid norgestrel was synthesized and tested between 1960 and 1965 through an international cooperation between Wyeth, USA and Schering, Berlin. It is a mixture of two "enantiomers," with only one form (designated as levonorgestrel) biologically active. When taken orally, it is rapidly absorbed, not subjected to a "first-pass" effect and is approximately 90% bioavailable, with a circulating half-life around 15 hours. Its contraceptive action is exerted at the central (hypothalamic) and peripheral (cervical mucus and endometrium) levels. Levonorgestrel (LNG), alone or in combination with ethinyl estradiol (EE), is the most widely employed contraceptive progestin: it is used in combined oral contraceptives, progestogen-only pills, long-acting contraceptive implants, intrauterine contraceptive systems and in emergency contraception. It is also the steroid of choice for new oral contraceptive regimens aimed at reducing the frequency of bleeding episodes. This novel approach, already tried more than 30 years ago, gained interest around the year 2000 when surveys of women's attitudes toward monthly menstrual bleeding started to show a major change: more and more women declared that they would welcome a hormonal contraceptive method that reduced bleeding episodes to 4, 2 or even 1 per year. At this point, while the debate on the significance and "usefulness" of menstruation went on, attention focused on new regimens. The first new modality consisted of changing the 7-day medication-free interval, either shortening it to fewer than 7 days, or by the administration of low-dose estrogens during the interval between packages. Then, continuous administration regimens started to be investigated. This, however, did not happen suddenly, since, in specific situations, doctors had for years empirically utilized various continuous administration regimens. The first extended-cycle oral contraceptive regimen introduced in clinical practice is an 84-day regimen that results in bleeding only 4 times a year. A commercial product specifically packed for continuous use is now available in Europe and contains 30 mug EE and 150 mug LNG. In a variation of this regimen, after administration of the same combination for 84 days, women are given 7 pills containing 10 mug EE. A 6-monthly regimen has also been tested in a small study using EE 20 mug plus LNG 100 mug taken with and without a hormone-free interval. Women in the continuous group reported significantly fewer bleeding days requiring protection and were more likely to have amenorrhea; in addition they also reported significantly fewer days of bloating and menstrual pain. A yearly regimen is now being developed. Each pill of this novel formulation contains EE 20 mug and LNG 90 mug to be taken continuously for 364 days (13 cycles) per year. A phase III trial has now evaluated safety, efficacy and menses inhibition. At the end of the 1-year trial amenorrhea was present in 58.7% of the women and a complete absence of bleeding in 79.0%. Overall, the number of bleeding and spotting days per pill pack declined with time and adverse events and discontinuations were comparable to those reported for cyclic oral contraceptive regimens.


Predictors of alternative medicine use by multiple sclerosis patients.
To determine the frequency of alternative medicine use among multiple sclerosis (MS) patients, and the factors which predict such use. We examined 20778 MS patients enrolled in the North American Research Consortium on Multiple Sclerosis (NARCOMS) Patient Registry, residing in the USA. We used demographic and clinical data to create multivariate logistic regression models for i) lifetime use of any alternative medicine, ii) lifetime use of any alternative provider (AP), and iii) lifetime use of each of the three most common AP. 20387 patients provided data regarding alternative medicine use. Lifetime use of any alternative medicine was 54% and current use was 30%. Chiropractors (51%), massage therapists (34%), and nutritionists (24%) were the most commonly used AP. In all five models, use of alternative medicine was most strongly predicted by use of a conventional provider, and more modestly by disease factors indicating more severe or prolonged disease. Predictive power of the models was poor (c-index = 0.62-0.68), despite good fits for the data. Demographic factors play only a minimal role in predicting the use of alternative medicine in this MS population while disease factors play a slightly stronger role. There must be other factors involved that may include accessibility, social acceptability and cultural factors. Given the frequency of alternative medicine use by this patient population, further characterization of these factors is important.


Alcohol, tobacco, and diet in relation to esophageal cancer: the Shanghai Cohort Study.
Prospective data on environmental exposures, especially with respect to alcohol, tobacco, and diet, in relation to the risk of esophageal cancer in high-risk populations are sparse. We analyzed data from a population-based cohort of 18,244 middle-aged and older men in Shanghai to identify risk factors for esophageal cancer in this high-risk population. The cohort was followed through 2006, and 101 incident esophageal cancer cases were identified. Cox proportional hazards models were used to estimate hazard ratios (HR) and their corresponding 95% confidence intervals (CI) for associations between exposures and esophageal cancer risk. With adjustment for tobacco use and other potential confounders, regular drinkers vs. nondrinkers of alcoholic beverages had a twofold risk of developing esophageal cancer (HR=2.02, 95% CI=1.31-3.12). With adjustment for alcohol and other potential confounders, long-term smokers (40+ yr) vs. nonsmokers of cigarettes showed a twofold risk of developing esophageal cancer (HR=2.06, 95% CI=1.11-3.82). Increased consumption of fruits (including oranges/tangerines), seafood, and milk were found to be protective against the development of esophageal cancer; HRs were decreased by 40-60% for high vs. low consumers after adjustment for cigarette smoking, alcohol drinking, and other confounders.


Broken barriers: human-induced changes to gene flow and introgression in animals: an examination of the ways in which humans increase genetic exchange among populations and species and the consequences for biodiversity.
We identify two processes by which humans increase genetic exchange among groups of individuals: by affecting the distribution of groups and dispersal patterns across a landscape, and by affecting interbreeding among sympatric or parapatric groups. Each of these processes might then have two different effects on biodiversity: changes in the number of taxa through merging or splitting of groups, and the extinction/extirpation of taxa through effects on fitness. We review the various ways in which humans are affecting genetic exchange, and highlight the difficulties in predicting the impacts on biodiversity. Gene flow and hybridization are crucially important evolutionary forces influencing biodiversity. Humans alter natural patterns of genetic exchange in myriad ways, and these anthropogenic effects are likely to influence the genetic integrity of populations and species. We argue that taking a gene-centric view towards conservation will help resolve issues pertaining to conservation and management. Editor's suggested further reading in BioEssays A systemic view of biodiversity and its conservation: Processes, interrelationships, and human culture Abstract.


Risk-stratified management strategies for intrahepatic cholestasis of pregnancy: A tertiary center population review over nearly 5 years.
Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of adverse perinatal outcomes, resulting in a higher risk of perinatal morbidity and mortality. The authors conducted a retrospective study of 2385 singletons with ICP who underwent risk-stratified management strategies. To explore the risks of perinatal outcomes of ICP, subgroup analyses were performed using different total bile acid (TBA) levels. In this study, there was only one stillbirth and one neonatal death. Among the study cohort, 2299 patients had ICP with a TBA level ≥10 μmol/L and 86 had ICP with a TBA level <10 μmol/L. The 2299 patients with ICP (TBA level ≥ 10 μmol/L) were divided into three groups: mild ICP (n = 1803), severe ICP (n = 400), and extremely severe ICP (n = 96). Increased TBA concentration was associated with an increased incidence of preterm birth, newborn asphyxia, neonatal intensive care unit hospitalization, meconium-stained amniotic fluid, and low birth weight in the three groups (P < 0.05). Furthermore, severe and extremely severe ICP with hypotonic absonant uterine contraction had a significant effect on neonatal asphyxia (odds ratio, 5.06 [95% confidence interval, 1.09-23.37]; P < 0.05) and meconium-stained amniotic fluid (odds ratio, 2.37 [95% confidence interval, 1.43-3.93]; P < 0.05). Hypotonic absonant uterine contractions could be high-risk stressors for severe and extremely severe ICP; hence, proper prenatal care is recommended. Risk-stratified management strategies for ICP are critical to obtaining better maternal-fetal outcomes.


Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma.
This study was undertaken with the hypothesis that certain common morphologic features of ovarian carcinomas are predictably associated with BRCA1 and BRCA2 deficiencies. We selected 43 high-grade serous carcinomas diagnosed at Memorial Sloan-Kettering Cancer Center that were studied as part of The Cancer Genome Atlas pilot project. In addition to 12 randomly selected nonfamilial BRCA-unassociated cases, all 31 Memorial Sloan-Kettering Cancer Center cases with BRCA1 or BRCA2 abnormality were included (n=43). Slides were examined to assess tumor architecture, mitotic index, tumor-infiltrating lymphocytes (TILs), nuclear pleomorphism, necrosis, and involvement of fallopian tube epithelium. Comparing BRCA1-associated cases (BRCA1 germline mutation, n=4, BRCA1 somatic mutation, n=6, BRCA1 promoter methylation, n=13) with unassociated cases (n=12) identified statistically significant differences in morphology. BRCA1-associated high-grade serous carcinomas had more frequent Solid, pseudoEndometrioid, and Transitional cell carcinoma-like morphology (SET features) (P=0.0045), higher mitotic indexes (P=0.012), more TILs (P=0.034), and either geographic or comedo necrosis (P=0.034). BRCA2-associated cases (germline mutation, n=4 and somatic mutation, n=4) tended to show SET features, but they were relatively deficient in TILs and necrosis. Two algorithms incorporating tumor architecture, necrosis, and either mitotic indexes or TILs separated cases that showed 2 of 3 features (BRCA1 associated) from those with 0 of 3 features (BRCA unassociated; P=0.0016 and P=0.0033). A test set comprising 9 BRCA1 germline mutants and 14 high-grade serous carcinoma controls lacking BRCA1 and BRCA2 germline mutation was used to validate the algorithms, with specific emphasis on the ability to detect cases with BRCA1 germline mutation. Best results were obtained with the algorithm that incorporated SET features, necrosis, and mitotic index (P=0.0072; sensitivity of 1.0 (95% CI, 0.66-1.0); specificity of 0.57 (95% CI, 0.29-0.82); positive predictive value of 0.60 (95% CI, 0.32-0.84) and a negative predictive value of 1.0 (95% CI, 0.63-1.0)). These preliminary data indicate potential strong associations between morphology and genotype in high-grade serous carcinomas.


Guided self-help concreteness training as an intervention for major depression in primary care: a Phase II randomized controlled trial.
The development of widely accessible, effective psychological interventions for depression is a priority. This randomized trial provides the first controlled data on an innovative cognitive bias modification (CBM) training guided self-help intervention for depression. One hundred and twenty-one consecutively recruited participants meeting criteria for current major depression were randomly allocated to treatment as usual (TAU) or to TAU plus concreteness training (CNT) guided self-help or to TAU plus relaxation training (RT) guided self-help. CNT involved repeated practice at mental exercises designed to switch patients from an unhelpful abstract thinking habit to a helpful concrete thinking habit, thereby targeting depressogenic cognitive processes (rumination, overgeneralization). The addition of CNT to TAU significantly improved depressive symptoms at post-treatment [mean difference on the Hamilton Rating Scale for Depression (HAMD) 4.28, 95% confidence interval (CI) 1.29-7.26], 3- and 6-month follow-ups, and for rumination and overgeneralization post-treatment. There was no difference in the reduction of symptoms between CNT and RT (mean difference on the HAMD 1.98, 95% CI -1.14 to 5.11), although CNT significantly reduced rumination and overgeneralization relative to RT post-treatment, suggesting a specific benefit on these cognitive processes. This study provides preliminary evidence that CNT guided self-help may be a useful addition to TAU in treating major depression in primary care, although the effect was not significantly different from an existing active treatment (RT) matched for structural and common factors. Because of its relative brevity and distinct format, it may have value as an additional innovative approach to increase the accessibility of treatment choices for depression.


Fibronectin binding protein and host cell tyrosine kinase are required for internalization of Staphylococcus aureus by epithelial cells.
Staphylococcus aureus expresses several surface proteins that promote adherence to host cell extracellular matrix proteins, including fibronectin (Fn). Since this organism has recently been shown to be internalized by nonprofessional phagocytes, a process that typically requires high-affinity binding to host cell receptors, we investigated the role of its Fn binding proteins (FnBPs) and other surface proteins in internalization by the bovine mammary gland epithelial cell line (MAC-T). Efficient internalization of S. aureus 8325-4 required expression of FnBPs; an isogenic mutant (DU5883), not expressing FnBPs, was reduced by more than 95% in its ability to invade MAC-T cells. Moreover, D3, a synthetic peptide derived from the ligand binding domain of FnBP, inhibited the internalization of the 8325-4 strain in a dose-dependent fashion and the efficiency of staphylococcal internalization was partially correlated with Fn binding ability. Interestingly, Fn also inhibited the internalization and adherence of S. aureus 8325-4 in a dose-dependent manner. In contrast to internalization, adherence of DU5883 to MAC-T was reduced by only approximately 40%, suggesting that surface binding proteins, other than FnBPs, can mediate bacterial adherence to cells. Adherence via these proteins, however, does not necessarily result in internalization of the staphylococci. An inhibitor of protein tyrosine kinase, genistein, reduced MAC-T internalization of S. aureus by 95%, indicating a requirement for a host signal transduction system in this process. Taken together, these results indicate that S. aureus invades nonprofessional phagocytes by a mechanism requiring interaction between FnBP and the host cell, leading to signal transduction and subsequent rearrangement of the host cell cytoskeleton.


Oral priming with replicating adenovirus serotype 4 followed by subunit H5N1 vaccine boost promotes antibody affinity maturation and expands H5N1 cross-clade neutralization.
A Phase I trial conducted in 2009-2010 demonstrated that oral vaccination with a replication competent Ad4-H5 (A/Vietnam) vector with dosages ranging from 107-1011 viral particles was well tolerated. HA-specific T-cell responses were efficiently induced, but very limited hemagglutination-inhibiting (HI) humoral responses were measured. However, a single boost of Ad4-H5-Vtn vaccinated individuals with a unadjuvanted licensed H5N1 (A/Vietnam) subunit vaccine resulted in superior HI titers compared with unprimed subjects. In the current study, the impact of Ad4-H5 priming on the quality of the polyclonal humoral immune response was evaluated using a real-time kinetics assay by surface plasmon resonance (SPR). Total binding of serum polyclonal antibodies from the Ad4-H5-Vtn primed groups against both homologous H5N1-A/Vietnam/1194/2004 (clade 1) and heterologous A/Indonesia-5/2005 (clade 2.1) HA1 head domain was significantly higher compared with sera from individuals that received subunit H5N1 vaccination alone. SPR measurements also demonstrated that the antigen-antibody complex dissociation rates (a surrogate for antibody affinity) of serum antibodies against the HA1 of H5N1-A/Vietnam were significantly higher in the Ad4-H5 primed groups compared with those from the unprimed group. Furthermore, strong correlations were observed between the antibody affinities for HA1 (but not HA2) and the virus neutralization titers against the homologous strain and a panel of heterologous clade 2 H5N1 strains. These findings support the concept of oral prime-boost vaccine approaches against pandemic influenza to elicit long-term memory B cells with high affinity capable of rapid response to variant pandemic viruses likely to emerge and adapt to human transmissions.


Cholesterol and development: the RSH ("Smith-Lemli-Opitz") syndrome and related conditions.
The half-century of lipophobia in the United States may be abating with some return of sanity on the discussion of health and dietary fat [Taubes, 2001]. The youngest victims of this collective, decades long madness are those infants deprived for one reason or another of breast milk. They are unable to speak for themselves at a time of greatest need for cholesterol during growth, the most critical period of myelination of central and peripheral nervous system, formation of bone and bile, and of every steroid hormone. Some of the commercial formulas they are fed contain only 1 or 2 mg of cholesterol per 100 g edible portion contrasted with almost 14 mg in breast milk. One can only hope that the confidence in their endogenous ability to synthesize sufficient amounts of cholesterol is not misplaced. Pediatric pathology has learned that when this endogenous ability fails during embryogenesis on the basis of mutations in the postsqualene biosynthesis of cholesterol, a startling variety of developmental pathology may present itself ranging from lethal forms of "idiopathic" hydrops, microcephaly with cerebral dysgenesis and dysmyelinization, agenesis of corpus callosum, cerebellar vermis dysgenesis, cataracts, cleft palate, many different forms of congenital heart defect, pyloric stenosis and/or Hirschsprung dysganglionosis, adrenal (cortical) insufficiency, cholestatic liver disease, limb malformations, and genital ambiguity in genetic males. Population genetic considerations suggest a hypothetical birth prevalence of the RSH (so-called Smith-Lemli-Opitz) syndrome, the commonest of these Garrodian errors of cholesterol biosynthesis, of 1/2500; since only about 1/15,000 to 1/20,000 homozygotes are liveborn and biochemically confirmed, over 80% prenatal or perinatal mortality must occur and deserves the most discerning of services from birth attendants, perinatologists, neonatologists, and fetal/pediatric pathologists. An easy, reliable, economical biochemical test for the presence of 7-dehydrocholesterol is available and the commonest mutation, the IVS8-1G-->C mutation, is quickly and reliably tested for molecularly. Thus, the successful diagnosis, even after death, will contribute substantially to correct genetic counseling, carrier detection, prenatal diagnosis, and treatment in those known to be affected prenatally andplanned to be liveborn. Thus, developmental pathology plays an integral, vital role in preventive medicine.


Improvement In Self-Reported Physical Functioning With Tiotropium/Olodaterol In Central And Eastern European COPD Patients.
Reduced physical activity is associated with increased morbidity and mortality in patients with COPD. Studies suggest that treatment with the long-acting muscarinic antagonist tiotropium and the long-acting β2-agonist olodaterol increases exercise capacity. This study assessed the effects of a fixed-dose combination (FDC) of tiotropium/olodaterol (delivered via Respimat®) on physical functioning in patients with stable COPD in a "real-world setting". An international, open-label, single-arm, non-interventional study conducted in nine countries measuring changes in self-reported physical functioning in COPD patients treated with tiotropium/olodaterol 5/5 μg FDC for approximately 6 weeks. The primary endpoint was therapeutic success, defined as a minimum 10-point increase in the 10-question Physical Functioning Questionnaire (PF-10) score. Secondary endpoints included absolute change in PF-10 from Visit 1 to Visit 2, patient general condition (measured by Physician's Global Evaluation score) and patient satisfaction with the treatment and device (assessed by Patient Satisfaction Questionnaire at the end of the study period). Therapeutic success was observed in 67.8% of 7218 patients (95% CI 66.7, 68.8) in the final analysis set after approximately 6 weeks of treatment with tiotropium/olodaterol. Mean change in PF-10 score between Visit 1 and Visit 2 was 16.6 points (95% CI 16.2, 17.0). Therapeutic success was 64.3% (95% CI 63.0-65.6%) in patients with infrequent (≤1) and 76.1% (95% CI 74.3-77.9%) in patients with frequent (≥2) exacerbations (p<0.0001). Patient general condition improved as indicated by an improvement in Physician's Global Evaluation scores between visits. Most patients were very satisfied or satisfied with tiotropium/olodaterol treatment in general (81%), reported inhalation satisfaction (85%), and satisfactory handling of the device (84%). 1.3% of patients reported an investigator-defined drug-related adverse event. Treatment with tiotropium/olodaterol led to an improvement in self-reported physical functioning in patients with COPD.


Growing older female.
Abstract An analysis of the age-related content of "Personals" ads placed by heterosexual and homosexual women was undertaken to test hypotheses derived from theoretical notions about differences and similarities between lesbian and nonlesbian aging. No support was found for a hypothesized overrepresentation of older advertisers of either sexual orientation. Contrary to popular notions, lesbians were not found to be seeking young partners. However, age differences between groups did indicate support for "accelerated aging" among heterosexual women. Possible advantages of lesbian over non-lesbian women in their experience of aging are presented.


Colloidal diamond.
Self-assembling colloidal particles in the cubic diamond crystal structure could potentially be used to make materials with a photonic bandgap1-3. Such materials are beneficial because they suppress spontaneous emission of light1 and are valued for their applications as optical waveguides, filters and laser resonators4, for improving light-harvesting technologies5-7 and for other applications4,8. Cubic diamond is preferred for these applications over more easily self-assembled structures, such as face-centred-cubic structures9,10, because diamond has a much wider bandgap and is less sensitive to imperfections11,12. In addition, the bandgap in diamond crystals appears at a refractive index contrast of about 2, which means that a photonic bandgap could be achieved using known materials at optical frequencies; this does not seem to be possible for face-centred-cubic crystals3,13. However, self-assembly of colloidal diamond is challenging. Because particles in a diamond lattice are tetrahedrally coordinated, one approach has been to self-assemble spherical particles with tetrahedral sticky patches14-16. But this approach lacks a mechanism to ensure that the patchy spheres select the staggered orientation of tetrahedral bonds on nearest-neighbour particles, which is required for cubic diamond15,17. Here we show that by using partially compressed tetrahedral clusters with retracted sticky patches, colloidal cubic diamond can be self-assembled using patch-patch adhesion in combination with a steric interlock mechanism that selects the required staggered bond orientation. Photonic bandstructure calculations reveal that the resulting lattices (direct and inverse) have promising optical properties, including a wide and complete photonic bandgap. The colloidal particles in the self-assembled cubic diamond structure are highly constrained and mechanically stable, which makes it possible to dry the suspension and retain the diamond structure. This makes these structures suitable templates for forming high-dielectric-contrast photonic crystals with cubic diamond symmetry.


Evidence that ethylene signalling is not involved in selective root placement by tobacco plants in response to nutrient-rich soil patches.
Ethylene is a strong controller of root development, and it has been suggested that it is involved in the increase of lateral root development in nutrient-rich soil patches (selective root placement). Here, this contention was tested by comparing selective root placement of an ethylene-insensitive transgenic tobacco (Nicotiana tabacum) genotype (Tetr) with that of wild-type (Wt) plants. Wt and Tetr plants were grown in pots with locally increased nitrate or phosphate concentrations, after which the root growth patterns were compared with those of plants grown in pots with homogeneous nutrient distribution. Tetr plants responded to nutrient patches in a similar way to Wt plants, by placing their roots preferentially at locations with higher nutrient content, and other aspects of plant morphology were also not greatly influenced by ethylene insensitivity. The response of both Wt and Tetr plants to high-nitrate patches was considerably stronger than to locally high phosphate, suggesting that the two responses are not linked in any functional or regulatory way. As the response to nutrient patches was similar in ethylene-sensing and ethylene-insensitive plants, it is concluded that selective root placement in response to nitrate or phosphate is, at least in tobacco, not mediated or modified by ethylene action.


CD39+ conventional CD4+ T cells with exhaustion traits and cytotoxic potential infiltrate tumors and expand upon CTLA-4 blockade.
Conventional CD4+ T (Tconv) lymphocytes play important roles in tumor immunity; however, their contribution to tumor elimination remains poorly understood. Here, we describe a subset of tumor-infiltrating Tconv cells characterized by the expression of CD39. In several mouse cancer models, we observed that CD39+ Tconv cells accumulated in tumors but were absent in lymphoid organs. Compared to tumor CD39- counterparts, CD39+ Tconv cells exhibited a cytotoxic and exhausted signature at the transcriptomic level, confirmed by high protein expression of inhibitory receptors and transcription factors related to the exhaustion. Additionally, CD39+ Tconv cells showed increased production of IFNγ, granzyme B, perforin and CD107a expression, but reduced production of TNF. Around 55% of OVA-specific Tconv from B16-OVA tumor-bearing mice, expressed CD39. In vivo CTLA-4 blockade induced the expansion of tumor CD39+ Tconv cells, which maintained their cytotoxic and exhausted features. In breast cancer patients, CD39+ Tconv cells were found in tumors and in metastatic lymph nodes but were less frequent in adjacent non-tumoral mammary tissue and not detected in non-metastatic lymph nodes and blood. Human tumor CD39+ Tconv cells constituted a heterogeneous cell population with features of exhaustion, high expression of inhibitory receptors and CD107a. We found that high CD4 and ENTPD1 (CD39) gene expression in human tumor tissues correlated with a higher overall survival rate in breast cancer patients. Our results identify CD39 as a biomarker of Tconv cells, with characteristics of both exhaustion and cytotoxic potential, and indicate CD39+ Tconv cells as players within the immune response against tumors.


[Atherosclerosis and vascular calcification in hemodialysis patients].
Cardiovascular disease is the largest cause of mortality in hemodialysis patients. Cardiovascular mortality is fivefold to twentyfold higher in hemodialysis patients than in the general population. Atherosclerosis and vascular calcification are the characteristic complications in hemodialysis patients. Hemodialysis patients have traditional risk factors such as abnormal lipid metabolism and uremia-related risk factors such as oxidative stress and hyperphosphatemia. Oxidative stress takes place by increased production of oxidants by leukocytes and antioxidant loss of vitamin C and E. Oxidatively modified LDL exist in the circulation by excess of oxidative stress in hemodialysis patients. Oxidative stress is a major contributor to accelerated development atherosclerosis. Oxidative stress and hyperphosphatemia also influence vascular calcification. The pattern of vascular calcification in hemodialysis patient is characterized by mineral deposition in the tunica media. It is reported that the obvious calcification in aorta and artery of the MGP knockout mouse is recognized. It is indicated that MGP has the inhibitory effect of the calcification of vessel wall. Vitamin E protects atherosclerosis and vascular calcification in hemodialysis patients. It is also important to control hyperphosphatemia for vascular calcification.


Who infects whom?-Reconstructing infection chains of Mycobacterium avium ssp. paratuberculosis in an endemically infected dairy herd by use of genomic data.
Recent evidence of circulation of multiple strains within herds and mixed infections of cows marks the beginning of a rethink of our knowledge on Mycobacterium avium ssp. paratuberculosis (MAP) epidemiology. Strain typing opens new ways to investigate MAP transmission. This work presents a method for reconstructing infection chains in a setting of endemic Johne's disease on a well-managed dairy farm. By linking genomic data with demographic field data, strain-specific differences in spreading patterns could be quantified for a densely sampled dairy herd. Mixed infections of dairy cows with MAP are common, and some strains spread more successfully. Infected cows remain susceptible for co-infections with other MAP genotypes. The model suggested that cows acquired infection from 1-4 other cows and spread infection to 0-17 individuals. Reconstructed infection chains supported the hypothesis that high shedding animals that started to shed at an early age and showed a progressive infection pattern represented a greater risk for spreading MAP. Transmission of more than one genotype between animals was recorded. In this farm with a good MAP control management program, adult-to-adult contact was proposed as the most important transmission route to explain the reconstructed networks. For each isolate, at least one more likely ancestor could be inferred. Our study results help to capture underlying transmission processes and to understand the challenges of tracing MAP spread within a herd. Only the combination of precise longitudinal field data and bacterial strain type information made it possible to trace infection in such detail.


Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition.
Chronic hepatitis C virus (HCV) infection and associated liver cirrhosis represent a major risk factor for hepatocellular carcinoma (HCC) development. TGF-beta is an important driver of liver fibrogenesis and cancer; however, its actual impact in human cancer progression is still poorly known. The aim of this study was to investigate the role of HCC-derived HCV core natural variants on cancer progression through their impact on TGF-beta signaling. We provide evidence that HCC-derived core protein expression in primary human or mouse hepatocyte alleviates TGF-beta responses in terms or growth inhibition or apoptosis. Instead, in these hepatocytes TGF-beta was still able to induce an epithelial to mesenchymal transition (EMT), a process that contributes to the promotion of cell invasion and metastasis. Moreover, we demonstrate that different thresholds of Smad3 activation dictate the TGF-beta responses in hepatic cells and that HCV core protein, by decreasing Smad3 activation, may switch TGF-beta growth inhibitory effects to tumor promoting responses. Our data illustrate the capacity of hepatocytes to develop EMT and plasticity under TGF-beta, emphasize the role of HCV core protein in the dynamic of these effects and provide evidence for a paradigm whereby a viral protein implicated in oncogenesis is capable to shift TGF-beta responses from cytostatic effects to EMT development.


Imaging heterogeneity in the mitochondrial redox state of premalignant pancreas in the pancreas-specific PTEN-null transgenic mouse model.
Metabolic alteration is one of the hallmarks of carcinogenesis. We aimed to identify certain metabolic biomarkers for the early detection of pancreatic cancer (PC) using the transgenic PTEN-null mouse model. Pancreas-specific deletion of PTEN in mouse caused progressive premalignant lesions such as highly proliferative ductal metaplasia. We imaged the mitochondrial redox state of the pancreases of the transgenic mice approximately eight months old using the redox scanner, i.e., the nicotinamide adenine dinucleotide/oxidized flavoproteins (NADH/Fp) fluorescence imager at low temperature. Two different approaches, the global averaging of the redox indices without considering tissue heterogeneity along tissue depth and the univariate analysis of multi-section data using tissue depth as a covariate were adopted for the statistical analysis of the multi-section imaging data. The standard deviations of the redox indices and the histogram analysis with Gaussian fit were used to determine the tissue heterogeneity. All methods show consistently that the PTEN deficient pancreases (Pdx1-Cre;PTENlox/lox) were significantly more heterogeneous in their mitochondrial redox state compared to the controls (PTENlox/lox). Statistical analysis taking into account the variations of the redox state with tissue depth further shows that PTEN deletion significantly shifted the pancreatic tissue to an overall more oxidized state. Oxidization of the PTEN-null group was not seen when the imaging data were analyzed by global averaging without considering the variation of the redox indices along tissue depth, indicating the importance of taking tissue heterogeneity into account for the statistical analysis of the multi-section imaging data. This study reveals a possible link between the mitochondrial redox state alteration of the pancreas and its malignant transformation and may be further developed for establishing potential metabolic biomarkers for the early diagnosis of pancreatic cancer.


A comparative analysis of the influence of refractive error on image acuity using three eye models.
To analyse and compare image acuity for different refractive errors generated by either altering axial length or corneal curvature and using three human eye models with two pupil sizes. Three different eye models, Liou-Brennan, Goncharov and Navarro, were used. Simulations were made (using Ansys Zemax OpticStudio 22.3) for real pupil sizes of 3 and 6 mm with refractive errors ranging from -2 to +2 D in 0.25 D increments. Refractive errors were simulated by varying axial length or corneal curvature. Root mean square (RMS) values were used to determine image acuity. For the 3-mm pupil, all models gave similar results, with the Navarro model having slightly higher RMS values for the emmetropic eye. For the 6-mm pupil, the Liou-Brennan and Goncharov eye models gave similar results, with RMS values lower than for the Navarro eye model. The highest RMS value was visible in the axial length-induced refractive errors. Refractive errors generated by altering corneal curvature give smaller RMS values than those generated by altering axial length. The axial length and corneal radius simulations indicate a wide spread of results for myopic, hyperopic and emmetropic eyes. There are multiple outcomes that give the same refractive error, even within a single-eye model. The axial length/corneal curvature ratio showed a higher ratio for myopes than hyperopes for every model. The influence of refractive error on image acuity varied depending on the simulation method of refractive error and the model used. The origins of refractive error and the influence it has on image acuity need further investigation. As models become more sophisticated, personalised and biologically relevant, they will better represent the image acuity of the eye for varying refractive errors, ethnicities, ages and pupil sizes.


A novel GBE1 gene variant in a child with glycogen storage disease type IV.
Glycogen storage disease type IV is an autosomal recessive disorder of carbohydrates caused by deficiency of amylo-1-4-glycanoglycosyltransferase, which leads to accumulation of amylopectin-like polysaccharides in tissues including liver, heart and neuromuscular system. More than 40 different mutations in the glycogen branching enzyme gene (GBE1) have been described. In this study, we report a 2-year-old boy who presented with developmental delay and muscle weakness. He subsequently was diagnosed with glycogen storage disease type IV based on a liver biopsy histology and electron microscopy. Glycogen branching enzyme activity was in the low range. Genetic analysis demonstrated a novel heterozygous variant (c.760A>G; p.Thr254Ala) in exon 6 of the GBE1 gene, which is believed to be pathogenic. This variant was inherited from the patient's mother who was asymptomatic with normal glycogen branching enzyme activity. Whole-exome sequencing failed to reveal additional variations in the GBE1 gene.


Dissolution behavior of ionic liquids for different ratios of lignin and cellulose in the preparation of nanocellulose/lignin blends.
Lignin is regarded as a potential solution for boosting the strength of cellulose-based products. However, the mechanism of co-solubilization for lignin and cellulose has not been investigated. In this study, the effect of lignin content on the interaction between lignin and nanocellulose during lignin/cellulose co-dissolution was examined. The results revealed that lignin binds to nanocellulose throughout the dissolution process to limit the degradation of cellulose and to prepare nanocellulose/lignin composites. Moreover, the S units in lignin were more likely to interact with cellulose during the dissolution process, whereas the G units were more likely to condense. However, when the lignin content exceeded 30 wt%, the excess lignin created a severe condensation reaction, which led to a decrease in the lignin content bound to cellulose, resulting in an unequal dissolution of cellulose. Thus, a small amount of lignin attached to cellulose during the co-dissolution of lignin and cellulose inhibits cellulose degradation and can be utilized to create nanocellulose/lignin to extend the potential applications of nanocellulosic materials.


Targeting Akt and heat shock protein 90 produces synergistic multiple myeloma cell cytotoxicity in the bone marrow microenvironment.
We hypothesized that targeting both Akt and heat shock protein (HSP) 90 would induce cytotoxic activity against multiple myeloma (MM) cells and target the bone marrow (BM) microenvironment to inhibit angiogenesis, osteoclast formation, as well as migration and adhesion of MM cells. MM cell lines were incubated with perifosine (5 and 10 micromol/L) and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG; 50 and 100 nmol/L) alone and in combination. The combination of Akt inhibitor perifosine and HSP90 inhibitor 17-DMAG was synergistic in inducing MM cell cytotoxicity, evidenced by inhibition of DNA synthesis and induction of apoptosis. In addition, perifosine and 17-DMAG almost completely inhibited osteoclast formation: perifosine interfered with both early and late stages of osteoclast progenitor development, whereas 17-DMAG targeted only early stages. We next showed that combined therapy overcomes tumor growth and resistance induced by BM stromal cells and endothelial cells as well as the proliferative effect of exogenous interleukin-6, insulin-like growth factor-I, and vascular endothelial growth factor. Moreover, the combination also induced apoptosis and growth inhibition in endothelial cells and inhibited angiogenesis. Finally, we showed that the two agents prevented migration of MM cells toward stromal-derived factor-1 and vascular endothelial growth factor, which are present in the BM milieu, and also prevented adhesion of MM cells to fibronectin. This study provides the preclinical framework for treatment protocols targeting both the Akt and HSP pathways in MM.


Sampling strategies for square and boll-feeding plant bugs (Hemiptera: Miridae) occurring on cotton.
Sampling methods for square and boll-feeding plant bugs (Hemiptera: Miridae) occurring on cotton, Gossypium hirsutum L., were compared with the intent to assess if one approach was viable for two species occurring from early-season squaring to late bloom in 25 fields located along the coastal cotton growing region of south Texas. Cotton fleaphopper, Pseudatomoscelis seriatus (Reuter), damages squares early-season and dominated collections using five sampling methods (approximately 99% of insects collected). A major species composition shift occurred beginning at peak bloom in coastal fields, when verde plant bug, Creontiades signatus Distant, represented 55-65% of collections. Significantly more cotton fleahoppers were captured by experienced samplers with the beat bucket and sweep net than with the other methods (30-100% more). There were more than twice as many verde plant bugs captured by experienced and inexperienced samplers with the beat bucket and sweep net than captured with the KISS and visual methods. Using a beat bucket or sweep net reduced sampling time compared with the visual method for the experienced samplers. For both species, comparing regressions of beat bucket-based counts to counts from the traditional visual method across nine cultivar and water regime combinations resulted in only one combination differing from the rest, suggesting broad applicability and ability to translate established visual-based economic thresholds to beat bucket-based thresholds. In a first look at sample size considerations, 40 plants (four 10-plant samples) per field site was no more variable than variation associated with larger sample sizes. Overall, the beat bucket is much more effective in sampling for cotton fleahopper and verde plant bug than the traditional visual method, it is more suited to cotton fleahopper sampling early-season when plants are small, it transitions well to sample for verde plant bug during bloom, and it performs well under a variety of soil moisture conditions and cultivar selections.


[Diagnosis and treatment of coagulopathic syndromes in ischemic stroke].
A study was made of blood coagulation, physiological anticoagulants and fibrinolysis in 120 elderly patients with cerebrovascular diseases, including 50 subjects in the acute period of ischemic brain stroke. To estimate activation of the fibrinolytic system, the levels of plasminogen and free plasmin were measured. Phasic changes in the system of blood coagulation were detected, variants of antithrombin III depression were delineated, and a relationship was established between the activity of enzymes of the fibrinolytic system and the site of an ischemic focus in the brain. Five coagulopathic syndromes of the acute period of brain stroke were distinguished, the principles of their differentiated treatment were based.


[Evaluation of the use of the International Classification of Diseases for the codification of AIDS].
The International Classification of Diseases (ICD) provides codes for all conditions and permits international comparisons of morbidity and mortality. Because it has to be used all over the world its codes are not always perfectly appropriate. There are revisions from time to time to bring up-to-date the classification. This has happened with AIDS, included in the chapter of infectious diseases in the last revision, ICD-10. The use of ICD-10 AIDS codes is here appraised. All surveillance report forms of one specialized hospital in infectious diseases, notified in 1994, have been codified, but it was found that many diagnoses could not be codified in accordance with a single ICD-10 AIDS code.


Recall of recent and more remote depressive episodes in a prospective cohort study.
In psychiatric epidemiology, symptoms are often assessed retrospectively. This raises concerns about the accuracy of the information recalled. In this study, we sought to examine the level of agreement between survey items assessing recent and more remote depressive episodes. Data from the Canadian National Population Health Survey (NPHS) were used. The NPHS is a prospective study following a representative cohort of household residents sampled in 1994 and 1995. Every 2 years, participants are administered the Composite International Diagnostic Interview Short Form for Major Depression (CIDI-SFMD). The 2004 NPHS interview also included items asking about past episodes of depression and diagnoses of depression done by health professionals. We used cross-tabulation and logistic regression to explore the relationship between these responses. Approximately, 90% of respondents with CIDI-SFMD-defined major depressive episodes in the year preceding the 2004 interview also reported lifetime episodes or professional diagnoses of depression in 2004. However, responses to the 2004 lifetime items corresponded less closely to CIDI-SFMD results from the same individuals earlier in the longitudinal survey. Only 40.8% of respondents having the most recently identified episode in 1994 subsequently affirmed a past episode of depression in 2004. Reporting of depressive episodes diminishes with time, suggesting that retrospective assessment of such episodes may be vulnerable to inaccuracy.


[Meaning of the "scientific validity clause" of private hospital insurance (section 5/1 f MB/KK 76). With reference to recent verdicts].
As per Section 5/1 f of the classic conditions 1976 of the "Association of private health insurance carriers" (Verband der privaten Krankenversicherung), benefits won't be paid for methods of examination or treatment and remedies which are from the scientific point of view generally not recognized. Basic reflections have led to the fact that today the term "scientifically recognized methods" and the term "traditional medicine" will be treated as equivalent. Contrary verdicts, according to which treatments on the basis of anthroposophic medicine or by means of electro-acupuncture by Voll would be considered as generally recognized medicine from the scientific point of view and would have to be paid by the private health insurance carriers, are consequently not comprehensible. Supposing that the trend continues that private health insurers have to pay more and more expenses incurred for all kind of outsider-methods, this would lead not only to a great drain on the purse of the private health insurance carriers, but have also unpleasant consequences for the whole medicine, because the uniformity of the medicine is endangered. To take steps against has not only to be the task of the private health insurance carriers, but it is also in the interest of the physicians and, at last, of the patients, too.


Reappraisal of clinical features of diverticular disease of the colon.
In patients with diverticular disease of the colon factors which indicate a worse prognosis include widespread abdominal pain, nausea and vomiting, disturbed bowel habit, a palpable abdominal mass, abdominal distension, and any of the inflammatory complications. While radiology is of prime importance in the initial diagnosis, it is often impossible to differentiate between diverticulosis and diverticulitis. A more accurate distinction can be made by assessing all the available clinical, radiological, and pathological data, but again there are limitations and inaccuracies. The use of the term "diverticular disease" is preferable.


Removing dye rhodamine B from aqueous medium via wet peroxidation with V-MCM-41 and H2O2.
A new heterogeneous Fenton-like system, consisting of V-MCM-41 catalyst and hydrogen peroxide, was proved to be effective in removing recalcitrant dye Rhodamine B (RhB) in aqueous solutions. V-MCM-41 was prepared following a direct hydrothermal procedure with tetraethyl silicate and ammonium metavanadate as precursor. The mesoporous structure has been characterized by XRD, and the specific surface area was determined as x m(2) g(-1) according to BET method. The catalytic reaction can proceed in a relatively wide pH range from acidic to alkaline. And the visible light irradiation cannot promote the reaction process. In addition, the mechanism implication for V-MCM-41 as a Fenton-like catalyst has been discussed.


Toward a Unified Framework for the Study of Between-Person and Within-Person Structures: Building a Bridge Between Two Research Paradigms.
The vast majority of empirical research in the behavioral sciences is based on the analysis of between-person variation. In contrast, much of applied psychology is concerned with the analysis of variation within individuals. Furthermore, the mechanisms specified by psychological theories generally operate within, rather than across, individuals. This disconnect between research practice, applied demands, and psychological theories constitutes a major threat to the conceptual integrity of the field. Following groundbreaking earlier work, we propose a conceptual framework that distinguishes within-person (WP) and between-person (BP) sources of variation in psychological constructs. By simultaneously considering both sources of variation, it is shown how to identify possible reasons for nonequivalence of BP and WP structures as well as establishing areas of convergence. For this purpose, we first introduce the concept of conditional equivalence as a way to study partial structural equivalence of BP and WP structures in the presence of unconditional nonequivalence. Second, we demonstrate the construction of likelihood planes to explore the causes of structural nonequivalence. Third, we examine 4 common causes for unconditional nonequivalence-autoregression, subgroup differences, linear trends, and cyclic trends-and demonstrate how to account for them. Fourth, we provide an empirical example on BP and WP differences in attentiveness.


The structure of oppositionality: response dispositions and situational aspects.
The Amsterdam Scale of Oppositionality (ASO) is a recently developed self-report instrument to measure the full range of oppositionality. It was used to test the assumption that oppositionality can best be conceptualized as a combination of emotions and behaviors varying across contexts, i.e., with parents, peers and authority figures. The sample consisted of 560 boys and 598 girls, aged 8 to 12 years. The thirty items of the ASO, grouped in item parcels, were analyzed using confirmatory factor analyses. Results confirmed the main hypothesis. The best fitting models contained strongly related emotional and behavioral factors and three mutually related situational factors. Oppositionality appeared to be to a large extent situation-specific. Girls are more affected by the situation than boys and show less oppositionality only outside the family context. Results are discussed with respect to the concept of oppositionality, varying expectations for interpersonal consequences, and implications for clinical assessment and studies of inter-informant reliability.


Informed consent and the readability of the written consent form.
Introduction The aim of this study was to objectively ascertain the level of readability of standardised consent forms for orthopaedic procedures. Methods Standardised consent forms (both in summary and detailed formats) endorsed by the British Orthopaedic Association (BOA) were retrieved from orthoconsent.com and assessed for readability. This involved using an online tool to calculate the validated Flesch reading ease score (FRES). This was compared with the FRES for the National Health Service (NHS) Consent Form 1. Data were analysed and interpreted according to the FRES grading table. Results The FRES for Consent Form 1 was 55.6, relating to the literacy expected of an A level student. The mean FRES for the BOA summary consent forms (n=27) was 63.6 (95% confidence interval [CI]: 61.2-66.0) while for the detailed consent forms (n=32), it was 68.9 (95% CI: 67.7-70.0). All BOA detailed forms scored >60, correlating to the literacy expected of a 13-15-year-old. The detailed forms had a higher FRES than the summary forms (p<0.001). Conclusions This study demonstrates that the BOA endorsed standardised consent forms are much easier to read and understand than the NHS Consent Form 1, with the detailed BOA forms being the easiest to read. Despite this, owing to varying literacy levels, a significant proportion of patients may struggle to give informed consent based on the written information provided to them.


Rising mortality from cryptogenic fibrosing alveolitis.
To determine the pattern of mortality ascribed to cryptogenic fibrosing alveolitis and to identify factors that might be important in the aetiology of the disease; and to assess the validity of death certification of the disease. A retrospective examination of mortality ascribed to cryptogenic fibrosing alveolitis in England and Wales between 1979 and 1988 with analysis, by multiple logistic regression, of independent effects of age, sex, region of residence, and social class as indicated by occupation on data for 1979-87; also a retrospective review of hospital records of patients certified as having died of cryptogenic fibrosing alveolitis in Nottingham and of the certified cause of death of patients known to have had the disease. Time trends in mortality nationally; effects on mortality of age, sex, and region of residence; validity of death certification in Nottingham. The annual number of deaths ascribed to cryptogenic fibrosing alveolitis doubled from 336 in 1979 to 702 in 1988, the increase occurring mainly at ages over 65. Mortality standardised for age for both sexes likewise increased steadily over the period. Deaths due to cryptogenic fibrosing alveolitis were commoner in men (odds ratio 2.24, 95% confidence interval 2.11 to 2.33) and increased substantially with age, being 7.84 (7.24 to 8.49) times higher in subjects aged much greater than 75 than those aged 45-64. Odds ratios of death due to cryptogenic fibrosing alveolitis adjusted for age and sex were increased in the traditionally industrialised central areas of England and Wales (p less than 0.02, maximum odds ratio between regions 1.25), but no significant increase in odds of death was found for manual occupations. Of 23 people whose deaths were registered in Nottingham as having been due to cryptogenic fibrosing alveolitis, 19 were ascertained from clinical records to have had the disease. Only 17 of 45 patients known to have had cryptogenic fibrosing alveolitis in life were recorded as having died from the disease. The diagnostic accuracy of death certification of cryptogenic fibrosing alveolitis is high, but the number of deaths recorded as being due to the disease may underestimate the number of patients dying with the disease by up to half. Mortality due to the disease is increasing, and the male predominance and regional differences in mortality suggest that environmental factors are important in its aetiology.


Tele-ophthalmology screening for retinal and anterior segment diseases.
A digital indirect ophthalmoscope (DIO) was developed and tested for use in tele-ophthalmology screening for posterior and anterior segment diseases. Using custom software, images from the DIO were digitized, compressed, stored and transmitted to a centralized eye clinic for interpretation. A total of 43 subjects were primarily screened for glaucoma using the DIO, a hand-held fundus camera and a stereo fundus camera. The photographic slides from the stereo fundus camera used as gold standards. Images (390 x 300 pixels x 3 bits) were stored using a laptop computer together with patient information. Image quality received at the central eye clinic was good and showed adequate diagnostic information. An ophthalmologist estimated cup-disc ratios and graded the quality of the images. The sensitivity and specificity of each instrument was calculated. A high sensitivity and specificity was found when using the DIO, indicating that it could be used in tele-ophthalmic screenings. Further modifications are needed to make the instrument more user-friendly and to enable it to be used with undilated pupils, so that it can be easily operated by health-care personnel in remote areas. The camera can also be used to image gross external eye pathology.


Neurogenic secretion mediated by the purinergic P2Y1 receptor in guinea-pig small intestine.
We tested the hypothesis that ATP is an enteric neurotransmitter that acts at P2Y1 excitatory purinergic receptors on intestinal secretomotor neurons to evoke neurogenic mucosal secretion in the guinea pig. Ussing chamber methods for studying neurogenic intestinal secretion were used to test the hypothesis. Application of ATP evoked concentration-dependent increases in short circuit current (Isc) indicative of stimulation of electrolyte secretion. MRS2179, a selective P2Y1 purinergic receptor antagonist, suppressed the ATP-evoked responses in a concentration-dependent manner with an IC50 of 0.9+/-0.1 microM. Tetrodotoxin or a selective vasoactive intestinal peptide (VPAC1) receptor antagonist suppressed or abolished the ATP-evoked responses. A selective VPAC1 receptor antagonist also suppressed Isc responses evoked by electrical field stimulation of the secretomotor neurons. Secretory responses to ATP were not suppressed by scopolamine, piroxicam nor selective adenosine receptor antagonists. Region-specific differences in responses to ATP corresponded to regional differences in the expression of mRNA transcripts for the P2Y1 receptor. Post-receptor signal transduction for the P2Y1-evoked responses involved stimulation of phospholipase C and an IP3/Ca2+-calmodulin/protein kinase C signaling cascade. Our evidence suggests that ATP is released as a neurotransmitter to stimulate neurogenic mucosal secretion by binding to P2Y1 receptors expressed by VIP-ergic secretomotor neurons.


A rapid sample preparation method for the determination of sulfamethazine in swine tissues by high-performance liquid chromatography.
A rapid procedure for the determination of sulfamethazine in swine muscle and kidney is described. The method comprises sonication-aided extraction with dichloromethane, cleaning-up of the extract on a combination of silica and reversed-phase C18 Sep-Pak cartridges and analysis by high-performance liquid chromatography on a Hypersil ODS column using acetonitrile/ammonium acetate solution (10 mmol X 1(-1), pH 6.8) 1 + 3 v/v as the mobile phase. Detection was performed at 254 nm. Mean recoveries of added sulfamethazine from swine muscle and kidney, at levels of 0.05 to 0.5 micrograms X g-1, were 89.5 and 80.5%, respectively. After intramuscular injection of sulfamethazine into swine, residues in tissues were also determined. The application of ultrasonic energy for the extraction of sulfamethazine residues from animal tissues is also discussed.


Current and novel practice of stereotactic radiosurgery.
Stereotactic radiosurgery emerged as a neurosurgical discipline in order to utilize energy for the manipulation of brain or nerve tissue, with the goal of minimal access and safe and effective care of a spectrum of neurosurgical disorders. Perhaps no other branch of neurosurgery has been so disruptive across the entire discipline of brain tumor care, treatment of vascular disorders, and management of functional problems. Radiosurgery is mainstream, supported by thousands of peer-reviewed outcomes reports. This article reviews current practice with a focus on challenges, emerging trends, and areas of investigation.


Development of the Problematic Mobile Gaming Questionnaire and Prevalence of Mobile Gaming Addiction Among Adolescents in Taiwan.
Mobile gaming has gained popularity among adolescents, and an increase in problematic use has been reported. The aims of this study are as follows: (a) develop a self-report questionnaire, the Problematic Mobile Gaming Questionnaire (PMGQ); (b) establish a validated cutoff value using structured interviews; and (c) evaluate the prevalence of mobile gaming addiction in adolescents. The PMGQ was built as a 12-item questionnaire rated on a 4-point Likert scale to evaluate the symptoms of problematic mobile gaming (PMG). The construct validity of the PMGQ was examined using exploratory factor analysis. Overall, 10,775 students with smartphones from grade 4 to senior high school were recruited to complete the questionnaire. A total of 113 senior high school students were interviewed using previously developed criteria for PMG to develop an optimal cutoff point measuring sensitivity, specificity, and diagnostic accuracy. The cutoff point was determined using the Youden index and optimal diagnostic accuracy. The PMGQ showed good internal consistency (Cronbach's α = 0.92) and adequate diagnostic efficiency (area under the receiver operating characteristic curve = 0.802). The items revealed three factors of addiction: compulsion, tolerance, and withdrawal. For the PMGQ, a cutoff point of 29/30 demonstrated the most optimal Youden index and diagnostic accuracy. Demographic data showed that the proportion of PMG was 19.1 percent among elementary school students, 20.5 percent among junior high school students, and 19.0 percent among senior high school students. The PMGQ demonstrated appropriate validity and accuracy in the assessment for PMG.


Synthetic antibodies block receptor binding and current-inhibiting effects of α-cobratoxin from Naja kaouthia.
Each year, thousands of people fall victim to envenomings caused by cobras. These incidents often result in death due to paralysis caused by α-neurotoxins from the three-finger toxin (3FTx) family, which are abundant in elapid venoms. Due to their small size, 3FTxs are among the snake toxins that are most poorly neutralized by current antivenoms, which are based on polyclonal antibodies of equine or ovine origin. While antivenoms have saved countless lives since their development in the late 18th century, an opportunity now exists to improve snakebite envenoming therapy via the application of new biotechnological methods, particularly by developing monoclonal antibodies against poorly neutralized α-neurotoxins. Here, we describe the use of phage-displayed synthetic antibody libraries and the development and characterization of six synthetic antibodies built on a human IgG framework and developed against α-cobratoxin - the most abundant long-chain α-neurotoxin from Naja kaouthia venom. The synthetic antibodies exhibited sub-nanomolar affinities to α-cobratoxin and neutralized the curare-mimetic effect of the toxin in vitro. These results demonstrate that phage display technology based on synthetic repertoires can be used to rapidly develop human antibodies with drug-grade potencies as inhibitors of venom toxins.


Burden of systemic hypertension in patients admitted to cardiology hospitalization units.
Hypertension is 1 of the most prevalent cardiovascular risk factors; nevertheless, some studies have reported that the antecedent of hypertension does not impair prognosis in patients with established cardiovascular disease. The objective of this study was to describe the impact of hypertension on readmission and 1-year mortality in patients admitted to a single cardiology hospitalization unit. All consecutive hospitalizations in a single cardiology department through 10 months were included, and 1-year follow-up was performed. Clinical antecedents, risk factors, and main discharge diagnoses were collected. A total of 1,007 patients were included (mean age 71.1 ± 13.5 years). The antecedent of hypertension was present in 69.0%, and these patients had older mean age and higher prevalence of risk factors and previous cardiovascular disease. No differences in hospital discharge main diagnoses were observed according to the antecedent of hypertension. During a mean follow-up period of 404.82 ± 122.2 days, patients with hypertension had higher rates of rehospitalization for cardiac causes (31.1% vs 17.9%, p = 0.01) and of total (17.4% vs 9.3%, p <0.01) and cardiovascular (13.9% vs 5.9%, p <0.01) mortality. Multivariate analysis identified the antecedent of hypertension as an independent risk factor for cardiovascular readmission (hazard ratio 1.46, 95% confidence interval 1.10 to 1.98) and the combined end point of readmission or mortality (hazard ratio 1.45, 95% confidence interval 1.12 to 1.88); no independent association was observed for total mortality. In conclusion, hypertension was present in most patients admitted to a cardiology unit, and they had higher rates of rehospitalization and mortality at 1-year follow-up.


Prostate cancer.
Prostate cancer continues to be a significant public health issue worldwide, particularly in countries where men have life expectancies long enough to clinically manifest the disease. In many countries, it remains one of the leading causes of cancer-related morbidity and mortality. Although significant progress has been made over the past few decades, many elements regarding the diagnosis and management of patients with prostate cancer remain enigmatic. In this Prostate Cancer special issue, our expert authors present and examine clinically relevant topics and look ahead to future research.


p53 involvement in clonal hematopoiesis of indeterminate potential.
Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and occurs when a single mutant hematopoietic stem cell (HSC) contributes to a significant clonal proportion of mature blood lineages. Somatic mutations in the TP53 gene, which encodes the tumor suppressor protein p53, rank in the top five among genes that were mutated in CHIP. This review focuses on mechanisms by which mutant p53 promotes CHIP progression and drives the pathogenesis of hematological malignancies, including myelodysplastic syndromes, and acute myeloid leukemia. TP53 was frequently mutated in individuals with CHIP. Although clinical studies suggest that expansion of HSCs with TP53 mutations predisposes the elderly to hematological neoplasms, there is a significant gap in knowledge regarding the mechanisms by which TP53 mutations promote HSC expansion. Recent findings suggest that several cellular stressors, including hematopoietic transplantation, genotoxic stress, and inflammation, promote the expansion of HSCs with TP53 mutations. Further, TP53 mutations identified in CHIP cooperate with genetic and/or epigenetic changes in leukemogenesis. TP53 mutations identified in CHIP are associated with increased risks of de novo and therapy-related hematological neoplasms. Thus, targeting mutant p53 and related pathways holds great potential in preventing CHIP progression and treating hematological malignancies.


[Plasma renin activity in chronic adrenal gland insufficiency].
Renin plasma activity (RPA) was studied in 25 patients with chronic adrenal insufficiency and in 5--with arterial hypotension caused by factors other than adrenal insufficiency. In patients with chronic adrenal insufficiency RPA was found to be elevated: in 74% of patients left without substitution therapy, and in 52% - given substitution therapy; in the first case RPA averaged 6.5 +/- 3.20, and in the second - 4.30 +/- 1.76 ng/ml/h A1 (normal value - 1.6 +/- 0.4 ng/ml/h A1). In patients with arterial hypotension not due to adrenal insufficiency RPA was within the normal range averaging 1.61 +/- 0.18 ng/ml/h A1). Clinical significance of RPA determination in patients with arterial hypotension, and also the importance of RPA determination in cases of chronic adrenal insufficiency during substitution therapy is discussed.


[Exercise training in cardiovascular diseases].
Physical activity and exercise training are effective in prevention, treatment and rehabilitation of cardiovascular disease, but the dose-response relationship is insufficiently documented. The manuscript is based on existing guidelines and searches in Pubmed for the period 1990-2006. Exercise training improves maximum oxygen consumption and prognosis in patients with cardiovascular disease. A single weekly bout of exercise reduces mortality from stroke and ischemic heart disease, but larger doses may provide additional protection. In patients with coronary heart disease, high intensity exercise seems to be more effective in improving maximal oxygen consumption than moderate exercise, but it is not known if such exercise is also more effective in improving survival. Further studies are also required to establish the safety of such exercise. Exercise has few contraindications, but patients should be screened in advance with an exercise-ECG. Future studies should to a larger extent include female, elderly and high-risk patients, and be precise in prescribing and reporting exercise intensity, duration and frequency. Maximum oxygen consumption is an accurate measure of cardiovascular fitness and a strong and independent prognostic marker for survival, both in patients and healthy subjects.


Interspecific competition promotes habitat and morphological divergence in a secondary contact zone between two hybridizing songbirds.
Interspecific competition is assumed to play an important role in the ecological differentiation of species and speciation. However, empirical evidence for competition's role in speciation remains surprisingly scarce. Here, we studied the role of interspecific competition in the ecological differentiation and speciation of two closely related songbird species, the Common Nightingale (Luscinia megarhynchos) and the Thrush Nightingale (Luscinia luscinia). Both species are insectivorous and ecologically very similar. They hybridize in a secondary contact zone, which is a mosaic of sites where both species co-occur (syntopy) and sites where only one species is present (allotopy). We analysed fine-scale habitat data for both species in both syntopic and allotopic sites and looked for associations between habitat use and bill morphology, which have been previously shown to be more divergent in sympatry than in allopatry. We found that the two nightingale species differ in habitat use in allotopic sites, where L. megarhynchos occurred in drier habitats and at slightly higher elevations, but not in syntopic sites. Birds from allotopic sites also showed higher interspecific divergence in relative bill size compared to birds from syntopic sites. Finally, we found an association between bill morphology and elevation. Our results are consistent with the view that interspecific competition in nightingales has resulted in partial habitat segregation in sympatry and that the habitat-specific food supply has in turn very likely led to bill size divergence. Such ecological divergence may enhance prezygotic as well as extrinsic postzygotic isolation and thus accelerate the completion of the speciation process.


Liver-Derived Exosomes and Their Implications in Liver Pathobiology.
The liver has a wide range of physiological functions in the body, and its health is maintained by complex cross-talk among hepatic cells, including parenchymal hepatocytes and nonparenchymal cells. Exosomes, which are one method of cellular communication, are endosomal-derived small vesicles that are released by donor cells and delivered to the target cells at both short and long distances. Because exosomes carry a variety of cargoes, including proteins, mRNAs, microRNAs and other noncoding RNAs originating from donor cells, exosomes convey cellular information that enables them to potentially serve as biomarkers and therapeutics in liver diseases. Hepatocytes release exosomes to neighboring hepatocytes or nonparenchymal cells to regulate liver regeneration and repair. Nonparenchymal cells, including hepatic stellate cells, liver sinusoidal endothelial cells, and cholangiocytes, also secrete exosomes to regulate liver remodeling upon liver injury. Exosomes that are released from liver cancer cells create a favorable microenvironment for cancer growth and progression. In this review, we summarize and discuss the current findings and understanding of exosome-mediated intercellular communication in the liver, with a particular focus on the function of exosomes in both health and disease. Based on the current findings, we suggest the potential applications of exosomes as biomarkers and therapeutics for liver diseases.