Evaluation of muscular activity duration in shoulders with rotator cuff tears using inertial sensors and electromyography.
Shoulder disorders, including rotator cuff tears, affect the shoulder function and result in adapted muscle activation. Although these adaptations have been studied in controlled conditions, free-living activities have not been investigated. Based on the kinematics measured with inertial sensors and portable electromyography, the objectives of this study were to quantify the duration of the muscular activation in the upper trapezius (UT), medial deltoid (MD) and biceps brachii (BB) during motion and to investigate the effect of rotator cuff tear in laboratory settings and daily conditions. The duration of movements and muscular activations were analysed separately and together using the relative time of activation (T(EMG/mov)). Laboratory measurements showed the parameter's reliability through movement repetitions (ICC > 0.74) and differences in painful shoulders compared with healthy ones (p < 0.05): longer activation for UT; longer activation for MD during abduction and tendency to shorter activation in other movements; shorter activation for BB. In daily conditions, T(EMG/mov) for UT was longer, whereas it was shorter for MD and BB (p < 0.05). Moreover, significant correlations were observed between these parameters and clinical scores. This study thus provides new insights into the rotator cuff tear effect on duration of muscular activation in daily activity.


Metabolic and lifestyle risk factors for acute pancreatitis in Chinese adults: A prospective cohort study of 0.5 million people.
Little prospective evidence exists about risk factors and prognosis of acute pancreatitis in China. We examined the associations of certain metabolic and lifestyle factors with risk of acute pancreatitis in Chinese adults. The prospective China Kadoorie Biobank (CKB) recruited 512,891 adults aged 30 to 79 years from 5 urban and 5 rural areas between 25 June 2004 and 15 July 2008. During 9.2 years of follow-up (to 1 January 2015), 1,079 cases of acute pancreatitis were recorded. Cox regression was used to estimate adjusted hazard ratios (HRs) for acute pancreatitis associated with various metabolic and lifestyle factors among all or male (for smoking and alcohol drinking) participants. Overall, the mean waist circumference (WC) was 82.1 cm (SD 9.8) cm in men and 79.0 cm (SD 9.5) cm in women, 6% had diabetes, and 6% had gallbladder disease at baseline. WC was positively associated with risk of acute pancreatitis, with an adjusted HR of 1.35 (95% CI 1.27-1.43; p < 0.001) per 1-SD-higher WC. Individuals with diabetes or gallbladder disease had HRs of 1.34 (1.07-1.69; p = 0.01) and 2.42 (2.03-2.88; p < 0.001), respectively. Physical activity was inversely associated with risk of acute pancreatitis, with each 4 metabolic equivalent of task (MET) hours per day (MET-h/day) higher physical activity associated with an adjusted HR of 0.95 (0.91-0.99; p = 0.03). Compared with those without any metabolic risk factors (i.e., obesity, diabetes, gallbladder disease, and physical inactivity), the HRs of acute pancreatitis for those with 1, 2, or ≥3 risk factors were 1.61 (1.47-1.76), 2.36 (2.01-2.78), and 3.41 (2.46-4.72), respectively (p < 0.001). Among men, heavy alcohol drinkers (≥420 g/week) had an HR of 1.52 (1.11-2.09; p = 0.04, compared with abstainers), and current regular smokers had an HR of 1.45 (1.28-1.64; p = 0.02, compared with never smokers). Following a diagnosis of acute pancreatitis, there were higher risks of pancreatic cancer (HR = 8.26 [3.42-19.98]; p < 0.001; 13 pancreatic cancer cases) and death (1.53 [1.17-2.01]; p = 0.002; 89 deaths). Other diseases of the pancreas had similar risk factor profiles and prognosis to acute pancreatitis. The main study limitations are ascertainment of pancreatitis using hospital records and residual confounding. In this relatively lean Chinese population, several modifiable metabolic and lifestyle factors were associated with higher risks of acute pancreatitis, and individuals with acute pancreatitis had higher risks of pancreatic cancer and death.


Five questions to consider before conducting a stepped wedge trial.
Researchers should consider five questions before starting a stepped wedge trial. Why are you planning one? Researchers sometimes think that stepped wedge trials are useful when there is little doubt about the benefit of the intervention being tested. However, if the primary reason for an intervention is to measure its effect, without equipoise there is no ethical justification for delaying implementation in some clusters. By contrast, if you are undertaking pragmatic research, where the primary reason for rolling out the intervention is for it to exert its benefits, and if phased implementation is inevitable, a stepped wedge trial is a valid option and provides better evidence than most non-randomized evaluations. What design will you use? Two common stepped wedge designs are based on the recruitment of a closed or open cohort. In both, individuals may experience both control and intervention conditions and you should be concerned about carry-over effects. In a third, continuous-recruitment, short-exposure design, individuals are recruited as they become eligible and experience either control or intervention condition, but not both. How will you conduct the primary analysis? In stepped wedge trials, control of confounding factors through secular variation is essential. 'Vertical' approaches preserve randomization and compare outcomes between randomized groups within periods. 'Horizontal' approaches compare outcomes before and after crossover to the intervention condition. Most analysis models used in practice combine both types of comparison. The appropriate analytic strategy should be considered on a case-by-case basis. How large will your trial be? Standard sample size calculations for cluster randomized trials do not accommodate the specific features of stepped wedge trials. Methods exist for many stepped wedge designs, but simulation-based calculations provide the greatest flexibility. In some scenarios, such as when the intracluster correlation coefficient is moderate or high, or the cluster size is large, a stepped wedge trial may require fewer clusters than a parallel cluster trial. How will you report your trial? Stepped wedge trials are currently challenging to report using CONSORT principles. Researchers should consider how to demonstrate balance achieved by randomization and how to describe trends for outcomes in both intervention and control clusters.


Effect of seasonal affective disorder and pathological tanning motives on efficacy of an appearance-focused intervention to prevent skin cancer.
To evaluate the robustness of an appearance-focused intervention to prevent skin cancer in individuals reporting seasonal affective disorder (SAD) symptoms and pathological tanning motives. Randomized, controlled clinical trial. College campus. Four hundred thirty adult female indoor tanners (200 in the intervention group and 230 control participants). A booklet discussing the history of tanning, current tanning norms, UV radiation's effects on skin, recommendations for indoor tanning use focusing on abstinence and harm reduction recommendations, and information on healthier, appearance-enhancing alternatives to tanning. Self-reported attitudes, intentions, and tanning behaviors; pathological tanning motives assessed by a questionnaire developed for this study; and SAD symptoms assessed by the Seasonal Pattern Assessment Questionnaire. Two of the 4 pathological tanning scales, opiatelike reactions to tanning and dissatisfaction with natural skin tone, were significant moderators demonstrating stronger treatment effects for individuals scoring higher on these scales. Treatment effects were equivalently positive (ie, no significant moderator effects) for all levels of SAD symptoms and all levels of the other 2 pathological tanning motive scales (ie, perceiving tanning as a problem and tolerance to the effects of tanning). The appearance-focused skin cancer prevention intervention is robust enough to reduce indoor tanning among tanners who exhibit SAD symptoms or pathological tanning motives. Tailored interventions may address individuals' motivations for tanning and their relation to maladaptive behavior, such as dissatisfaction with appearance or the need for relaxation because of anxiety.


Forecasting of COVID-19 cases using deep learning models: Is it reliable and practically significant?
The ongoing outbreak of the COVID-19 pandemic prevails as an ultimatum to the global economic growth and henceforth, all of society since neither a curing drug nor a preventing vaccine is discovered. The spread of COVID-19 is increasing day by day, imposing human lives and economy at risk. Due to the increased enormity of the number of COVID-19 cases, the role of Artificial Intelligence (AI) is imperative in the current scenario. AI would be a powerful tool to fight against this pandemic outbreak by predicting the number of cases in advance. Deep learning-based time series techniques are considered to predict world-wide COVID-19 cases in advance for short-term and medium-term dependencies with adaptive learning. Initially, the data pre-processing and feature extraction is made with the real world COVID-19 dataset. Subsequently, the prediction of cumulative confirmed, death and recovered global cases are modelled with Auto-Regressive Integrated Moving Average (ARIMA), Long Short-Term Memory (LSTM), Stacked Long Short-Term Memory (SLSTM) and Prophet approaches. For long-term forecasting of COVID-19 cases, multivariate LSTM models is employed. The performance metrics are computed for all the models and the prediction results are subjected to comparative analysis to identify the most reliable model. From the results, it is evident that the Stacked LSTM algorithm yields higher accuracy with an error of less than 2% as compared to the other considered algorithms for the studied performance metrics. Country-specific analysis and city-specific analysis of COVID-19 cases for India and Chennai, respectively, are predicted and analyzed in detail. Also, statistical hypothesis analysis and correlation analysis are done on the COVID-19 datasets by including the features like temperature, rainfall, population, total infected cases, area and population density during the months of May, June, July and August to find out the best suitable model. Further, practical significance of predicting COVID-19 cases is elucidated in terms of assessing pandemic characteristics, scenario planning, optimization of models and supporting Sustainable Development Goals (SDGs).


A case of imported Plasmodium ovale malaria.
There have been reports in Korea of imported malaria cases of four Plasmodium species, but there has been no report of imported Plasmodium ovale malaria confirmed by molecular biological methods. We report an imported case of that was confirmed by Wright-Giemsa-stained peripheral blood smear and nested polymerase chain reaction targeting the small subunit ribosomal RNA gene. The amplified DNA was sequenced and compared with other registered P. ovale isolates. The isolate in this study was a member of the classic type group. The patient was a 44-yr-old male who had worked as a woodcutter in Côte d'Ivoire in tropical West Africa. He was treated with hydroxychloroquine and primaquine and discharged following improvement. In conclusion, P. ovale should be considered as an etiology in the imported malaria in Korea, because the number of travelers to P. ovale endemic regions has recently increased.


Treatment, Outcome and Prognostic Factors in Renal Cell Carcinoma - A Single Center Study (2000-2010).
In Switzerland efficient availability of novel drugs for renal cell cancer (RCC) has been granted early. Since the advent of the targeted agents for RCC the usage of these drugs has been reported to improve progression free survival. Here, we find that patients who are able to receive sequential targeted therapy, including tyrosine kinase inhibitors (TKI) and mTOR inhibitors (mTORi), have a largely better outcome than those who have less exposure to these agents. The value of the prognostic scores developed by Motzer and Heng is fully reflected by the outcomes according to prognostic risk groups in our unselected patient cohort. Also, the use of surgical intervention appears to be an important prognostic factor, however with a somehow diminished effect by novel systemic therapies. The importance of multiple lines of targeted therapies is underlined by this retrospective analysis. For patients with metastatic RCC not receiving targeted therapy the median OS was 22.6 months compared to those with one TKI 25.4 months. Patients receiving a second-line therapy (median overall survival 27.6 months) and those patients with three or more lines of therapy (43.8 months) have the greatest benefit. Also, exposure to a mTORi improves survival versus non-exposure to mTORi (63.3 vs. 22.3 months, p=0.038). In conclusion a trend towards improved survival is confirmed for an unselected population when the full variety of therapeutic options is available and can be used for the individual patient.


Applying data mining techniques to medical time series: an empirical case study in electroencephalography and stabilometry.
One of the major challenges in the medical domain today is how to exploit the huge amount of data that this field generates. To do this, approaches are required that are capable of discovering knowledge that is useful for decision making in the medical field. Time series are data types that are common in the medical domain and require specialized analysis techniques and tools, especially if the information of interest to specialists is concentrated within particular time series regions, known as events. This research followed the steps specified by the so-called knowledge discovery in databases (KDD) process to discover knowledge from medical time series derived from stabilometric (396 series) and electroencephalographic (200) patient electronic health records (EHR). The view offered in the paper is based on the experience gathered as part of the VIIP project. Knowledge discovery in medical time series has a number of difficulties and implications that are highlighted by illustrating the application of several techniques that cover the entire KDD process through two case studies. This paper illustrates the application of different knowledge discovery techniques for the purposes of classification within the above domains. The accuracy of this application for the two classes considered in each case is 99.86% and 98.11% for epilepsy diagnosis in the electroencephalography (EEG) domain and 99.4% and 99.1% for early-age sports talent classification in the stabilometry domain. The KDD techniques achieve better results than other traditional neural network-based classification techniques.


Mesoamerican tree squirrels evolution (Rodentia: Sciuridae): a molecular phylogenetic analysis.
The tribe Sciurini comprehends the genera Sciurus, Syntheosiurus, Microsciurus, Tamiasciurus and Rheinthrosciurus. The phylogenetic relationships within Sciurus have been only partially done, and the relationship between Mesoamerican species remains unsolved. The phylogenetic relationships of the Mesoamerican tree squirrels were examined using molecular data. Sequence data publicly available (12S, 16S, CYTB mitochondrial genes and IRBP nuclear gene) and cytochrome B gene sequences of four previously not sampled Mesoamerican Sciurus species were analyzed under a Bayesian multispecies coalescence model. Phylogenetic analysis of the multilocus data set showed the neotropical tree squirrels as a monophyletic clade. The genus Sciurus was paraphyletic due to the inclusion of Microsciurus species (M. alfari and M. flaviventer). The South American species S. aestuans and S. stramineus showed a sister taxa relationship. Single locus analysis based on the most compact and complete data set (i.e. CYTB gene sequences), supported the monophyly of the South American species and recovered a Mesoamerican clade including S. aureogaster, S. granatensis and S. variegatoides. These results corroborated previous findings based on cladistic analysis of cranial and post-cranial characters. Our data support a close relationship between Mesoamerican Sciurus species and a sister relationship with South American species, and corroborates previous findings in relation to the polyphyly of Microsciurus and Syntheosciurus paraphyly.


Sport Injuries Sustained by Athletes with Disability: A Systematic Review.
Fifteen percent of the world's population live with disability, and many of these individuals choose to play sport. There are barriers to sport participation for athletes with disability and sports injury can greatly impact on daily life, which makes sports injury prevention additionally important. The purpose of this review is to systematically review the definitions, methodologies and injury rates in disability sport, which should assist future identification of risk factors and development of injury prevention strategies. A secondary aim is to highlight the most pressing issues for improvement of the quality of injury epidemiology research for disability sport. A search of NICE, AMED, British Nursing Index, CINAHL, EMBASE and Medline was conducted to identify all publications up to 16 June 2015. Of 489 potentially relevant articles and reference searching, a total of 15 studies were included. Wide study sample heterogeneity prevented data pooling and meta-analysis. Results demonstrated an evolving field of epidemiology, but with wide differences in sports injury definition and with studies focused on short competitions. Background data were generally sparse; there was minimal exposure analysis, and no analysis of injury severity, all of which made comparison of injury risk and injury severity difficult. There is an urgent need for consensus on sports injury definition and methodology in disability sports. The quality of studies is variable, with inconsistent sports injury definitions, methodologies and injury rates, which prevents comparison, conclusions and development of injury prevention strategies. The authors highlight the most pressing issues for improvement of the quality in injury epidemiology research for disability sport.


Legal highs: staying on top of the flood of novel psychoactive substances.
There has been growing clinical, public, and media awareness and concern about the availability and potential harmfulness of so-called 'legal highs', which are more appropriately called new or novel psychoactive substances (NPS). A cat-and-mouse process has emerged wherein unknown chemists and laboratories are producing new, and as yet nonproscribed, compounds for human consumption; and as soon as they are banned, which they inevitably are, slightly modified analogues are produced to circumvent new laws. This rapidly changing environment, 81 new substances were identified in 2013 alone, has led to confusion for clinicians, psychopharmacologists, and the public at large. Our difficulties in keeping up with the process has had a two-fold negative effect: the danger of ignoring what is confusing; and the problem that some of the newer synthesized compounds appear ever more potent. This review aims to circumscribe a quick moving and growing field, and to categorize NPS into five major groups based upon their 'parent' compounds: stimulants similar to cocaine, amphetamines and ecstasy; cannabinoids; benzodiazepine based drugs; dissociatives similar to ketamine and phencyclidine (PCP); and those modelled after classic hallucinogens such as LSD and psilocybin. Pharmacodynamic actions, subjective and physical effects, harmfulness, risk of dependency and, where appropriate, putative clinical potentials are described for each class. Clinicians might encounter NPS in various ways: anecdotal reportage; acute intoxication; as part of a substance misuse profile; and as a precipitant or perpetuating factor for longer-term physical and psychological ill health. Current data are overall limited, and much of our knowledge and treatment strategies are based upon those of the 'parent' compound. There is a critical need for more research in this field, and for professionals to make themselves more aware of this growing issue and how it might affect those we see clinically and try to help: a brave new world of so-called 'psychonauts' consuming NPS will also need informed 'psychotherapeutonauts'. The paper should serve as a primer for clinicians and interested readers, as well as provide a framework into which to place the new substances that will inevitably be synthesized in the future.


Trauma care in India: A review of the literature.
We reviewed the published literature related to prehospital and hospital trauma care in India to identify how trauma care is defined in the literature and what factors limit the delivery of appropriate trauma care. In summarizing the evidence and recommendations regarding trauma care, this review identifies essential research and development goals to address the burden of injury in India. A review of the literature was conducted between August 2014 and September 2014. The literature was sorted into 3 categories: prehospital care, hospital clinical care, and hospital administrative care. The characteristics of trauma care were explored using the Essential Trauma Care Project of the World Health Organization. A total of 38 studies were included. Prehospital care lacked care provided at the scene of the injury, timely transport to a hospital, and transport via ambulance. With regard to hospital care, we found a lack of capabilities of basic clinical care, such as airway management, insertion of chest tubes, and efforts at resuscitation. There was a lack of administrative capabilities, including trauma data systems, trauma-specific training, quality improvement, and development of designated trauma teams. The high rate of injury-related deaths and disabilities in India could be in part due to the absence of integrated and organized systems of trauma care. In the prehospital setting, a multisector approach must be implemented to address the training of emergency medical service providers and community members. Prehospital transport time can be decreased through improved communication and transport modalities. The Indian trauma care system could also be strengthened through hospital-based training programs and trauma response teams.


The prevalence of dementia and depression in the elderly community in a southern European population. The Zaragoza study.
Provocative international disparities reported in the prevalence rates of dementia and depression require further investigation. This is the first psychiatric study, to the best of our knowledge, about the prevalence of DSM-III-R dementing and depressive disorders and their relationships in a representative, stratified community sample of the elderly in both a Spanish-speaking country and southern Europe. A two-stage screening was completed in 1080 elderly. Sampling with replacement was done, and the cumulative response rate was 88%. In phase 1, lay interviewers administered the Spanish versions of the Mini-Mental State examination and the Geriatric Mental State Schedule-Automated Geriatric Examination for Computer Assisted Taxonomy package. In phase 2, research psychiatrists administered the same instruments and the History and Aetiology Schedule to all the probable cases and a similar number of randomly selected, probably normal subjects. An estimated 5.5% of the elderly were considered to have a dementing disorder, the most prevalent types being primary degenerative dementia, Alzheimer's type (4.3%), and multi-infarct dementia (0.6%). Depressive disorders were found in 4.8% of the elderly. Psychiatric morbidity, specifically depression, was associated with lower educational levels. "Case levels" of depression were documented in 25.4% of the demented cases and case levels of "organic" disturbance were seen in 18.2% of cases of major depression. Among the elderly, the prevalence of Alzheimer's disease and multi-infarct dementia, as opposed to depression, increases steeply with age. The overlap found between dementia and depression may have nosological implications. There could be an effect of lower education levels on psychiatric morbidity, particularly on depression.


Integrated nanozymes: facile preparation and biomedical applications.
Nanozymes have been viewed as the next generation of artificial enzymes due to their low cost, large specific surface area, and good robustness under extreme conditions. However, the moderate activity and limited selectivity of nanozymes have impeded their usage. To overcome these shortcomings, integrated nanozymes (INAzymes) have been developed by encapsulating two or more different biocatalysts (e.g., natural oxidases and peroxidase mimics) together within confined frameworks. On the one hand, with the assistance of natural enzymes, INAzymes are capable of specifically recognizing targets. On the other hand, nanoscale confinement brought about by integration significantly enhances the cascade reaction efficiency. In this Feature Article, we highlight the newly developed INAzymes, covering from synthetic strategies to versatile applications in biodetection and therapeutics. Moreover, it is predicted that INAzymes with superior activities, specificity, and stability will enrich the research of nanozymes and pave new ways in designing multifunctional nanozymes.


[Mental disorders among immigrants in Chile].
Chile is receiving immigrant populations coming from other Latin-American countries. To determine the prevalence of Common Mental Disorders (CMD) among immigrants who live in Independencia, a quarter in Santiago, Chile. A cross sectional study was carried out in the primary health care clinic and in the state-funded school of Independencia. A representative sample of 282 adults and 341 children were interviewed. Mental disorders were diagnosed using CIS-R and MINI structured interviews. The interviewed immigrants came mostly from Peru. The prevalence of mental disorders in the adult population was 17.8% and among children, it was 29.3%. The adult immigrants have a lower prevalence of mental disorders than the Chilean population but it increases among children. Barriers of access to health services, that should be solved, were detected.


Novel treatment for lithium-induced nephrogenic diabetes insipidus rat model using the Sendai-virus vector carrying aquaporin 2 gene.
Congenital nephrogenic diabetes insipidus (NDI) is a chronic disorder involving polyuria and polydipsia that results from unresponsiveness of the renal collecting ducts to the antidiuretic hormone vasopressin. Either of the genetic defects in vasopressin V2 receptor or the water channel aquaporin 2 (AQP2) cause the disease, which interfere the water reabsorption at the epithelium of the collecting duct. An unconscious state including a perioperative situation can be life threatening because of the difficulty to regulate their water balance. The Sendai virus (SeV) vector system deleting fusion protein (F) gene (SeV/DeltaF) is considered most suitable because of the short replication cycle and nontransmissible character. An animal model for NDI with reduced AQP2 by lithium chloride was used to develop the therapy. When the SeV/DeltaF vector carrying a human AQP2 gene (AQP2-SeV/DeltaF) was administered retrogradely via ureter to renal pelvis, AQP2 was expressed in the renal collecting duct to reduce urine output and water intake by up to 40%. In combination with the retorograde administration to pelvis, this system could be the cornerstone for the applicable therapies on not only NDI patients but also other diseases associate with the medullary collecting duct.


Do medical homes increase medication adherence for persons with multiple chronic conditions?
Medications are an integral component of management for many chronic conditions, and suboptimal adherence limits medication effectiveness among persons with multiple chronic conditions (MCC). Medical homes may provide a mechanism for increasing adherence among persons with MCC, thereby enhancing management of chronic conditions. To examine the association between medical home enrollment and adherence to newly initiated medications among Medicaid enrollees with MCC. Retrospective cohort study comparing Community Care of North Carolina medical home enrollees to nonenrollees using merged North Carolina Medicaid claims data (fiscal years 2008-2010). Among North Carolina Medicaid-enrolled adults with MCC, we created separate longitudinal cohorts of new users of antidepressants (N=9303), antihypertensive agents (N=12,595), oral diabetic agents (N=6409), and statins (N=9263). Outcomes were the proportion of days covered (PDC) on treatment medication each month for 12 months and a dichotomous measure of adherence (PDC>0.80). Our primary analysis utilized person-level fixed effects models. Sensitivity analyses included propensity score and person-level random-effect models. Compared with nonenrollees, medical home enrollees exhibited higher PDC by 4.7, 6.0, 4.8, and 5.1 percentage points for depression, hypertension, diabetes, and hyperlipidemia, respectively (P's<0.001). The dichotomous adherence measure showed similar increases, with absolute differences of 4.1, 4.5, 3.5, and 4.6 percentage points, respectively (P's<0.001). Among Medicaid enrollees with MCC, adherence to new medications is greater for those enrolled in medical homes.


Regulation of ubiquitin-proteasome system mediated degradation by cytosolic stress.
ER-associated, ubiquitin-proteasome system (UPS)-mediated degradation of the wild-type (WT) gap junction protein connexin32 (Cx32) is inhibited by mild forms of cytosolic stress at a step before its dislocation into the cytosol. We show that the same conditions (a 30-min, 42 degrees C heat shock or oxidative stress induced by arsenite) also reduce the endoplasmic reticulum (ER)-associated turnover of disease-causing mutants of Cx32 and the cystic fibrosis transmembrane conductance regulator (CFTR), as well as that of WT CFTR and unassembled Ig light chain. Stress-stabilized WT Cx32 and CFTR, but not the mutant/unassembled proteins examined, could traverse the secretory pathway. Heat shock also slowed the otherwise rapid UPS-mediated turnover of the cytosolic proteins myoD and GFPu, but not the degradation of an ubiquitination-independent construct (GFP-ODC) closely related to the latter. Analysis of mutant Cx32 from cells exposed to proteasome inhibitors and/or cytosolic stress indicated that stress reduces degradation at the level of substrate polyubiquitination. These findings reveal a new link between the cytosolic stress-induced heat shock response, ER-associated degradation, and polyubiquitination. Stress-denatured proteins may titer a limiting component of the ubiquitination machinery away from pre-existing UPS substrates, thereby sparing the latter from degradation.


Change and variability in East antarctic sea ice seasonality, 1979/80-2009/10.
Recent analyses have shown that significant changes have occurred in patterns of sea ice seasonality in West Antarctica since 1979, with wide-ranging climatic, biological and biogeochemical consequences. Here, we provide the first detailed report on long-term change and variability in annual timings of sea ice advance, retreat and resultant ice season duration in East Antarctica. These were calculated from satellite-derived ice concentration data for the period 1979/80 to 2009/10. The pattern of change in sea ice seasonality off East Antarctica comprises mixed signals on regional to local scales, with pockets of strongly positive and negative trends occurring in near juxtaposition in certain regions e.g., Prydz Bay. This pattern strongly reflects change and variability in different elements of the marine "icescape", including fast ice, polynyas and the marginal ice zone. A trend towards shorter sea-ice duration (of 1 to 3 days per annum) occurs in fairly isolated pockets in the outer pack from∼95-110°E, and in various near-coastal areas that include an area of particularly strong and persistent change near Australia's Davis Station and between the Amery and West Ice Shelves. These areas are largely associated with coastal polynyas that are important as sites of enhanced sea ice production/melt. Areas of positive trend in ice season duration are more extensive, and include an extensive zone from 160-170°E (i.e., the western Ross Sea sector) and the near-coastal zone between 40-100°E. The East Antarctic pattern is considerably more complex than the well-documented trends in West Antarctica e.g., in the Antarctic Peninsula-Bellingshausen Sea and western Ross Sea sectors.


Development and characterization of pepducins as Gs-biased allosteric agonists.
The β2-adrenergic receptor (β2AR) is a prototypical G protein-coupled receptor that mediates many hormonal responses, including cardiovascular and pulmonary function. β-Agonists used to combat hypercontractility in airway smooth muscle stimulate β2AR-dependent cAMP production that ultimately promotes airway relaxation. Chronic stimulation of the β2AR by long acting β-agonists used in the treatment of asthma can promote attenuated responsiveness to agonists and an increased frequency of fatal asthmatic attacks. β2AR desensitization to β-agonists is primarily mediated by G protein-coupled receptor kinases and β-arrestins that attenuate receptor-Gs coupling and promote β2AR internalization and degradation. A biased agonist that can selectively stimulate Gs signaling without promoting receptor interaction with G protein-coupled receptor kinases and β-arrestins should serve as an advantageous asthma therapeutic. To identify such molecules, we screened ∼50 lipidated peptides derived from the intracellular loops of the β2AR, known as pepducins. This screen revealed two classes of Gs-biased pepducins, receptor-independent and receptor-dependent, as well as several β-arrestin-biased pepducins. The receptor-independent Gs-biased pepducins operate by directly stimulating G protein activation. In contrast, receptor-dependent Gs-biased pepducins appear to stabilize a Gs-biased conformation of the β2AR that couples to Gs but does not undergo G protein-coupled receptor kinase-mediated phosphorylation or β-arrestin-mediated internalization. Functional studies in primary human airway smooth muscle cells demonstrate that Gs-biased pepducins are not subject to conventional desensitization and thus may be good candidates for the development of next generation asthma therapeutics. Our study reports the first Gs-biased activator of the β2AR and provides valuable tools for the study of β2AR function.


Pansynaptic enlargement at adult cortical connections strengthened by experience.
Behavioral experience alters the strength of neuronal connections in adult neocortex. These changes in synaptic strength are thought to be central to experience-dependent plasticity, learning, and memory. However, it is not known how changes in synaptic transmission between neurons become persistent, thereby enabling the storage of previous experience. A long-standing hypothesis is that altered synaptic strength is maintained by structural modifications to synapses. However, the extent of synaptic modifications and the changes in neurotransmission that the modifications support remain unclear. To address these questions, we recorded from pairs of synaptically connected layer 2/3 pyramidal neurons in the barrel cortex and imaged their contacts with high-resolution confocal microscopy after altering sensory experience by whisker trimming. Excitatory connections strengthened by experience exhibited larger axonal varicosities, dendritic spines, and interposed contact zones. Electron microscopy showed that contact zone size was strongly correlated with postsynaptic density area. Therefore, our findings indicate that whole synapses are larger at strengthened connections. Synaptic transmission was both stronger and more reliable following experience-dependent synapse enlargement. Hence, sensory experience modified both presynaptic and postsynaptic function. Our findings suggest that the enlargement of synaptic contacts is an integral part of long-lasting strengthening of cortical connections and, hence, of information storage in the neocortex.


Fatty acid composition in major depression: decreased omega 3 fractions in cholesteryl esters and increased C20: 4 omega 6/C20:5 omega 3 ratio in cholesteryl esters and phospholipids.
Recently, there were some reports that major depression may be accompanied by alterations in serum total cholesterol, cholesterol ester and omega 3 essential fatty acid levels and by an increased C20: 4 omega 6/C20: 5 omega 3, i.e., arachidonic acid/eicosapentaenoic, ratio. The present study aimed to examine fatty acid composition of serum cholesteryl esters and phospholipids in 36 major depressed, 14 minor depressed and 24 normal subjects. Individual saturated (e.g., C14:0; C16:0, C18:0) and unsaturated (e.g., C18:1, C18:2, C20:4) fatty acids in phospholipid and cholesteryl ester fractions were assayed and the sums of the percentages of omega 6 and omega 3, saturated, branched chain and odd chain fatty acids, monoenes as well as the ratios omega 6/omega 3 and C20:4 omega 6/C20:5 omega 3 were calculated. Major depressed subjects had significantly higher C20:4 omega 6/C20:5 omega 3 ratio in both serum cholesteryl esters and phospholipids and a significantly increased omega 6/omega 3 ratio in cholesteryl ester fraction than healthy volunteers and minor depressed subjects. Major depressed subjects had significantly lower C18:3 omega 3 in cholesteryl esters than normal controls. Major depressed subjects showed significantly lower total omega 3 polyunsaturated fatty acids in cholesteryl esters and significantly lower C20:5 omega 3 in serum cholesteryl esters and phospholipids than minor depressed subjects and healthy controls. These findings suggest an abnormal intake or metabolism of essential fatty acids in conjunction with decreased formation of cholesteryl esters in major depression.


Dynamic Coupling among Protein Binding, Sliding, and DNA Bending Revealed by Molecular Dynamics.
Protein binding to DNA changes the DNA's structure, and altered DNA structure can, in turn, modulate the dynamics of protein binding. This mutual dependency is poorly understood. Here we investigated dynamic couplings among protein binding to DNA, protein sliding on DNA, and DNA bending by applying a coarse-grained simulation method to the bacterial architectural protein HU and 14 other DNA-binding proteins. First, we verified our method by showing that the simulated HU exhibits a weak preference for A/T-rich regions of DNA and a much higher affinity for gapped and nicked DNA, consistent with biochemical experiments. The high affinity was attributed to a local DNA bend, but not the specific chemical moiety of the gap/nick. The long-time dynamic analysis revealed that HU sliding is associated with the movement of the local DNA bending site. Deciphering single sliding steps, we found the coupling between HU sliding and DNA bending is akin to neither induced-fit nor population-shift; instead they moved concomitantly. This is reminiscent of a cation transfer on DNA and can be viewed as a protein version of polaron-like sliding. Interestingly, on shorter time scales, HU paused when the DNA was highly bent at the bound position and escaped from pauses once the DNA spontaneously returned to a less bent structure. The HU sliding is largely regulated by DNA bending dynamics. With 14 other proteins, we explored the generality and versatility of the dynamic coupling and found that 6 of the 15 assayed proteins exhibit the polaron-like sliding.


Topoisomerase I activity and sensitivity to camptothecin in breast cancer-derived cells: a comparative study.
Camptothecin (CPT) and its derivatives are currently used as second- or third-line treatment for patients with endocrine-resistant breast cancer (BC). These drugs convert nuclear enzyme DNA topoisomerase I (TOP1) to a cell poison with the potential to damage DNA by increasing the half-life of TOP1-DNA cleavage complexes (TOP1cc), ultimately resulting in cell death. In small and non-randomized trials for BC, researchers have observed extensive variation in CPT response rates, ranging from 14 to 64%. This variability may be due to the absence of reliable selective parameters for patient stratification. BC cell lines may serve as feasible models for generation of functional criteria that may be used to predict drug sensitivity for patient stratification and, thus, lead to more appropriate applications of CPT in clinical trials. However, no study published to date has included a comparison of multiple relevant parameters and CPT response across cell lines corresponding to specific BC subtypes. We evaluated the levels and possible associations of seven parameters including the status of the TOP1 gene (i.e. amplification), TOP1 protein expression level, TOP1 activity and CPT susceptibility, activity of the tyrosyl-DNA phosphodiesterase 1 (TDP1), the cellular CPT response and the cellular growth rate across a representative panel of BC cell lines, which exemplifies three major BC subtypes: Luminal, HER2 and TNBC. In all BC cell lines analyzed (without regard to subtype classification), we observed a significant overall correlation between growth rate and CPT response. In cell lines derived from Luminal and HER2 subtypes, we observed a correlation between TOP1 gene copy number, TOP1 activity, and CPT response, although the data were too limited for statistical analyses. In cell lines representing Luminal and TNBC subtypes, we observed a direct correlation between TOP1 protein abundancy and levels of enzymatic activity. In all three subtypes (Luminal, HER2, and TNBC), TOP1 exhibits approximately the same susceptibility to CPT. Of the three subtypes examined, the TNBC-like cell lines exhibited the highest CPT sensitivity and were characterized by the fastest growth rate. This indicates that breast tumors belonging to the TNBC subtype, may benefit from treatment with CPT derivatives. TOP1 activity is not a marker for CPT sensitivity in breast cancer.


Why entrepreneurs don't scale.
It's well known that many executives who excel at starting businesses or projects fizzle out--in other words, they fail to "scale"--as their ventures grow. But the reasons have remained fuzzy. In this article, leadership coach John Hamm identifies four management tendencies that work for small-company or business-unit leaders but become Achilles' heels as those individuals try to run larger organizations. The first tendency is loyalty to comrades. In entrepreneurial mode, you need to lead as though you're in charge of a combat unit on the wrong side of enemy lines. But blind loyalty can become a liability in managing a complex organization. The second tendency, task orientation, is critical in driving toward a big product launch, but excessive attention to detail can cause a large organization to lose sight of its long-term goals. The third tendency, single-mindedness, is important in a visionary unleashing a revolutionary product or service on the world but can limit the company's potential as it grows. And the fourth tendency, working in isolation, is fine for the brilliant scientist focused on an ingenious idea. But it's disastrous for a leader whose expanding organization increasingly relies on many other people. Leaders who scale deal honestly with problems and quickly weed out nonperformers. They see past distractions and establish strategic priorities. They learn how to deal effectively with diverse employees, customers, and external constituencies. And, most important, they make the company's continuing health and welfare their top concern.


Direct estimate of the rate of germline mutation in a bird.
The fidelity of DNA replication together with repair mechanisms ensure that the genetic material is properly copied from one generation to another. However, on extremely rare occasions when damages to DNA or replication errors are not repaired, germline mutations can be transmitted to the next generation. Because of the rarity of these events, studying the rate at which new mutations arise across organisms has been a great challenge, especially in multicellular nonmodel organisms with large genomes. We sequenced the genomes of 11 birds from a three-generation pedigree of the collared flycatcher (Ficedula albicollis) and used highly stringent bioinformatic criteria for mutation detection and used several procedures to validate mutations, including following the stable inheritance of new mutations to subsequent generations. We identified 55 de novo mutations with a 10-fold enrichment of mutations at CpG sites and with only a modest male mutation bias. The estimated rate of mutation per site per generation was 4.6 × 10(-9), which corresponds to 2.3 × 10(-9) mutations per site per year. Compared to mammals, this is similar to mouse but about half of that reported for humans, which may be due to the higher frequency of male mutations in humans. We confirm that mutation rate scales positively with genome size and that there is a strong negative relationship between mutation rate and effective population size, in line with the drift-barrier hypothesis. Our study illustrates that it should be feasible to obtain direct estimates of the rate of mutation in essentially any organism from which family material can be obtained.


Predictors of a health promoting lifestyle in women with fibromyalgia syndrome.
The purpose of this study was to describe the health practices of women with fibromyalgia syndrome (FMS) and the predictors of an overall health promoting lifestyle in these individuals. The predictors of a health promoting lifestyle examined in this study were barriers, social support, self-efficacy, demographic characteristics and illness factors. The sample consisted of 198 women who participated in a randomised clinical trial to test the effectiveness of a health promotion intervention for women with FMS. The women in this sample engaged most frequently in health practices in the domains of interpersonal relations and spiritual growth and least frequently in the domain of physical activity. Self-efficacy and social support were significant predictors of an overall health promoting lifestyle.


Do patients with long-term side effects of cancer treatment benefit from general practitioner support? A literature review.
Alongside specialist cancer clinics, general practitioners have an important role in cancer patients' follow-up care, yet no literature summarises the nature, extent and impact of their involvement. This paper addresses this issue through a review of the literature. Studies were sourced from six academic databases - AustHealth (n = 202), CINAHL (n = 500), the Cochrane Library (reviews and trials; n = 200), Embase (n = 368), PHCRIS (n = 132) and PubMed/Medline (n = 410). Studies that focused on interventions designed for patients receiving follow-up care and reported cancer care provided by a general practitioner delivered alongside specialist care were reviewed. A total of 19 papers were identified as relevant for this review (3 randomised control trials; 4 cross-sectional, 5 cohort and 3 qualitative studies, and 3 systematic reviews). The reviewed studies indicated that providing general practitioner-led supportive interventions for post-treatment care of cancer patients is feasible and acceptable to patients. General practitioner involvement resulted in improved physical and psychosocial well-being of patients and continuity of care, especially for patients with concomitant health conditions. Involving general practitioners in post-treatment cancer care is beneficial to patients. However, proactive initiatives that encourage and facilitate patients to consult their general practitioner about their needs or symptoms of recurrence should be considered.


Constrained evolution drives limited influenza diversity.
H3N2 influenza A viruses have been widely circulating in human populations since the pandemic of 1968. A striking feature of the evolutionary development of this strain has been its 'canalized' nature, with narrow evolutionary trees dominated by long trunks with few branching, or bifurcation events and a consequent lack of standing diversity at any single point. This is puzzling, as one might expect that the strong human immune response against the virus would create an environment encouraging more diversity, not less. Previous models have used various assumptions in order to account for this finding. A new analysis published in BMC Biology suggests that this processive evolution down a single path can be recapitulated by a relatively simple model incorporating only two primary parameters - the mutation rate of the virus, and the immunological distance created by each mutation - so long as these parameters are within a particular narrow but biologically plausible range.


Jaw-opening accuracy is not affected by masseter muscle vibration in healthy men.
There is a functional integration between the jaw and neck regions with head extension-flexion movements during jaw-opening/closing tasks. We recently reported that trigeminal nociceptive input by injection of hypertonic saline into the masseter muscle altered this integrated jaw-neck function during jaw-opening/closing tasks. Thus, in jaw-opening to a predefined position, the head-neck component increased during pain. Previous studies have indicated that muscle spindle stimulation by vibration of the masseter muscle may influence jaw movement amplitudes, but the possible effect on the integrated jaw-neck function is unknown. The aim of this study was to investigate the effect of masseter muscle vibration on jaw-head movements during a continuous jaw-opening/closing task to a target position. Sixteen healthy men performed two trials without vibration (Control) and two trials with bilateral masseter muscle vibration (Vibration). Movements of the mandible and the head were registered with a wireless three-dimensional optoelectronic recording system. Differences in jaw-opening and head movement amplitudes between Control and Vibration, as well as achievement of the predefined jaw-opening target position, were analysed with Wilcoxon's matched pairs test. No significant group effects from vibration were found for jaw or head movement amplitudes, or in the achievement of the target jaw-opening position. A covariation between the jaw and head movement amplitudes was observed. The results imply a high stability for the jaw motor system in a target jaw-opening task and that this task was achieved with the head-neck and jaw working as an integrated system.


Ano1 is a better marker than c-Kit for transcript analysis of single interstitial cells of Cajal in culture.
The interstitial cells of Cajal (ICC) drive the slow wave-associated contractions in the small intestine. A commonly used marker for these cells is c-Kit, but another marker named Ano1 was recently described. This study uses single-cell RT-PCR, qPCR and immunohistochemistry to determine if Ano1 could be reliably used as a molecular marker for ICC in single-cell mRNA analysis. Here, we report on the relationship between the expression of c-Kit and Ano1 in single ICC in culture. We observed that Ano1 is expressed in more than 60% of the collected cells, whereas c-Kit is found only in 22% of the cells (n = 18). When we stained ICC primary cultures for c-KIT and ANO1 protein, we found complete co-localization in all the preparations. We propose that this difference is due to the regulation of c-Kit mRNA in culture. This regulation gives rise to low levels of its transcript, while Ano1 is expressed more prominently in culture on day 4. We also propose that Ano1 is more suitable for single-cell expression analysis as a marker for cell identity than c-Kit at the mRNA level. We hope this evidence will help to validate and increase the success of future studies characterizing single ICC expression patterns.


Fragment-guided approach to incorporating structural information into a CoMFA study: BACE-1 as an example.
Alzheimer's disease is an ultimately fatal neurodegenerative disease, and BACE-1 has become an attractive validated target for its therapy, with more than a hundred crystal structures deposited in the PDB. In the present study, we present a new methodology that integrates ligand-based methods with structural information derived from the receptor. 128 BACE-1 inhibitors recently disclosed by GlaxoSmithKline R&D were selected specifically because the crystal structures of 9 of these compounds complexed to BACE-1, as well as five closely related analogs, have been made available. A new fragment-guided approach was designed to incorporate this wealth of structural information into a CoMFA study, and the methodology was systematically compared to other popular approaches, such as docking, for generating a molecular alignment. The influence of the partial charges calculation method was also analyzed. Several consistent and predictive models are reported, including one with r (2) = 0.88, q (2) = 0.69 and r (pred) (2) = 0.72. The models obtained with the new methodology performed consistently better than those obtained by other methodologies, particularly in terms of external predictive power. The visual analyses of the contour maps in the context of the enzyme drew attention to a number of possible opportunities for the development of analogs with improved potency. These results suggest that 3D-QSAR studies may benefit from the additional structural information added by the presented methodology.


Small-intestinal transplantation.
The management of patients with intestinal failure has benefited from progress in parenteral nutrition (PN), especially home-based PN. Intestinal transplantation is therefore possible and is now, in some conditions, the logical therapeutic option. Since 1985, more than 180 small-bowel grafts have been done, involving the isolated small bowel with or without the colon (38%), the liver-small bowel (46%) or several organs (16%). Two-thirds of recipients were under 20 years of age, and indications were short-bowel syndrome (64%), severe intractable diarrhoea (13%), abdominal cancer (13%) or chronic intestinal pseudo-obstruction syndrome (8%). Of the patients, 51% survived > 2 years after the graft. Patient and graft survival depends on the type of immunosuppression, i.e. cyclosporine or FK506. The results must be interpreted carefully as they represent the first experience in numerous centres using different immunosuppressive protocols, without any randomization. The results from the largest of these centres reflect the current situation more closely. Functional grafts lead to gastrointestinal autonomy (weaning of PN) while maintaining satisfactory nutritional status and normal growth in childhood. Intestinal transplantation is theoretically indicated for all patients permanently or dependent for a long time on PN. However, as PN is generally well tolerated, even for long periods, each indication for transplantation must be carefully weighed up in terms of the iatrogenic risk and quality of life. When PN has reached its limits, especially in those associated with vascular, infectious, hepatic or metabolic complications, intestinal transplantation must be undertaken. Transplantation of the small bowel alone remains the first option, as combined liver-small bowel grafting is only indicated in the case of life-threatening progressive cirrhogenic liver disease.


Chromosome-nuclear envelope attachments affect interphase chromosome territories and entanglement.
It is well recognized that the interphase chromatin of higher eukaryotes folds into non-random configurations forming territories within the nucleus. Chromosome territories have biologically significant properties, and understanding how these properties change with time during lifetime of the cell is important. Chromosome-nuclear envelope (Chr-NE) interactions play a role in epigenetic regulation of DNA replication, repair, and transcription. However, their role in maintaining chromosome territories remains unclear. We use coarse-grained molecular dynamics simulations to study the effects of Chr-NE interactions on the dynamics of chromosomes within a model of the Drosophila melanogaster regular (non-polytene) interphase nucleus, on timescales comparable to the duration of interphase. The model simulates the dynamics of chromosomes bounded by the NE. Initially, the chromosomes in the model are prearranged in fractal-like configurations with physical parameters such as nucleus size and chromosome persistence length taken directly from experiment. Time evolution of several key observables that characterize the chromosomes is quantified during each simulation: chromosome territories, chromosome entanglement, compactness, and presence of the Rabl (polarized) chromosome arrangement. We find that Chr-NE interactions help maintain chromosome territories by slowing down and limiting, but not eliminating, chromosome entanglement on biologically relevant timescales. At the same time, Chr-NE interactions have little effect on the Rabl chromosome arrangement as well as on how chromosome compactness changes with time. These results are rationalized by simple dimensionality arguments, robust to model details. All results are robust to the simulated activity of topoisomerase, which may be present in the interphase cell nucleus. Our study demonstrates that Chr-NE attachments may help maintain chromosome territories, while slowing down and limiting chromosome entanglement on biologically relevant timescales. However, Chr-NE attachments have little effect on chromosome compactness or the Rabl chromosome arrangement.


Biomechanical analysis of gait adaptation in the nematode Caenorhabditis elegans.
To navigate different environments, an animal must be able to adapt its locomotory gait to its physical surroundings. The nematode Caenorhabditis elegans, between swimming in water and crawling on surfaces, adapts its locomotory gait to surroundings that impose approximately 10,000-fold differences in mechanical resistance. Here we investigate this feat by studying the undulatory movements of C. elegans in Newtonian fluids spanning nearly five orders of magnitude in viscosity. In these fluids, the worm undulatory gait varies continuously with changes in external load: As load increases, both wavelength and frequency of undulation decrease. We also quantify the internal viscoelastic properties of the worm's body and their role in locomotory dynamics. We incorporate muscle activity, internal load, and external load into a biomechanical model of locomotion and show that (i) muscle power is nearly constant across changes in locomotory gait, and (ii) the onset of gait adaptation occurs as external load becomes comparable to internal load. During the swimming gait, which is evoked by small external loads, muscle power is primarily devoted to bending the worm's elastic body. During the crawling gait, evoked by large external loads, comparable muscle power is used to drive the external load and the elastic body. Our results suggest that C. elegans locomotory gait continuously adapts to external mechanical load in order to maintain propulsive thrust.


Basophilic leukocytes in allergic contact dermatitis.
A variety of cell-mediated hypersensitivity reactions in experimental animals include a prominent infiltrate of basophilic leukocytes. This form of reactivity has been designated cutaneous basophil hypersensitivity and is favored when sensitization to several types of antigen is accomplished without the use of complete Freund's adjuvant. A similar type of hypersensitivity response was sought in man using morphologic techniques which permit identification of basophilic leukocytes. Eight individuals with allergic contact dermatitis to a variety of allergens were studied and six of these developed typical contact reactions with erythema, edema, and epidermal vesicles. The microscopic findings in 3-day biopsies from these individuals differed significantly from classic descriptions of tuberculin hypersensitivity and showed, in addition to mononuclear cells and the characteristic epidermal changes, a substantial infiltrate of basophilic leukocytes and evidence of altered vascular permeability with vascular compaction, dermal edema, and fibrin deposition. Serial biopsies from one individual permitted analysis of the microscopic pathology as it unfolded at successive intervals after patch test. The initial lesion consisted of perivascular accumulations of lymphocytes; this was followed by an influx of basophils and, subsequently, of eosinophils. These findings associate contact allergy in man with the parallel reactions of cutaneous basophil hypersensitivity in animals and provide further evidence for the heterogeneity of the cellular immune response. The data are consistent with the hypothesis that interaction between sensitized lymphocytes and antigen, at a local test site, is responsible for the attraction of basophils. They also directly implicate the clotting system in delayed-type reactions and suggest the possibility of a synergistic relationship between cellular immunity and reactions mediated by basophil-bound, homocytotrophic antibody.


The Effects of Aloe Vera on TNF-a Levels, the Percentage of Nk Cells and Th 17 Cells in Rat That Received Izoniazid and Rifampycin.
The present study was undertaken to investigate the hepatoprotective effect of Aloe vera against side effect of antituberculosis drug. Twenty-five rats will be divided into five groups, namely the control group (without any treatment), the group of rats treated with anti-tuberculosis drugs, and a group of rats were treated antituberculosis drugs and got Aloe vera extract at a dose of 40; 80; and 120 mg/kg body weight. Antituberculosis drugs are isoniazid and rifampicin a dose of 50 mg/kg body weight. Antituberculosis treated group showed significantly increase levels of TNF-a, the percentage of NK cells and the number of Th17 cells compared with the control group (p < 0.05). All doses of Aloe vera reduce levels of TNF-a compared with the antituberculosis group (p < 0.05), although it has not yet reached levels comparable to the control group (p > 0.05). Aloe vera at first and the third dose lower the number of NK cells compared to the antituberculosis group, although it has not yet reached a significant difference (p > 0.05). The first dose of Aloe vera was significantly decreased the percentage of Th17 cells compared to the antituberculosis drug group (p < 0.05), although it has not yet reached levels comparable to the control group (p > 0.05). It was concluded that administration of Aloe vera can suppress the production of TNF-a and the percentage of Th17 cells as a result of antituberculosis drug administration. Thus, Aloe vera can be a useful alternative to natural materials in the successful treatment of tuberculosis through the inhibition of side effect.


Impact of Adrenal Steroids on Regulation of Adipose Tissue.
Corticosteroids are secreted by the adrenal glands and control the functions of adipose tissue via the activation of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). In turn, adipocytes release a large variety of adipokines into the bloodstream, regulating the function of several organs and tissues, including the adrenal glands, hereby controlling corticosteroid production. In adipose tissue, the activation of the MR by glucocorticoids (GC) and aldosterone affects important processes such as adipocyte differentiation, oxidative stress, autophagic flux, adipokine expression as well as local production of GC through upregulation of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Notably, the proinflammatory responses induced by the MR are counteracted by activation of the GR, whose activity inhibits the expression of inflammatory adipokines. Both GR and MR are deeply involved in adipogenesis and adipose expansion; hence pharmacological blockade of these two receptors has proven effective against adipose tissue dysfunction in experimental models of obesity and metabolic syndrome (MetS), suggesting a potential use for MR and GR antagonists in these clinical settings. Importantly, obesity and Cushing's syndrome (CS) share metabolic similarities and are characterized by high levels of circulating corticosteroids, which in turn are able to deeply affect adipose tissue. In addition, pharmacological approaches aimed at reducing aldosterone and GC levels, by means of the inhibition of CYP11B2 (aldosterone synthase) or 11β-HSD1, represent alternative strategies to counter the detrimental effects of excessive levels of corticosteroids, which are often observed in obesity and, more general, in MetS. © 2017 American Physiological Society. Compr Physiol 7:1425-1447, 2017.


The structure of the Myo4p globular tail and its function in ASH1 mRNA localization.
Type V myosin (MyoV)-dependent transport of cargo is an essential process in eukaryotes. Studies on yeast and vertebrate MyoV showed that their globular tails mediate binding to the cargo complexes. In Saccharomyces cerevisiae, the MyoV motor Myo4p interacts with She3p to localize asymmetric synthesis of HO 1 (ASH1) mRNA into the bud of dividing cells. A recent study showed that localization of GFP-MS2-tethered ASH1 particles does not require the Myo4p globular tail, challenging the supposed role of this domain. We assessed ASH1 mRNA and Myo4p distribution more directly and found that their localization is impaired in cells expressing globular tail-lacking Myo4p. In vitro studies further show that the globular tail together with a more N-terminal linker region is required for efficient She3p binding. We also determined the x-ray structure of the Myo4p globular tail and identify a conserved surface patch important for She3p binding. The structure shows pronounced similarities to membrane-tethering complexes and indicates that Myo4p may not undergo auto-inhibition of its motor domain.


Normothermic machine perfusion of the kidney.
Normothermic machine perfusion (NMP) is a preservation method that is generating increasing interest. The aim of this review is to summarise the current status of NMP in regards of kidney viability assessment, reducing organ damage and improving transplant logistics. The results of recent large animal experiments and clinical trials show that continuous prolonged normothermic ex-vivo kidney perfusion appears better than a brief period of NMP after static cold storage in terms of renal injury and function. A recently developed clinical scoring system appears to correlate with renal and tubular function. A prospective clinical phase II trial to investigate the initial graft function after 1 h of NMP or static cold storage in kidneys from donors after circulatory death has been initiated in the United Kingdom. Progress has been made in normothermic kidney perfusion, mainly in experimental settings. These results need to be translated into clinical trials to evaluate long-term NMP and its impact in human organs. Future investigations of optimal perfusion parameters are needed.


Functional role of GTPase-activating protein in cell transformation by pp60v-src.
Morphological transformation of NIH 3T3 cells was observed following coexpression of a portion of the ras GTPase-activating protein (GAP) comprising the amino terminus (GAP-N) and a mutant of v-src (MDSRC) lacking the membrane-localizing sequence. Cells expressing either of these genes alone remained nontransformed. Coexpression of GAP-N with MDSRC did not alter the subcellular localization, kinase activity, or pattern of cellular substrates phosphorylated by the MDSRC product. In contrast to SHC, phospholipase C-gamma 1, and the p85 alpha phosphatidylinositol 3'-kinase subunit, the endogenous GAP product (p120GAP) was highly tyrosine-phosphorylated only in cells transformed by wild-type v-src. Furthermore, for transformation induced by wild-type v-src as well as by coexpression of MDSRC and GAP-N, a strict correlation was observed between cell transformation, elevated tyrosine phosphorylation of p62, p190, and a novel protein of 150 kDa, and complex formation between these proteins and p120GAP. As with cells transformed by wild-type v-src, the MDSRC plus GAP-N transformants remained dependent on endogenous Ras. The results suggest that tyrosine phosphorylation and complex formation involving p120GAP represent critical elements of cell transformation by v-src and that complementation of the cytosolic v-src mutant by GAP-N results, at least in part, from the formation of these complexes.


Occurrence of Tetracampos ciliotheca and Proteocephalus glanduligerus in Clarias gariepinus (Burchell, 1822) collected from the Vaal Dam, South Africa.
Cestodes are parasitic flatworms that live in the digestive tract of vertebrates as adults and often in the liver, muscle, haemocoel, mesentery and brain of various animals as larval stages. To identify the cestodes infecting Clarias gariepinus Burchell, 1822 (sharptooth catfish) in the Vaal Dam, a total of 45 host specimens were collected with the aid of gill nets between October 2011, January and April 2012. The fish were sacrificed and examined for cestode parasites. Two adult cestodes, Tetracampos ciliotheca Wedl, 1861 (prevalence 86.7%, mean intensity = 15, n = 45) and Proteocephalus glanduligerus (Janicki, 1928) (prevalence 51.1%, mean intensity = 5, n = 45) were found in the intestines of the catfish. Both T. ciliotheca and P. glanduligerus are new locality records. There were statistically insignificant differences in the infection of the male and female C. gariepinu. Fish with standard length ranging from 40 cm - 54 cm (≥ 3 years) had the highest prevalence and mean intensity while those ranging from 10 cm - 24 cm (< 1 year) had the lowest prevalence and mean intensity for both cestodes. The study highlights the importance of changing feeding habits of C. gariepinus with age on the prevalence and mean intensity of the two gastrointestinal cestode parasites.


SU-E-T-419: MU Verification for Small Lesions in Lung SBRT.
To determine if a secondary MU calculation can validate the treatment planning system MU calculation for objects less than 4cm in diameter in small field lung SBRT. To determine the small object modifier to better predict the correct MU. Four polystyrene spheres were embedded into lung mimicking material. The sphere diameters are 4cm, 3cm, 2cm, and 1.2cm. The spheres are made up of two dome TLD-100 chip holders. Each TLD holder holds two 0.125' square × 0.035' TLDs. The output (cGy/MU) was measured at the center of each sphere for three depth and effective depth combinations. The depth, effective depth, field size, and energy were kept constant. The effective depth was kept constant by adding tissue equivalent water to the top of the phantom as the sphere diameter got smaller. The three depths were 5cm, 10cm, and 15cm, with an effective depth of 5cm, 6cm, and 7cm, respectively. The collimator field size and the effective field size was 3cm × 3cm. The energy was 6MV. The measured results were compared with the output predicted by our treatment planning system. Dose measurements were made with both TLD and film and the results were averaged. The secondary MU calculation predicted that the output would be the same for each sphere. However, the measured output dropped as the sphere diameter got smaller, especially for the 1.2cm diameter sphere. The output dropped by 5% at a 10cm depth and by 9% at a depth of 15cm. Secondary MU calculations cannot reliably predict the MU's for small objects less than 3cm in diameter without modifiers. A modifier of 3% is needed for a 2cm sphere and 7% for a 1.2cm diameter sphere.


Adipose tissue cellularity and muscle growth in young steers fed the beta-adrenergic agonist clenbuterol for 50 days and after 78 days of withdrawal.
Angus steers (n = 40; approximate weight = 300 kg) were administered the beta-adrenergic agonist clenbuterol for 50 d (7 mg.hd-1.d-1), followed by a 78-d withdrawal period. Carcass fatness variables did not differ (P greater than .05) between treated and control animals either after 50 d or after 128 d. Weights of the 9-10-11th rib longissimus muscle were 25% larger, and longissimus cross-sectional areas were 28% greater, in clenbuterol-fed steers relative to controls from 0 to 50 d (P less than .05). After withdrawal these measurements increased no further in the treated steers. Marbling scores were decreased (P less than .05) in clenbuterol-fed steers after 50 d of treatment; this effect persisted after 128 d of withdrawal from treatment. Shear force values were increased 19% (P less than .05) by feeding clenbuterol for 50 d and remained greater (P less than .05) in treated animals after 128 d. Subcutaneous adipocytes in clenbuterol-fed steers were smaller (P less than .05) than those of controls after 50 d, and this effect was still apparent after the 78-d withdrawal period. Rates of lipogenesis did not differ (P less than .05) between treated and control animals at any time. Perirenal (p.r.) adipocytes were smaller (P less than .05) in treated animals after 50 d, but this effect disappeared by the end of the experiment. There was no indication of a bimodal distribution of smaller s.c. or p.r. adipocytes in either of the treatment groups. Apparent hyperplasia of s.c. adipocytes occurred in the area of the 9-10-11th rib in both treated (P less than .10) and control animals (P less than .05) from 0 to 50 d on trial. Within treated animals there was a significant increase (P less than .05) in total adipocytes in this depot during the withdrawal period. Although the effects of clenbuterol on muscle growth generally were reversed after 78 d, the effects of the beta-adrenergic agonist on adipose tissue development were more permanent.


Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity.
Amyotrophic lateral sclerosis is a progressive neurologic disorder that commonly results in paralysis and death. Despite more than a century of research, no cause of, cure for, or means of preventing this disorder has been found. In a minority of cases, it is familial and inherited as an autosomal dominant trait with age-dependent penetrance. In contrast to the sporadic form of amyotrophic lateral sclerosis, the familial form provides the opportunity to use molecular genetic techniques to localize an inherited defect. Furthermore, such studies have the potential to discover the basic molecular defect causing motor-neuron degeneration. We evaluated 23 families with familial amyotrophic lateral sclerosis for linkage of the gene causing this disease to four DNA markers on the long arm of chromosome 21. Multipoint linkage analyses demonstrated linkage between the gene and these markers. The maximum lod score--5.03--was obtained 10 centimorgans distal (telomeric) to the DNA marker D21S58. There was a significant probability (P less than 0.0001) of genetic-locus heterogeneity in the families. The localization of a gene causing familial amyotrophic lateral sclerosis provides a means of isolating this gene and studying its function. Insight gained from understanding the function of this gene may be applicable to the design of rational therapy for both the familial and sporadic forms of the disease.


Visualizing early splenic memory CD8+ T cells reactivation against intracellular bacteria in the mouse.
Memory CD8(+) T cells represent an important effector arm of the immune response in maintaining long-lived protective immunity against viruses and some intracellular bacteria such as Listeria monocytogenes (L.m). Memory CD8(+) T cells are endowed with enhanced antimicrobial effector functions that perfectly tail them to rapidly eradicate invading pathogens. It is largely accepted that these functions are sufficient to explain how memory CD8(+) T cells can mediate rapid protection. However, it is important to point out that such improved functional features would be useless if memory cells were unable to rapidly find the pathogen loaded/infected cells within the infected organ. Growing evidences suggest that the anatomy of secondary lymphoid organs (SLOs) fosters the cellular interactions required to initiate naive adaptive immune responses. However, very little is known on how the SLOs structures regulate memory immune responses. Using Listeria monocytogenes (L.m) as a murine infection model and imaging techniques, we have investigated if and how the architecture of the spleen plays a role in the reactivation of memory CD8(+) T cells and the subsequent control of L.m growth. We observed that in the mouse, memory CD8(+) T cells start to control L.m burden 6 hours after the challenge infection. At this very early time point, L.m-specific and non-specific memory CD8(+) T cells localize in the splenic red pulp and form clusters around L.m infected cells while naïve CD8(+) T cells remain in the white pulp. Within these clusters that only last few hours, memory CD8(+) T produce inflammatory cytokines such as IFN-gamma and CCL3 nearby infected myeloid cells known to be crucial for L.m killing. Altogether, we describe how memory CD8(+) T cells trafficking properties and the splenic micro-anatomy conjugate to create a spatio-temporal window during which memory CD8(+) T cells provide a local response by secreting effector molecules around infected cells.


Successful obliteration of a ruptured partially thrombosed giant m1 fusiform aneurysm with coil embolization at distal m1 after extracranial-intracranial bypass.
Proximal occlusion or trapping combined with EC-IC bypass is usually employed as a definite treatment for a giant fusiform aneurysm in cases where it is impossible to apply clips and do vascular reconstruction. Endovascular treatment is very important as an alternative or combined technique if direct surgery is impossible. The authors report a young male who presented with a 2 nd episode of intracranial bleeding in basal ganglion and subarachnoid hemorrhage with mild right hemiparesis. His 3D-CT scan revealed left ruptured partially thrombosed giant M1 fusiform aneurysm and left unruptured C3 saccular aneurysm. He underwent STA-MCA bypass with attempted M1 reconstruction and a week later attempted total occlusion of the M1 aneurysm with coils. But only a ruptured point at the distal M1 was occluded which, however, resulted in temporary mild right hemiparesis and aphasia. A month later when he was supposed to have his 2 nd coiling procedure his angiogram demonstrated spontaneous and complete obliteration of both the M1 and C3 aneurysms without any new neurological deficit, so no further endovascular procedure was attempted. The discussion is based on this case and previous reports regarding difficult giant M1 fusiform aneurysms, its treatment and spontaneous thrombosis of aneurysmal sac after bypass and distal occlusion. Conclusions are drawn that 1) spontaneous thrombosis of M1 and C3 aneurysms should be the result of hemodynamic alteration in both aneurysms due to a lower flow velocity induced by distal bypass and distal occlusion of M1, 2) combined distal bypass and endovascular obliteration of the aneurysmal sac with coils is a good alternative if vascular reconstruction is difficult or impossible.


Appearance of macrophage migration inhibition factor in patients with systemic reactions to bee venom.
Cellular responses in bee venom (BV) allergy is a controversial issue. Previous studies could not reach an agreement whether this mechanism is activated as a result of allergic sensitization to bee venom. All previous works have used lymphocyte proliferation as their method to analyze cell-mediated immunity. In the present work, we tried to explore whether the production of macrophage migration inhibition factor (MIF), which is another in vitro correlate with cellular responses, is increased in these patients. We also examined which of the major antigenic components of BV played a significant role in the cellular response. Peripheral blood lymphocytes from 10 patients with systemic allergic reactions to bee sting and 9 healthy volunteers were examined for their ability to induce positive MIF responses. Macrophage inhibition was significantly increased in allergic patients when tested with BV, phospholipase A2 (PLA2) and with melittin. Positive MIF responses to other components were also more common in allergic patients than in the control group. Our results indicate that cellular response to BV is expressed in patients with systemic allergic reaction to BV. When major antigenic components of BV are examined, PLA2 seems to play the major role in inducing this response.


Heterochromatin-Enriched Assemblies Reveal the Sequence and Organization of the Drosophila melanogaster Y Chromosome.
Heterochromatic regions of the genome are repeat-rich and poor in protein coding genes, and are therefore underrepresented in even the best genome assemblies. One of the most difficult regions of the genome to assemble are sex-limited chromosomes. The Drosophila melanogaster Y chromosome is entirely heterochromatic, yet has wide-ranging effects on male fertility, fitness, and genome-wide gene expression. The genetic basis of this phenotypic variation is difficult to study, in part because we do not know the detailed organization of the Y chromosome. To study Y chromosome organization in D. melanogaster, we develop an assembly strategy involving the in silico enrichment of heterochromatic long single-molecule reads and use these reads to create targeted de novo assemblies of heterochromatic sequences. We assigned contigs to the Y chromosome using Illumina reads to identify male-specific sequences. Our pipeline extends the D. melanogaster reference genome by 11.9 Mb, closes 43.8% of the gaps, and improves overall contiguity. The addition of 10.6 MB of Y-linked sequence permitted us to study the organization of repeats and genes along the Y chromosome. We detected a high rate of duplication to the pericentric regions of the Y chromosome from other regions in the genome. Most of these duplicated genes exist in multiple copies. We detail the evolutionary history of one sex-linked gene family, crystal-Stellate While the Y chromosome does not undergo crossing over, we observed high gene conversion rates within and between members of the crystal-Stellate gene family, Su(Ste), and PCKR, compared to genome-wide estimates. Our results suggest that gene conversion and gene duplication play an important role in the evolution of Y-linked genes.


Intracortical neural activity distal to seizure-onset-areas predicts human focal seizures.
The apparent unpredictability of epileptic seizures has a major impact in the quality of life of people with pharmacologically resistant seizures. Here, we present initial results and a proof-of-concept of how focal seizures can be predicted early in advance based on intracortical signals recorded from small neocortical patches away from identified seizure onset areas. We show that machine learning algorithms can discriminate between interictal and preictal periods based on multiunit activity (i.e. thresholded action potential counts) and multi-frequency band local field potentials recorded via 4 X 4 mm2 microelectrode arrays. Microelectrode arrays were implanted in 5 patients undergoing neuromonitoring for resective surgery. Post-implant analysis revealed arrays were outside the seizure onset areas. Preictal periods were defined as the 1-hour period leading to a seizure. A 5-minute gap between the preictal period and the putative seizure onset was enforced to account for potential errors in the determination of actual seizure onset times. We used extreme gradient boosting and long short-term memory networks for prediction. Prediction accuracy based on the area under the receiver operating characteristic curves reached 90% for at least one feature type in each patient. Importantly, successful prediction could be achieved based exclusively on multiunit activity. This result indicates that preictal activity in the recorded neocortical patches involved not only subthreshold postsynaptic potentials, perhaps driven by the distal seizure onset areas, but also neuronal spiking in distal recurrent neocortical networks. Beyond the commonly identified seizure onset areas, our findings point to the engagement of large-scale neuronal networks in the neural dynamics building up toward a seizure. Our initial results obtained on currently available human intracortical microelectrode array recordings warrant new studies on larger datasets, and open new perspectives for seizure prediction and control by emphasizing the contribution of multiscale neural signals in large-scale neuronal networks.


Efficacy and safety of corticosteroids in COVID-19 based on evidence for COVID-19, other coronavirus infections, influenza, community-acquired pneumonia and acute respiratory distress syndrome: a systematic review and meta-analysis.
Very little direct evidence exists on use of corticosteroids in patients with coronavirus disease 2019 (COVID-19). Indirect evidence from related conditions must therefore inform inferences regarding benefits and harms. To support a guideline for managing COVID-19, we conducted systematic reviews examining the impact of corticosteroids in COVID-19 and related severe acute respiratory illnesses. We searched standard international and Chinese biomedical literature databases and prepublication sources for randomized controlled trials (RCTs) and observational studies comparing corticosteroids versus no corticosteroids in patients with COVID-19, severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS). For acute respiratory distress syndrome (ARDS), influenza and community-acquired pneumonia (CAP), we updated the most recent rigorous systematic review. We conducted random-effects meta-analyses to pool relative risks and then used baseline risk in patients with COVID-19 to generate absolute effects. In ARDS, according to 1 small cohort study in patients with COVID-19 and 7 RCTs in non-COVID-19 populations (risk ratio [RR] 0.72, 95% confidence interval [CI] 0.55 to 0.93, mean difference 17.3% fewer; low-quality evidence), corticosteroids may reduce mortality. In patients with severe COVID-19 but without ARDS, direct evidence from 2 observational studies provided very low-quality evidence of an increase in mortality with corticosteroids (hazard ratio [HR] 2.30, 95% CI 1.00 to 5.29, mean difference 11.9% more), as did observational data from influenza studies. Observational data from SARS and MERS studies provided very low-quality evidence of a small or no reduction in mortality. Randomized controlled trials in CAP suggest that corticosteroids may reduce mortality (RR 0.70, 95% CI 0.50 to 0.98, 3.1% lower; very low-quality evidence), and may increase hyperglycemia. Corticosteroids may reduce mortality for patients with COVID-19 and ARDS. For patients with severe COVID-19 but without ARDS, evidence regarding benefit from different bodies of evidence is inconsistent and of very low quality.


WeCareAdvisor™: The Development of a Caregiver-focused, Web-based Program to Assess and Manage Behavioral and Psychological Symptoms of Dementia.
Behavioral and psychological symptoms of dementia (BPSD) are nearly universal in dementia and associated with multiple negative outcomes. Current real-world management is largely pharmacologic, despite poor risk/benefit. The WeCareAdvisor was designed to enable family caregivers to assess, manage, and track BPSD using nonpharmacologic strategies. In-depth qualitative data were collected from family caregivers of people with dementia to inform: (1) style of approach and "look and feel" of the tool, and (2) the types of psychoeducation most needed by caregivers. We conducted 4 focus groups and a technology survey (n=26) as well as additional individual semistructured interviews (n=12) with family caregivers. Main themes of the qualitative work included: (1) need to minimize difficulty and training time; (2) importance of "one-stop shopping" for information; and (3) necessity for information to be tailored to the caregiver and person with dementia. This information was then combined with effective existing evidence-based behavioral strategies to create a web-based tailored caregiver-support tool. The WeCareAdvisor was designed with input on functionality and content by end-users, family caregivers. The randomized controlled trial of WeCareAdvisor will test whether the tool improves outcomes including caregiver upset and burden and frequency and severity of BPSD.


Evidence for laser cooling in a magnesium atomic beam.
Laser cooling in a Mg atomic beam is reported for the first time to our knowledge. Previous cooling experiments were performed by using visible or infrared lasers. The Mg atoms were cooled by using an intracavity frequency-doubled dye laser at 285 nm to reach the resonant (1)S(0)-(1)P(1) transition. Evidence of laser cooling was obtained even with the limited available laser power ( approximately 1-2 mW).


Role of solvent properties of water in crowding effects induced by macromolecular agents and osmolytes.
Solvent properties of water in aqueous solutions of polyethylene glycols of various molecular weights, l-proline, betaine, and a series of chlorides of varied concentrations are assayed using three solvatochromic dyes. The properties include solvent dipolarity/polarizability, hydrogen bond donor acidity, and hydrogen bond acceptor basicity. These properties are also evaluated in mixtures of two polymers, polymer and osmolyte, and two osmolytes. It is shown that linear combinations of solvent dipolarity/polarizability and hydrogen bond donor acidity assayed in individual solutions of crowders strongly correlate with the effects of the crowders on the stability of various proteins and nucleic acids reported in the literature. The solvent properties of water in aqueous mixtures of two macromolecular crowders, two osmolytes, or mixtures of an osmolyte and a macromolecular crowder vary differently for various solvent properties. The overall effects of the two components in the mixture on a given solvent property of water may be additive, reduced or enhanced depending on the particular composition of the mixture. It is hypothesized that changes in the solvent properties of water are related to changes in the water hydrogen-bonding structuring. It is suggested that the observed crowder-induced changes in the solvent properties of water should be taken into account in theoretical considerations of crowding effects in biological systems.


Mitochondrial DNA analyses and the origin and relative age of parthenogenetic lizards (genus Cnemidophorus).
Morphological, karyological, and allozyme analyses indicate that the parthenogenetic lizards Cnemidophorus neomexicanus and diploid C. tesselatus are hybrids formed, respectively, by crosses involving the bisexual species C. tigris and C. inornatus, and C. tigris and C. septemvittatus. Mitochondrial DNA, which is inherited maternally, was obtained from each of these species. Analyses of the mitochondrial DNA's and their restriction endonuclease digestion products by electron microscopy and agarose gel electrophoresis support the hybridization hypothesis by indicating that C. tigris (specifically the subspecies marmoratus) was the maternal parent species for both C. neomexicanus and C. tesselatus. Furthermore, these data imply that these two parthenogenetic species are younger than some races of C. tigris.


Nursing the statistics: a demonstration study of nurse turnover and retention.
This paper demonstrates how a health authority can use personnel records of nurses' working histories as an effective tool in manpower planning. Suggestions are given as to how these histories might be analysed and interpreted. Methods described range from the use of simple summary statistics and graphical methods to advanced statistical modelling techniques. Data from a study by researchers at the Centre for Applied Statistics and Department of Sociology at Lancaster University are used to give examples of these approaches. A description is also given of the practical difficulties experienced when attempting to extract the appropriate data from the health authority's personnel records.


Leptin potentiates astrogenesis in the developing hypothalamus.
The proper establishment of hypothalamic feeding circuits during early development has a profound influence on energy homeostasis, and perturbing this process could predispose individuals to obesity and its associated consequences later in life. The maturation of hypothalamic neuronal circuitry in rodents takes place during the initial postnatal weeks, and this coincides with a dramatic surge in the circulating level of leptin, which is known to regulate the outgrowth of key neuronal projections in the maturing hypothalamus. Coincidently, this early postnatal period also marks the rapid proliferation and expansion of astrocytes in the brain. Here we examined the effects of leptin on the proliferative capacity of astrocytes in the developing hypothalamus by treating postnatal mice with leptin. Mutant mice were also generated to conditionally remove leptin receptors from glial fibrillary acidic protein (GFAP)-expressing cells in the postnatal period. We show that GFAP-expressing cells in the periventricular zone of the 3rd ventricle were responsive to leptin during the initial postnatal week. Leptin enhanced the proliferation of astrocytes in the postnatal hypothalamus and conditional removal of leptin receptors from GFAP-expressing cells during early postnatal period limited astrocyte proliferation. While increasing evidence demonstrates a direct role of leptin in regulating astrocytes in the adult brain, and given the essential function of astrocytes in modulating neuronal function and connectivity, our study indicates that leptin may exert its metabolic effects, in part, by promoting hypothalamic astrogenesis during early postnatal development.


Estimating tempo and mode of Y chromosome turnover: explaining Y chromosome loss with the fragile Y hypothesis.
Chromosomal sex determination is phylogenetically widespread, having arisen independently in many lineages. Decades of theoretical work provide predictions about sex chromosome differentiation that are well supported by observations in both XY and ZW systems. However, the phylogenetic scope of previous work gives us a limited understanding of the pace of sex chromosome gain and loss and why Y or W chromosomes are more often lost in some lineages than others, creating XO or ZO systems. To gain phylogenetic breadth we therefore assembled a database of 4724 beetle species' karyotypes and found substantial variation in sex chromosome systems. We used the data to estimate rates of Y chromosome gain and loss across a phylogeny of 1126 taxa estimated from seven genes. Contrary to our initial expectations, we find that highly degenerated Y chromosomes of many members of the suborder Polyphaga are rarely lost, and that cases of Y chromosome loss are strongly associated with chiasmatic segregation during male meiosis. We propose the "fragile Y" hypothesis, that recurrent selection to reduce recombination between the X and Y chromosome leads to the evolution of a small pseudoautosomal region (PAR), which, in taxa that require XY chiasmata for proper segregation during meiosis, increases the probability of aneuploid gamete production, with Y chromosome loss. This hypothesis predicts that taxa that evolve achiasmatic segregation during male meiosis will rarely lose the Y chromosome. We discuss data from mammals, which are consistent with our prediction.


Biological assessment of abnormal genitalia.
Biological assessment of abnormal genitalia is based on an ordered sequence of endocrine and genetic investigations that are predicated on knowledge obtained from a suitable history and detailed examination of the external genital anatomy. Investigations are particularly relevant in 46,XY DSD where the diagnostic yield is less successful than in the 46,XX counterpart. Advantage should be taken of spontaneous activity of the pituitary-gonadal axis in early infancy rendering measurements of gonadotrophins and sex steroids by sensitive, validated assays key to assessing testicular function. Allied measurement of serum anti-Müllerian hormone completes a comprehensive testis profile of Leydig and Sertoli cell function. Genetic assessment is dominated by analysis of a plethora of genes that attempts to delineate a cause for gonadal dysgenesis. In essence, this is successful in up to 20% of cases from analysis of SRY and SF1 (NR5A1) genes. In contrast, gene mutation analysis is highly successful in 46,XY DSD due to defects in androgen synthesis or action. The era of next generation sequencing is increasingly being applied to investigate complex medical conditions of unknown cause, including DSD. The challenge for health professionals will lie in integrating vast amounts of genetic information with phenotypes and counselling families appropriately. How tissues respond to hormones is apposite to assessing the range of genital phenotypes that characterise DSD, particularly for syndromes associated with androgen resistance. In vitro methods are available to undertake quantitative and qualitative analysis of hormone action. The in vivo equivalent is some assessment of the degree of under-masculinisation in the male, such as an external masculinisation score, and measurement of the ano-genital distance. This anthropometric marker is effectively a postnatal readout of the effects of prenatal androgens acting during the masculinisation programming window. For investigation of the newborn with abnormal genitalia, a pragmatic approach can be taken to guide the clinician using appropriate algorithms.