Inbreeding depression in non-human primates: a historical review of methods used and empirical data.
Offspring born to related parents may show reduced fitness due to inbreeding depression. Although evidence of inbreeding depression has accumulated for a variety of taxa during the past two decades, such analyses remain rare for primate species, probably because of their long generation time. However, inbreeding can have important fitness costs and is likely to shape life-history traits in all living species. As a consequence, selection should have favored inbreeding avoidance via sex-biased dispersal, extra-group paternity, or kin discrimination. In this paper, we review empirical studies on the effects of inbreeding on fitness traits or fitness correlates in primate species. In addition, we report the methods that have been used to detect inbreeding in primate populations, and their development with the improvement of laboratory techniques. We focus particularly on the advantages and disadvantages using microsatellite loci to detect inbreeding. Although the genetic data that are typically available (partial pedigrees, use of microsatellite heterozygosity as an estimate of genomewide inbreeding) tend to impose constraints on analyses, we encourage primatologists to explore the potential effects of inbreeding if they have access to even partial pedigrees or genetic information. Such studies are important because of both the value of basic research in inbreeding depression in the wild and the conservation issues associated with inbreeding, particularly in threatened species, which include more than half of the currently living primate species.


The influence of rhythm and personality in the endurance response to motivational asynchronous music.
In this study, we examined participants' responses to motivational asynchronous music by isolating rhythmical properties and exploring personality correlates. Fifty-eight physically active participants (41 men and 17 women) aged 22.3 +/- 6.4 years performed an isometric weight-holding task on three occasions while being randomly exposed to no music, rhythm and motivational music. The rhythm and music conditions were edited portions of the same musical selection and had identical fast tempi, although the rhythm condition contained no melody, harmonies or lyrics. Participants each completed a copy of Cattell's 16PF following the third and final trial. A repeated-measures analysis of variance found the participants held the weight suspended for significantly longer when listening to motivational music in comparison to rhythm or no music. When listening to rhythm, participants endured the task for significantly longer than when listening to no music. The response to music was found to be significantly related to liveliness, while sensitivity correlated with responses to music factors (harmony, melody, lyrics, etc.) not present in the rhythm condition. These results suggest that responses to motivational music are subtle in nature and are determined by both musical factors and individual characteristics, and potentially an interaction between the two.


BrdU-positive cells in the neonatal mouse hippocampus following hypoxic-ischemic brain injury.
Mechanisms that affect recovery from fetal and neonatal hypoxic-ischemic (H-I) brain injury have not been fully elucidated. The incidence of intrapartum asphyxia is approximately 2.5%, but the occurrence of adverse clinical outcome is much lower. One of the factors which may account for this relatively good outcome is the process of neurogenesis, which has been described in adult animals. We used a neonatal mouse model to assess new cells in the hippocampus after H-I injury. Neonatal mice underwent permanent unilateral carotid ligation on the seventh postnatal day followed by exposure to 8% hypoxia for 75 minutes. The presence of new cells was determined by bromodeoxyuridine (BrdU) incorporation into cells with sacrifice of the animals at intervals. Brain sections were stained for BrdU in combination with neuronal, glial, endothelial and microglial stains. We found a significant increase in BrdU-positive cells in the neonatal mouse hippocampus in the injured area compared to the non-injured area, most prominent in the dentate gyrus (DG) (154.5 +/- 59.6 v. 92.9 +/- 32.7 at 3 days after injury; 68.9 +/- 23.4 v. 52.4 +/- 17.1 at 35 days after injury, p < 0.0011). Among the cells which showed differentiation, those which were stained as either microglial or endothelial cells showed a peak increase at three days after the injury in the DG, injured versus non-injured side (30.5 +/- 17.8 v. 2.7 +/- 2.6, p < 0.0002). As in the adult animal, neurogenesis was significantly increased in the DG with injury (15.0 +/- 4.6 v. 5.2 +/- 1.6 at 35 days after injury, p < 0.0002), and this increase was subsequent to the appearance of the other dividing cells. Numbers of new oligodendrocytes were significantly higher in the DG on the non-injured side (7.0 +/- 24.2 v. 0.1 +/- 0.3, p < 0.0002), suggesting that oligodendrocyte synthesis was reduced in the injured hippocampus. These findings demonstrate that the neonatal animal responds to brain injury with neurogenesis, much like the adult animal. In addition, H-I insult leads to more neurogenesis than hypoxia alone. This process may play a role in the recovery of the neonatal animal from H-I insult, and if so, enhancement of the process may improve recovery.


Role of PKCδ in Enhanced Expression of Gqα/PLCβ1 Proteins and VSMC Hypertrophy in Spontaneously Hypertensive Rats.
Gqα signaling has been implicated in cardiac hypertrophy. In addition, angiotensin II (Ang II) was also shown to induce its hypertrophic effect through Gqα and PKCδ activation. We recently showed the role of enhanced expression of Gqα/PLCβ1 proteins in vascular smooth muscle cell (VSMC) hypertrophy, however, the role of PKCδ in VSMC hypertrophy in animal model is still lacking. The present study was therefore undertaken to examine the role of PKCδ and the associated signaling mechanisms in VSMC hypertrophy using 16-week-old spontaneously hypertensive rats (SHR). VSMC from 16-week-old SHR exhibited enhanced phosphorylation of PKCδ-Tyr311 and increased protein synthesis, marker of hypertrophy, as compared to WKY rats which was attenuated by rottlerin, an inhibitor of PKCδ. In addition, knocking down of PKCδ by PKCδ-siRNA also attenuated enhanced protein synthesis in VSMC from SHR. Furthermore, rottlerin attenuated the increased production of superoxide anion, NAD(P)H oxidase activity, increased expression of Gqα, phospholipase C (PLC)β1, insulin like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR) proteins in VSMC from SHR. In addition, the enhanced phosphorylation of c-Src, PKCδ-Tyr311, IGF-1R, EGFR and ERK1/2 exhibited by VSMC from SHR was also attenuated by rottlerin. These results suggest that VSMC from SHR exhibit enhanced activity of PKCδ and that PKCδ is the upstream molecule of reactive oxygen species (ROS) and contributes to the enhanced expression of Gqα and PLCβ1 proteins and resultant VSMC hypertrophy involving c-Src, growth factor receptor transactivation and MAP kinase signaling.


Patterns of genetic variation in a prairie wildflower, Silphium integrifolium, suggest a non-prairie origin and locally adaptive variation.
Understanding the relationship between genetic structure and geography provides information about a species' history and can be used for breeding and conservation goals. The North American prairie is interesting because of its recent origin and subsequent fragmentation. Silphium integrifolium, an iconic perennial American prairie wildflower, is targeted for domestication, having undergone a few generations of improvement. We present the first application of population genetic data in this species to address the following goals: (1) improve breeding by characterizing genetic structure and (2) identify the species geographic origin and potential targets and drivers of selection during range expansion. We developed a reference transcriptome as a genotyping reference for samples from throughout the species range. Population genetic analyses were used to describe patterns of genetic variation, and demographic modeling was used to characterize potential processes that shaped variation. Outlier scans for selection and associations with environmental variables were used to identify loci linked to putative targets and drivers of selection. Genetic variation partitioned samples into three geographic clusters. Patterns of variation and demographic modeling suggest that the species origin is in the American Southeast. Breeding program accessions are from the region with lowest observed genetic variation. This prairie species did not originate within the prairie. Breeding may be improved by including accessions from outside of the germplasm founding region. The geographic structuring and the identified targets and drivers of adaptation can guide collecting efforts toward populations with beneficial agronomic traits.


Nonarticular tenderness and functional status in patients with diffuse idiopathic skeletal hyperostosis.
To investigate the degree of nonarticular tenderness and functional status in patients with diffuse idiopathic skeletal hyperostosis (DISH). We assessed these variables' correlation with their clinical, radiographic, and constitutional measurements and with metabolic syndrome (MS). Eighty-seven patients with DISH were compared with 65 controls without DISH. Examination of nonarticular tenderness was performed by thumb palpation. Tenderness was scored for the 18 fibromyalgia tender points (TP), and 4 control points. Nonarticular tenderness was expressed by the number of TP and by the total tenderness score (TTS). The Short Health Assessment Questionnaire (HAQ II) was administered to all participants. Clinical and laboratory data were collected from all patients. Patients were classified as having MS by both the National Cholesterol Education Program and World Health Organization definitions. There was a statistically significant difference in TTS between controls and patients with DISH. The mean tenderness of many individual TP was significantly higher in the DISH group compared with the control group. TP counts, TTS, and body mass index (BMI) positively correlated with the HAQ II. There was a linear trend in intensity of T-spine bony bridges (BB) and the total number of TP as well as many individual TP. Patients with DISH were more likely to be affected by MS. No correlation was found between TP count, TTS, and MS. Patients with DISH have a lower pain threshold than patients who do not have DISH. TP count and TTS correlate with the functional status, BMI, waist circumference, and high-grade BB. No correlation was observed between pain threshold and MS.


Assessment of liver fibrosis in the clinical setting: something is changing?
Clinical management of compensated chronic liver diseases (CLD) requires precise definition of the stage of liver fibrosis which is the key histologic predictor of progression to cirrhosis. Several methods are used to assess liver fibrosis. Among those, percutaneous liver biopsy is still the gold standard. However, the recent introduction of liver imaging techniques, the rising of statistical tests able to classify CLD noninvasively, and a reconsideration of its potential complications, have contributed to an audit of the evolving role of liver biopsy. At present, there is an increasing interest for noninvasive approaches to evaluate the stage of liver fibrosis in the clinical work-up of patients with CLD. Transient elastography (FibroScan) is a new, noninvasive method to assess liver stiffness and, consequently, the degree of liver fibrosis. Since its use in the clinical setting is of great interest, further studies should define the exact role of this procedure.


Cellular Proteomes Drive Tissue-Specific Regulation of the Heat Shock Response.
The heat shock response (HSR) is a cellular stress response that senses protein misfolding and restores protein folding homeostasis, or proteostasis. We previously identified an HSR regulatory network in Caenorhabditis elegans consisting of highly conserved genes that have important cellular roles in maintaining proteostasis. Unexpectedly, the effects of these genes on the HSR are distinctly tissue-specific. Here, we explore this apparent discrepancy and find that muscle-specific regulation of the HSR by the TRiC/CCT chaperonin is not driven by an enrichment of TRiC/CCT in muscle, but rather by the levels of one of its most abundant substrates, actin. Knockdown of actin subunits reduces induction of the HSR in muscle upon TRiC/CCT knockdown; conversely, overexpression of an actin subunit sensitizes the intestine so that it induces the HSR upon TRiC/CCT knockdown. Similarly, intestine-specific HSR regulation by the signal recognition particle (SRP), a component of the secretory pathway, is driven by the vitellogenins, some of the most abundant secretory proteins. Together, these data indicate that the specific protein folding requirements from the unique cellular proteomes sensitizes each tissue to disruption of distinct subsets of the proteostasis network. These findings are relevant for tissue-specific, HSR-associated human diseases such as cancer and neurodegenerative diseases. Additionally, we characterize organismal phenotypes of actin overexpression including a shortened lifespan, supporting a recent hypothesis that maintenance of the actin cytoskeleton is an important factor for longevity.


Increased extra-pair paternity in broods of aging males and enhanced recruitment of extra-pair young in a migratory bird.
Despite keen interest in extra-pair mating in birds, its adaptive significance remains unresolved. Here, we use a multi-year dataset to test whether traits of a female's social mate influence her propensity to produce extra-pair offspring in a population of house wrens, and whether producing extra-pair young has consequences for a female's fitness through effects on offspring survival. Females were most likely to produce extra-pair offspring when paired with old males and when paired with males on poor-quality territories, although this latter effect was marginally nonsignificant. Among offspring, the cutaneous immunity of within-pair young decreased as the age of their sires increased, but cutaneous immunity of extra-pair young was not affected by the age of their extra-pair sires or by the age of the males rearing them. Extra-pair offspring were more likely than within-pair offspring to return as breeding adults to the local population, with extra-pair sons being more likely to return as a breeder for multiple years. Our findings support the hypothesis that females produce extra-pair offspring to enhance their inclusive fitness beyond what they are capable of given the male with which they are socially paired.


Secular trends in physiological capital: implications for equity in health care.
Over the past three centuries, there has been a rapid accumulation of physiological capital in Organisation for Economic Cooperation and Development (OECD) countries. Enhanced physiological capital is tied to long-term reduction in environmental hazards and to the conquest of chronic malnutrition, since both nutritional status and the quality of the external and intrauterine environments appear to be linked to the quality of organ development and to the onset of chronic diseases later in life. Data on heights and birth weights suggest that physiological capital has become more equally distributed, thereby reducing socioeconomic disparities in the burden of disease. These developments have a number of health care policy implications: (1) enhanced physiological capital has done more to reduce inequities in health status than has wider access to health care; (2) the main contribution of more advanced medical treatment so far has been to retard depreciation in individuals' physiological capital; (3) prenatal and early childhood care and environmental issues are key for interventions aimed at enhancing physiological capital and at affecting its rate of depreciation; (4) lifestyle change is the most important issue affecting health equity in rich countries; and (5) greater access to clinical care should be promoted through aggressive outreach, since expanded insurance coverage by itself is inadequate.


Health Professionals' Experience with Patients Accessing Their Electronic Health Records: Results from an Online Survey.
The aim of this study was to investigate hospital professionals' experience and attitude with patients accessing their own electronic health records. The study was conducted one year after service establishment. Data was collected through an online survey. In total, 457 replies were received. The results revealed a quarter of the administrative staff received feedback from patients or relatives regarding mistakes or missing information in their EHR. In addition, 67.5% of health professionals expected more patients to have basic knowledge of their health status in the future, and 21.4% found patients already gained better knowledge about diagnosis, treatment, or follow-up. The results also revealed some challenges with the service, especially for health professionals working in psychiatry, with some scepticism on whether the service is suitable for the sickest and most vulnerable patients.


Effects of a new piezoelectric device on periosteal microcirculation after subperiosteal preparation.
Subperiosteal preparation using a periosteal elevator leads to disturbances of local periosteal microcirculation. Soft-tissue damage can usually be considerably reduced using piezoelectric technology. For this reason, we investigated the effects of a novel piezoelectric device on local periosteal microcirculation and compared this approach with the conventional preparation of the periosteum using a periosteal elevator. A total of 20 Lewis rats were randomly assigned to one of two groups. Subperiosteal preparation was performed using either a piezoelectric device or a periosteal elevator. Intravital microscopy was performed immediately after the procedure as well as three and eight days postoperatively. Statistical analysis of microcirculatory parameters was performed offline using analysis of variance (ANOVA) on ranks (p<0.05). At all time points investigated, intravital microscopy demonstrated significantly higher levels of periosteal perfusion in the group of rats that underwent piezosurgery than in the group of rats that underwent treatment with a periosteal elevator. The use of a piezoelectric device for subperiosteal preparation is associated with better periosteal microcirculation than the use of a conventional periosteal elevator. As a result, piezoelectric devices can be expected to have a positive effect on bone metabolism.


Effects of age, cigarette smoking, and other factors on fertility: findings in a large prospective study.
Of 17 032 women taking part in the Oxford Family Planning Association contraceptive study, 4104 stopped using a birth control method to plan a pregnancy on a total of 6199 occasions. The influence of various factors on fertility in these women was assessed by measuring the time taken to give birth to a child. An appreciable inverse relation was observed between age at stopping contraception and fertility both in nulliparous and parous women, but the effect was much greater in the nulliparous women. The most important finding was a consistent and highly significant trend of decreasing fertility with increasing numbers of cigarettes smoked per day; it was estimated that five years after stopping contraception 10.7% of smokers smoking more than 20 cigarettes a day, but only 5.4% of non-smokers, remained undelivered. Some relation was found between fertility and social class, age at marriage, and a history of gynaecological disease, but weight, height, and Quetelet's index were without noticeable effect.


Comparative analysis of three brevetoxin-associated bottlenose dolphin (Tursiops truncatus) mortality events in the Florida Panhandle region (USA).
In the Florida Panhandle region, bottlenose dolphins (Tursiops truncatus) have been highly susceptible to large-scale unusual mortality events (UMEs) that may have been the result of exposure to blooms of the dinoflagellate Karenia brevis and its neurotoxin, brevetoxin (PbTx). Between 1999 and 2006, three bottlenose dolphin UMEs occurred in the Florida Panhandle region. The primary objective of this study was to determine if these mortality events were due to brevetoxicosis. Analysis of over 850 samples from 105 bottlenose dolphins and associated prey items were analyzed for algal toxins and have provided details on tissue distribution, pathways of trophic transfer, and spatial-temporal trends for each mortality event. In 1999/2000, 152 dolphins died following extensive K. brevis blooms and brevetoxin was detected in 52% of animals tested at concentrations up to 500 ng/g. In 2004, 105 bottlenose dolphins died in the absence of an identifiable K. brevis bloom; however, 100% of the tested animals were positive for brevetoxin at concentrations up to 29,126 ng/mL. Dolphin stomach contents frequently consisted of brevetoxin-contaminated menhaden. In addition, another potentially toxigenic algal species, Pseudo-nitzschia, was present and low levels of the neurotoxin domoic acid (DA) were detected in nearly all tested animals (89%). In 2005/2006, 90 bottlenose dolphins died that were initially coincident with high densities of K. brevis. Most (93%) of the tested animals were positive for brevetoxin at concentrations up to 2,724 ng/mL. No DA was detected in these animals despite the presence of an intense DA-producing Pseudo-nitzschia bloom. In contrast to the absence or very low levels of brevetoxins measured in live dolphins, and those stranding in the absence of a K. brevis bloom, these data, taken together with the absence of any other obvious pathology, provide strong evidence that brevetoxin was the causative agent involved in these bottlenose dolphin mortality events.


Pharmacology Update: Low-Dose Naltrexone as a Possible Nonopioid Modality for Some Chronic, Nonmalignant Pain Syndromes.
Pain can have a devastating effect on the quality of life of patients in palliative medicine. Thus far, majority of research has been centered on opioid-based pain management, with a limited empirical evidence for the use of nonopioid medications in palliative care. However, opioid and nonopioid medications such as nonsteroidal anti-inflammatory drugs have their limitations in the clinical use due to risk of adverse effects, therefore, there is a need for more research to be directed to finding an alternative approach to pain management in comfort care setting. The purpose of this article is to discuss a potential new drug that would adequately alleviate pain and enhance quality of life without significant risks of adverse effects that would limit its use. Naltrexone is a reversible competitive antagonist at μ-opioid and κ-opioid receptors, which when used at standard doses of 50 to 150 mg was initially intended for use in opioid and alcohol use disorders. However, it was discovered that its use in low doses follows alternate pharmacodynamic pathways with various effects. When used in doses of 1 to 5 mg it acts as a glial modulator with a neuroprotective effect via inhibition of microglial activation. It binds to Toll-like receptor 4 and acts as an antagonist, therefore inhibiting the downstream cellular signaling pathways that ultimately lead to pro-inflammatory cytokines, therefore reducing inflammatory response. Its other mode of action involves transient opioid receptor blockade ensuing from low-dose use which upregulates opioid signaling resulting in increased levels of endogenous opioid production, known as opioid rebound effect. Low dose naltrexone has gained popularity as an off-label treatment of several autoimmune diseases including multiple sclerosis and inflammatory bowel disease, as well as chronic pain disorders including fibromyalgia, complex regional pain syndrome, and diabetic neuropathy. Low-dose naltrexone (LDN) may also have utility in improving mood disorders and the potential to enhance the quality of life. This article will therefore propose the potential off-label use of LDN in management of nonmalignant pain in the palliative medicine setting.


An injectable alginate/extra cellular matrix (ECM) hydrogel towards acellular treatment of heart failure.
As treatments for myocardial infarction (MI) continue to improve, the population of people suffering from heart failure (HF) is rising significantly. Novel treatment strategies aimed at achieving long-term functional stabilisation and improvement in heart function post MI include the delivery of biomaterial hydrogels and myocardial matrix-based therapies to the left ventricle wall. Individually alginate hydrogels and myocardial matrix-based therapies are at the most advanced stages of commercial/clinical development for this potential treatment option. However, despite these individual successes, the potential synergistic effect gained by combining the two therapies remains unexplored. This study serves as a translational step in evaluating the minimally invasive delivery of dual acting alginate-based hydrogels to the heart. We have successfully developed new production methods for hybrid alginate/extracellular matrix (ECM) hydrogels. We have identified that the high G block alginate/ECM hybrid hydrogel has appropriate rheological and mechanical properties (1.6 KPa storage modulus, 29 KPa compressive modulus and 14 KPa dynamic modulus at day 1) and can be delivered using a minimally invasive delivery device. Furthermore, we have determined that these novel hydrogels are not cytotoxic and are capable of enhancing the metabolic activity of dermal fibroblasts in vitro (p < 0.01). Overall these results suggest that an effective minimally invasive HF treatment option could be achieved by combining alginate and ECM particles.


Patchy populations in stochastic environments: critical number of patches for persistence.
We introduce a model for the dynamics of a patchy population in a stochastic environment and derive a criterion for its persistence. This criterion is based on the geometric mean (GM) through time of the spatial-arithmetic mean of growth rates. For the population to persist, the GM has to be >/=1. The GM increases with the number of patches (because the sampling error is reduced) and decreases with both the variance and the spatial covariance of growth rates. We derive analytical expressions for the minimum number of patches (and the maximum harvesting rate) required for the persistence of the population. As the magnitude of environmental fluctuations increases, the number of patches required for persistence increases, and the fraction of individuals that can be harvested decreases. The novelty of our approach is that we focus on Malthusian local population dynamics with high dispersal and strong environmental variability from year to year. Unlike previous models of patchy populations that assume an infinite number of patches, we focus specifically on the effect that the number of patches has on population persistence. Our work is therefore directly relevant to patchily distributed organisms that are restricted to a small number of habitat patches.


Analyzing Personal Happiness from Global Survey and Weather Data: A Geospatial Approach.
Past studies have shown that personal subjective happiness is associated with various macro- and micro-level background factors, including environmental conditions, such as weather and the economic situation, and personal health behaviors, such as smoking and exercise. We contribute to this literature of happiness studies by using a geospatial approach to examine both macro and micro links to personal happiness. Our geospatial approach incorporates two major global datasets: representative national survey data from the International Social Survey Program (ISSP) and corresponding world weather data from the National Oceanic and Atmospheric Administration (NOAA). After processing and filtering 55,081 records of ISSP 2011 survey data from 32 countries, we extracted 5,420 records from China and 25,441 records from 28 other countries. Sensitivity analyses of different intervals for average weather variables showed that macro-level conditions, including temperature, wind speed, elevation, and GDP, are positively correlated with happiness. To distinguish the effects of weather conditions on happiness in different seasons, we also adopted climate zone and seasonal variables. The micro-level analysis indicated that better health status and eating more vegetables or fruits are highly associated with happiness. Never engaging in physical activity appears to make people less happy. The findings suggest that weather conditions, economic situations, and personal health behaviors are all correlated with levels of happiness.


Complex evolution of the DAL5 transporter family.
Genes continuously duplicate and the duplicated copies remain in the genome or get deleted. The DAL5 subfamily of transmembrane transporter genes has eight known members in S. cerevisiae. All are putative anion:cation symporters of vitamins (such as allantoate, nicotinate, panthotenate and biotin). The DAL5 subfamily is an old and important group since it is represented in both Basidiomycetes ("mushrooms") and Ascomycetes ("yeast"). We studied the complex evolution of this group in species from the kingdom of fungi particularly the Ascomycetes. We identified numerous gene duplications creating sets of orthologous and paralogous genes. In different lineages the DAL5 subfamily members expanded or contracted and in some lineages a specific member could not be found at all. We also observed a close relationship between the gene YIL166C and its homologs in the Saccharomyces sensu stricto species and two "wine spoiler" yeasts, Dekkera bruxellensis and Candida guilliermondi, which could possibly be the result of horizontal gene transfer between these distantly related species. In the analyses we detect several well defined groups without S. cerevisiae representation suggesting new gene members in this subfamily with perhaps altered specialization or function. The transmembrane DAL5 subfamily was found to have a very complex evolution in yeast with intra- and interspecific duplications and unusual relationships indicating specialization, specific deletions and maybe even horizontal gene transfer. We believe that this group will be important in future investigations of evolution in fungi and especially the evolution of transmembrane proteins and their specialization.


Currently prescribed drugs in the UK that could upregulate or downregulate ACE2 in COVID-19 disease: a systematic review.
To review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate ACE2 and potentially affect COVID-19 disease. Systematic review. MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science. Any design with animal or human models examining a currently prescribed UK drug compared with a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1 April 2020. Methodological quality was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool for animal studies and Cochrane risk-of-bias tool for human studies. We screened 3360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and one hundred and two were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were angiotensin receptor blockers (ARBs) (n=55) and ACE inhibitors (ACE-I) (n=22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel blockers (n=3) glucagon-like peptide 1 (GLP-1) agonists (n=2) and Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2). There is an abundance of the academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty among patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.


The effect of esophageal cooling on esophageal injury during radiofrequency catheter ablation of atrial fibrillation.
Catheter ablation of atrial fibrillation (AF) may lead to collateral damage to the esophagus. We tested the hypothesis that luminal esophageal temperature (LET)-guided esophageal cooling might reduce the incidence of esophageal thermal lesions (ETL). Seventy-six patients from August 2015 to March 2017 with paroxysmal or persistent AF underwent a first-time catheter ablation procedure with or without LET-guided active esophageal cooling through an orogastric tube placed in the esophagus. Esophageal cooling occurred if and only if LET exceeded 0.5 °C from baseline while ablating the LA posterior wall. All patients underwent esophagogastric endoscopy the next day. Of the 76 patients studied, 38 (50%) patients underwent esophageal cooling. Baseline characteristics of the non-cooled and cooled groups were comparable. Of these, 59% of patients had ETL. There was a non-significant trend for more severe lesions (grades 3, 4) in the non-cooled group (29% vs. 13.5%, p = 0.10). Average power delivered on the left atrial posterior wall (27 ± 1.8 W vs. 27 ± 3.8 W, p = 0.34) and average force of contact (10.1 g vs. 9.8 g, p = 0.38) were similar in both groups while more time was spent ablating on the posterior wall in the non-cooled group (24.6 ± 7.3 min vs. 20.4 ± 5.9 min, p = 0.014). In a multivariate analysis, esophageal cooling had no significant effect on the esophageal lesion grade post-ablation. The incidence of ETL in patients undergoing left atrial posterior wall isolation is substantial. Our method of esophageal cooling did not decrease the incidence of ETL. There was a non-significant trend toward fewer severe lesions with cooling, but one cannot conclude the value of cooling from this pilot study.


Improvement in Patient-Reported Outcomes With Intensity-Modulated Radiotherapy (RT) Compared With Standard RT: A Report From the NRG Oncology RTOG 1203 Study.
In oncology trials, the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) is the standard tool for reporting adverse events (AEs), but it may underreport symptoms experienced by patients. This analysis of the NRG Oncology RTOG 1203 compared symptom reporting by patients and clinicians during radiotherapy (RT). Patients with cervical or endometrial cancer requiring postoperative RT were randomly assigned to standard 4-field RT or intensity-modulated RT (IMRT). Patients completed the 6-item patient-reported outcomes version of the CTCAE (PRO-CTCAE) for GI toxicity assessing abdominal pain, diarrhea, and fecal incontinence at various time points. Patients reported symptoms on a 5-point scale. Clinicians recorded these AEs as CTCAE grades 1 to 5. Clinician- and patient-reported AEs were compared using McNemar's test for rates > 0%. Of 278 eligible patients, 234 consented and completed the PRO-CTCAE. Patients reported high-grade abdominal pain 19.1% (P < .0001), high-grade diarrhea 38.5% (P < .0001), and fecal incontinence 6.8% more frequently than clinicians. Similar effects were seen between grade ≥ 1 CTCAE toxicity and any-grade patient-reported toxicity. Between-arm comparison of patient-reported high-grade AEs revealed that at 5 weeks of RT, patients who received IMRT experienced fewer GI AEs than patients who received 4-field pelvic RT with regard to frequency of diarrhea (18.2% difference; P = .01), frequency of fecal incontinence (8.2% difference; P = .01), and interference of fecal incontinence (8.5% difference; P = .04). Patient-reported AEs showed a reduction in symptoms with IMRT compared with standard RT, whereas clinician-reported AEs revealed no difference. Clinicians also underreported symptomatic GI AEs compared with patients. This suggests that patient-reported symptomatic AEs are important to assess in this disease setting.


HPV vaccination syndrome. A questionnaire-based study.
Isolated cases and small series have described the development of complex regional pain syndrome, postural orthostatic tachycardia, and fibromyalgia after human papillomavirus (HPV) vaccination. These illnesses are difficult to diagnose and have overlapping clinical features. Small fiber neuropathy and dysautonomia may play a major role in the pathogenesis of these entities. We used the following validated questionnaires to appraise the chronic illness that might appear after HPV vaccination: The 2010 American College of Rheumatology Fibromyalgia Diagnostic Criteria, COMPASS 31 dysautonomia questionnaire, and S-LANSS neuropathic pain form. These questionnaires and a "present illness" survey were e-mailed to persons who had the onset of a chronic ailment soon after HPV vaccination. Forty-five filled questionnaires from individuals living in 13 different countries were collected in a month's period. Mean (±SD) age at vaccination time was 14 ± 5 years. Twenty-nine percent of the cases had immediate (within 24 h) post-vaccination illness onset. The most common presenting complaints were musculoskeletal pain (66%), fatigue (57%), headache (57%), dizziness/vertigo (43%), and paresthesias/allodynia (36%). Fifty-three percent of affected individuals fulfill the fibromyalgia criteria. COMPASS-31 score was 43 ± 21, implying advanced autonomic dysfunction. Eighty-three percent of the patients who had ongoing pain displayed S-LANSS values >12, suggesting a neuropathic component in their pain experience. After a mean period of 4.2 ± 2.5 years post-vaccination, 93% of patients continue to have incapacitating symptoms and remain unable to attend school or work. In conclusion, a disabling syndrome of chronic neuropathic pain, fatigue, and autonomic dysfunction may appear after HPV vaccination.


Tsc2-Rheb signaling regulates EphA-mediated axon guidance.
Tuberous sclerosis complex is a disease caused by mutations in the TSC1 or TSC2 genes, which encode a protein complex that inhibits mTOR kinase signaling by inactivating the Rheb GTPase. Activation of mTOR promotes the formation of benign tumors in various organs and the mechanisms underlying the neurological symptoms of the disease remain largely unknown. We found that Tsc2 haploinsufficiency in mice caused aberrant retinogeniculate projections that suggest defects in EphA receptor-dependent axon guidance. We also found that EphA receptor activation by ephrin-A ligands in neurons led to inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activity and decreased inhibition of Tsc2 by ERK1/2. Thus, ephrin stimulation inactivates the mTOR pathway by enhancing Tsc2 activity. Furthermore, Tsc2 deficiency and hyperactive Rheb constitutively activated mTOR and inhibited ephrin-induced growth cone collapse. Our results indicate that TSC2-Rheb-mTOR signaling cooperates with the ephrin-Eph receptor system to control axon guidance in the visual system.


A meta-analysis of two high-risk prospective cohort studies reveals autism-specific transcriptional changes to chromatin, autoimmune, and environmental response genes in umbilical cord blood.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects more than 1% of children in the USA. ASD risk is thought to arise from both genetic and environmental factors, with the perinatal period as a critical window. Understanding early transcriptional changes in ASD would assist in clarifying disease pathogenesis and identifying biomarkers. However, little is known about umbilical cord blood gene expression profiles in babies later diagnosed with ASD compared to non-typically developing and non-ASD (Non-TD) or typically developing (TD) children. Genome-wide transcript levels were measured by Affymetrix Human Gene 2.0 array in RNA from cord blood samples from both the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) and the Early Autism Risk Longitudinal Investigation (EARLI) high-risk pregnancy cohorts that enroll younger siblings of a child previously diagnosed with ASD. Younger siblings were diagnosed based on assessments at 36 months, and 59 ASD, 92 Non-TD, and 120 TD subjects were included. Using both differential expression analysis and weighted gene correlation network analysis, gene expression between ASD and TD, and between Non-TD and TD, was compared within each study and via meta-analysis. While cord blood gene expression differences comparing either ASD or Non-TD to TD did not reach genome-wide significance, 172 genes were nominally differentially expressed between ASD and TD cord blood (log2(fold change) > 0.1, p < 0.01). These genes were significantly enriched for functions in xenobiotic metabolism, chromatin regulation, and systemic lupus erythematosus (FDR q < 0.05). In contrast, 66 genes were nominally differentially expressed between Non-TD and TD, including 8 genes that were also differentially expressed in ASD. Gene coexpression modules were significantly correlated with demographic factors and cell type proportions. ASD-associated gene expression differences identified in this study are subtle, as cord blood is not the main affected tissue, it is composed of many cell types, and ASD is a heterogeneous disorder. This is the first study to identify gene expression differences in cord blood specific to ASD through a meta-analysis across two prospective pregnancy cohorts. The enriched gene pathways support involvement of environmental, immune, and epigenetic mechanisms in ASD etiology.


Step Crowding Effects Dampen the Stochasticity of Crystal Growth Kinetics.
Crystals grow by laying down new layers of material which can either correspond in size to the height of one unit cell (elementary steps) or multiple unit cells (macrosteps). Surprisingly, experiments have shown that macrosteps can grow under conditions of low supersaturation and high impurity density such that elementary step growth is completely arrested. We use atomistic simulations to show that this is due to two effects: the fact that the additional layers bias fluctuations in the position of the bottom layer towards growth and by a transition, as step height increases, from a 2D to a 3D nucleation mechanism.


Network integration of multi-tumour omics data suggests novel targeting strategies.
We characterize different tumour types in search for multi-tumour drug targets, in particular aiming for drug repurposing and novel drug combinations. Starting from 11 tumour types from The Cancer Genome Atlas, we obtain three clusters based on transcriptomic correlation profiles. A network-based analysis, integrating gene expression profiles and protein interactions of cancer-related genes, allows us to define three cluster-specific signatures, with genes belonging to NF-κB signaling, chromosomal instability, ubiquitin-proteasome system, DNA metabolism, and apoptosis biological processes. These signatures have been characterized by different approaches based on mutational, pharmacological and clinical evidences, demonstrating the validity of our selection. Moreover, we define new pharmacological strategies validated by in vitro experiments that show inhibition of cell growth in two tumour cell lines, with significant synergistic effect. Our study thus provides a list of genes and pathways that could possibly be used, singularly or in combination, for the design of novel treatment strategies.


Ivermectin for onchocercal eye disease (river blindness).
It is believed that ivermectin (a microfilaricide) could prevent blindness due to onchocerciasis. However, when given to everyone in communities where onchocerciasis is common, the effects of ivermectin on lesions affecting the eye are uncertain and data on whether the drug prevents visual loss are unclear. The aim of this review was to assess the effectiveness of ivermectin in preventing visual impairment and visual field loss in onchocercal eye disease. The secondary aim was to assess the effects of ivermectin on lesions affecting the eye in onchocerciasis. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 3), MEDLINE (January 1950 to April 2012), EMBASE (January 1980 to April 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 2 April 2012. We included randomised controlled trials with at least one year of follow-up comparing ivermectin with placebo or no treatment. Participants in the trials were people normally resident in endemic onchocercal communities with or without one or more characteristic signs of ocular onchocerciasis. Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional information. As trials varied in design and setting, we were unable to perform a meta-analysis. The review included four trials: two small studies (n = 398) in which people with onchocercal infection were given one dose of ivermectin or placebo and followed up for one year; and two larger community-based studies (n = 4941) whereby all individuals in selected communities were treated every six or 12 months with ivermectin or placebo, whether or not they were infected, and followed for two to three years. The studies provide evidence that treating people who have onchocerciasis with ivermectin reduces the number of microfilariae in their skin and eye(s) and reduces the number of punctate opacities. There was weaker evidence that ivermectin reduced the risk of chorioretinitis. The studies were too small and of too short a duration to provide evidence for an effect on sclerosing keratitis, iridocyclitis, optic nerve disease or visual loss. One community-based study in communities mesoendemic for the savannah strain of O.volvulus provided evidence that annual mass treatment with ivermectin reduces the risk of new cases of optic nerve disease and visual field loss. The other community-based study of mass biannual treatment of ivermectin in communities affected by the forest strain of O.volvulus demonstrated reductions in microfilarial load, punctate keratitis and iridocyclitis but not sclerosing keratitis, chorioretinitis, optic atrophy or visual impairment. The study was underpowered to estimate the effect of ivermectin on visual impairment and other less frequent clinical signs. The studies included in this review reported some adverse effects, in particular an increased risk of postural hypotension in people treated with ivermectin. The lack of evidence for prevention of visual impairment and blindness should not be interpreted to mean that ivermectin is not effective, however, clearly this is a key question that remains unanswered. The main evidence for a protective effect of mass treatment with ivermectin on visual field loss and optic nerve disease comes from communities mesoendemic for the savannah strain of O.volvulus. Whether these findings can be applied to communities with different endemicity and affected by the forest strain is unclear. Serious adverse effects were rarely reported. None of the studies, however, were conducted in areas where people are infected with Loa loa (loiasis).


High resolution atomic force microscopy of double-stranded RNA.
Double-stranded (ds) RNA mediates the suppression of specific gene expression, it is the genetic material of a number of viruses, and a key activator of the innate immune response against viral infections. The ever increasing list of roles played by dsRNA in the cell and its potential biotechnological applications over the last decade has raised an interest for the characterization of its mechanical properties and structure, and that includes approaches using Atomic Force Microscopy (AFM) and other single-molecule techniques. Recent reports have resolved the structure of dsDNA with AFM at unprecedented resolution. However, an equivalent study with dsRNA is still lacking. Here, we have visualized the double helix of dsRNA under near-physiological conditions and at sufficient resolution to resolve the A-form sub-helical pitch periodicity. We have employed different high-sensitive force-detection methods and obtained images with similar spatial resolution. Therefore, we show here that the limiting factors for high-resolution AFM imaging of soft materials in liquid medium are, rather than the imaging mode, the force between the tip and the sample and the sharpness of the tip apex.


Breakage on chromosome 2 brings the Ck gene to a region 3' of c-myc in a Burkitt's lymphoma line carrying a (2;8) translocation.
We have shown using in situ hybridization that the constant region of the kappa light chain immunoglobulin gene (Ck) is translocated from chromosome 2 to chromosome 8 in Burkitt's lymphoma cells with a (2;8) translocation. The Ck gene then ends up adjacent to and on the 3' side of c-myc. The breakpoint probably falls between the gene for the variable region of the kappa light chain (Vk) and the Ck gene.


Effects of changing climate on aquatic habitat and connectivity for remnant populations of a wide-ranging frog species in an arid landscape.
Amphibian species persisting in isolated streams and wetlands in desert environments can be susceptible to low connectivity, genetic isolation, and climate changes. We evaluated the past (1900-1930), recent (1981-2010), and future (2071-2100) climate suitability of the arid Great Basin (USA) for the Columbia spotted frog (Rana luteiventris) and assessed whether changes in surface water may affect connectivity for remaining populations. We developed a predictive model of current climate suitability and used it to predict the historic and future distribution of suitable climates. We then modeled changes in surface water availability at each time period. Finally, we quantified connectivity among existing populations on the basis of hydrology and correlated it with interpopulation genetic distance. We found that the area of the Great Basin with suitable climate conditions has declined by approximately 49% over the last century and will likely continue to decline under future climate scenarios. Climate conditions at currently occupied locations have been relatively stable over the last century, which may explain persistence at these sites. However, future climates at these currently occupied locations are predicted to become warmer throughout the year and drier during the frog's activity period (May - September). Fall and winter precipitation may increase, but as rain instead of snow. Earlier runoff and lower summer base flows may reduce connectivity between neighboring populations, which is already limited. Many of these changes could have negative effects on remaining populations over the next 50-80 years, but milder winters, longer growing seasons, and wetter falls might positively affect survival and dispersal. Collectively, however, seasonal shifts in temperature, precipitation, and stream flow patterns could reduce habitat suitability and connectivity for frogs and possibly other aquatic species inhabiting streams in this arid region.


Effect of nitric oxide synthase inhibition on blood flow after retinal ischemia in cats.
To determine the effect of nitric oxide synthase inhibition on blood flow in the cat retina and on changes in the electroretinogram after 1 hour of ocular ischemia. After the induction of general anesthesia, one eye in each of 18 cats was subjected to 60 minutes of ischemia by raising intraocular pressure above systolic arterial pressure. One group (n = 9) was administered 30 mg/kg L-NG-nitro-arginine-methylester (L-NAME) intravenously 60 minutes before ischemia. The other group (n = 9) was administered an equivalent volume of saline intravenously. Five minutes after the end of ischemia, blood flow in the retina, choroid, and iris-ciliary body was measured using injections of radioactively labeled microspheres. Electroretinographic studies were carried out before, during, and 1, 2, 3, and 4 hours after ischemia ended. Arterial blood gas tension, systemic arterial pressure, hematocrit, and anesthetic levels were controlled in each experiment. Basal blood flow in iris-ciliary body was decreased by L-NAME, whereas retinal and choroidal blood flow was unchanged. Postischemic hyperemia was unaltered in the choroid and reduced in the retina. There was enhancement of postischemic hyperemia in the iris-ciliary body, but this effect may have resulted from a decrease in basal flow in the L-NAME group. Electroretinographic a- and b-wave recoveries were not altered by L-NAME; L-NAME infusion significantly decreased b-wave amplitude. Nitric oxide appears to be a significant factor in the regulation of uveal circulation and may contribute to the regulation of retinal, but not choroidal, blood flow after ischemia. The authors could not detect a difference in outcome by electroretinography with or without nitric oxide synthase inhibition.


Toxicity of a novel HMG-CoA reductase inhibitor in the common marmoset (Callithrix jacchus).
1. GR95030X, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, was administered daily to marmosets by gavage. In a Maximum Repeatable Dose (MRD) study, doses of up to 30 mg kg-1 day-1 were administered for 49 days. In a chronic study, animals received dosages equivalent to 0, 1, 2.5, 7.5 and 20 mg kg-1 day-1 for 204 or 205 days. Some animals were maintained without treatment for a recovery period of 29 or 30 days. 2. Clinical signs included poor coat condition, weakness with impaired coordination, lethargy and other behavioural changes. There was also alimentary disturbance, and some deaths occurred at doses of 20 mg kg-1 day-1 and above. 3. Adverse effects upon body weight were seen although some recovery was apparent after the cessation of treatment. 4. Serum cholesterol concentrations were reduced. Very large increases in serum ALT, AST and CK activities were recorded with CK-MM isoenzymes accounting for 80% or more of the total CK enzyme activity. 5. Treatment was associated with muscle fibre atrophy and a sarcolemmal response with little evidence of regeneration. Histological examination revealed vascular changes, glial proliferation and cell death in the brain, with no consistent distribution. Alveolar capillary congestion and alveolar proteinosis indicated that there may have been a reduction in cardiac function. 6. HMG-CoA reductase inhibitors have evident potential to cause myopathy in marmosets. This is believed to be the first report of such an effect.


Single-Scaffold Genome Sequence of Probiotic Strain Bifidobacterium breve BR03 (DSM 16604), Obtained by Combining Hybrid Sequencing and Optical Mapping.
Bifidobacterium breve BR03 (DSM 16604) is known for its health-promoting activity. We present a single-scaffold genome obtained by using a hybrid approach combining long- and short-read sequencing techniques integrated by an optical map. This approach could be set as an industry standard for probiotic strain characterization.


Effective Mental Health Screening in Adolescents: Should We Collect Data from Youth, Parents or Both?
Youth- and parent-rated screening measures derived from the Strengths and Difficulties Questionnaire (SDQ) and Development and Well-Being Assessment (DAWBA) were compared on their psychometric properties as predictors of caseness in adolescence (mean age 14). Successful screening was judged firstly against the likelihood of having an ICD-10 psychiatric diagnosis and secondly by the ability to discriminate between community (N = 252) and clinical (N = 86) samples (sample status). Both, SDQ and DAWBA measures adequately predicted the presence of an ICD-10 disorder as well as sample status. The hypothesis that there was an informant gradient was confirmed: youth self-reports were less discriminating than parent reports, whereas combined parent and youth reports were more discriminating-a finding replicated across a diversity of measures. When practical constraints only permit screening for caseness using either a parent or an adolescent informant, parents are the better source of information.


Testing predictability of disease outbreaks with a simple model of pathogen biogeography.
Predicting disease emergence and outbreak events is a critical task for public health professionals and epidemiologists. Advances in global disease surveillance are increasingly generating datasets that are worth more than their component parts for prediction-oriented work. Here, we use a trait-free approach which leverages information on the global community of human infectious diseases to predict the biogeography of pathogens through time. Our approach takes pairwise dissimilarities between countries' pathogen communities and pathogens' geographical distributions and uses these to predict country-pathogen associations. We compare the success rates of our model for predicting pathogen outbreak, emergence and re-emergence potential as a function of time (e.g. number of years between training and prediction), pathogen type (e.g. virus) and transmission mode (e.g. vector-borne). With only these simple predictors, our model successfully predicts basic network structure up to a decade into the future. We find that while outbreak and re-emergence potential are especially well captured by our simple model, prediction of emergence events remains more elusive, and sudden global emergences like an influenza pandemic are beyond the predictive capacity of the model. However, these stochastic pandemic events are unlikely to be predictable from such coarse data. Together, our model is able to use the information on the existing country-pathogen network to predict pathogen outbreaks fairly well, suggesting the importance in considering information on co-occurring pathogens in a more global view even to estimate outbreak events in a single location or for a single pathogen.


A nuclear factor, ASC-2, as a cancer-amplified transcriptional coactivator essential for ligand-dependent transactivation by nuclear receptors in vivo.
Many transcription coactivators interact with nuclear receptors in a ligand- and C-terminal transactivation function (AF2)-dependent manner. We isolated a nuclear factor (designated ASC-2) with such properties by using the ligand-binding domain of retinoid X receptor as a bait in a yeast two-hybrid screening. ASC-2 also interacted with other nuclear receptors, including retinoic acid receptor, thyroid hormone receptor, estrogen receptor alpha, and glucocorticoid receptor, basal factors TFIIA and TBP, and transcription integrators CBP/p300 and SRC-1. In transient cotransfections, ASC-2, either alone or in conjunction with CBP/p300 and SRC-1, stimulated ligand-dependent transactivation by wild type nuclear receptors but not mutant receptors lacking the AF2 domain. Consistent with an idea that ASC-2 is essential for the nuclear receptor function in vivo, microinjection of anti-ASC-2 antibody abrogated the ligand-dependent transactivation of retinoic acid receptor, and this repression was fully relieved by coinjection of ASC-2-expression vector. Surprisingly, ASC-2 was identical to a gene previously identified during a search for genes amplified and overexpressed in breast and other human cancers. From these results, we concluded that ASC-2 is a bona fide transcription coactivator molecule of nuclear receptors, and its altered expression may contribute to the development of cancers.


Extended state-space Monte Carlo methods.
In this paper various extensions of the parallel-tempering algorithm are developed and their properties are analyzed. The algorithms are designed to alleviate quasiergodic sampling in systems which have rough energy landscapes by coupling individual Monte Carlo chains to form a composite chain. As with parallel tempering, the procedures are based upon extending the state space to include parameters to encourage sampling mobility. One of the drawbacks of the parallel-tempering method is the stochastic nature of the Monte Carlo dynamics in the auxiliary variables which extend the state space. In this work, the possibility of improving the sampling rate by designing deterministic methods of moving through the parameter space is investigated. The methods developed in this article, which are based upon a statistical quenching and heating procedure similar in spirit to simulated annealing, are tested on a simple two-dimensional spin system (xy model) and on a model in vacuo polypeptide system. In the coupled Monte Carlo chain algorithms, we find that the net mobility of the composite chain is determined by the competition between the characteristic time of coupling between adjacent chains and the degree of overlap of their distributions. Extensive studies of all methods are carried out to obtain optimal sampling conditions. In particular, the most efficient parallel-tempering procedure is to attempt to swap configurations after very few Monte Carlo updates of the composite chains. Furthermore, it is demonstrated that, contrary to expectations, the deterministic procedure does not improve the sampling rate over that of parallel tempering.


The effects of genetic variation in FTO rs9939609 on obesity and dietary preferences in Chinese Han children and adolescents.
The association of the rs9939609 single nucleotide polymorphism in FTO gene with obesity has been extensively investigated in studies of populations of European, African, and Asian ancestry. However, inconsistent results have been reported in Asian populations, and the relationship of FTO variation and dietary behaviors has only rarely been examined in Chinese children and adolescents. The aim of this study was to assess the association of rs9939609 with obesity and dietary preferences in childhood in a Chinese population. Epidemiological data including dietary preferences were collected in interviews using survey questionnaires, and rs9939609 genotype was determined by real-time PCR. The associations of rs9939609 genotypes with obesity and dietary preferences were analyzed by multivariate logistic regression using both additive and dominant models. The results showed that subjects with a TA or AA genotype had an increased risk of obesity compared with the TT participants; the odds ratios (ORs) were 1.47 (95% CI: 1.25-1.71, P = 1.73×10-6), and 3.32 (95% CI: 2.01-5.47, P = 2.68×10-6), respectively. After adjusting for age and gender, body mass index, waist circumference, hip circumference, systolic blood pressure, diastolic blood pressure, fasting blood glucose, triglycerides, and low-density lipoprotein cholesterol were higher, and high-density lipoprotein cholesterol was lower in TA and AA participants than in those with the TT genotype. After additionally controlling for body mass index, the association remained significant only for systolic blood pressure (P = 0.005). Compared with TT participants, those with the AA genotype were more likely to prefer a meat-based diet (OR = 2.81, 95% CI: 1.52-5.21). The combined OR for obesity in participants with TA/AA genotypes and preference for a meat-based diet was 4.04 (95% CI: 2.8-5.81) compared with the TT participants who preferred a plant-based diet. These findings indicate the genetic variation of rs9939609 is associated with obesity and dietary preferences in Chinese children and adolescents.


Are there gender differences in diabetes care among elderly Medicare enrolled veterans?
To examine gender differences in diabetes care process measures and intermediate outcomes among veteran clinic users. A retrospective cohort study using Veterans Health Administration (VHA) and Medicare files of VHA clinic users with diabetes. Diabetes care process measures were tests for hemoglobin A1c (HbA1c), low-density lipoprotein (LDL-C) values, and eye exams. Intermediate outcomes were HbA1c and LDL-C values below recommended thresholds. Chi-square tests and logistic regressions were used to assess gender differences. Study population included 3,225 women and 231,922 men veterans with diabetes, enrolled in Medicare fee-for-service and alive at the end of fiscal year 2000. Overall, there were no significant gender differences in HbA1c or LDL-C testing. However, women had higher rates in these process measures than men among the non-African American minorities. Women were more likely to have completed eye exams (odds ratio [OR]=1.11; 99% confidence interval [CI]=1.10, 1.23) but were less likely to have LDL-C under 130 mg/dL (OR=0.77; 99% CI=0.69, 0.87). Among VHA patients with diabetes, clinically significant gender inequality was not apparent in most of diabetes care measures. However, there was evidence of better care among nonwhite and non-African American women than their male counterparts. Further research on interaction of race and gender on diabetes care is needed. This includes evaluation of integrated VHA women's health programs as well as cultural issues. Lower LDL-C control among women suggests areas of unmet needs for women and opportunities for future targeted quality improvement interventions at system and provider levels.


A novel variant of the infectious bronchitis virus resulting from recombination events in Italy and Spain.
Infectious bronchitis is considered to be one of the most devastating diseases in poultry. Control of its spread is typically attempted through biosecurity measures and extensive vaccination. However, the remarkable genetic and antigenic variability of the virus, which originate from both mutations and recombination events, represents an unsolved challenge for this disease. The present study reports on the emergence and spread of recombinant clusters detected in Italy and Spain between 2012 and 2014. A total of 36 Spanish and Italian infectious bronchitis virus (IBV) field strains were investigated and genetically characterized using phylogenetic, molecular, recombination and selection pressure analyses of the complete S1 gene. Based on the partial S1 sequencing, 27 IBV strains originating from Spain and nine from Italy were initially classified as being closely related to the Guandong/Xindadi (XDN) genotype. Phylogenetic analysis of the complete S1 gene revealed that the XDN strains formed a homogeneous clade with the Spanish IBV isolates within the QX genotype, whereas there was higher variability within the Italian strains. Recombination analysis determined that these strains belonged to four groups, which originated from independent recombination events between the QX and 793B IBV genotypes. Our data support the hypothesis of two different scenarios: firstly, in Spain, the large and homogeneous clade probably originated from a single offspring of the recombinant founder, which became dominant and spread throughout the country. Secondly, the nine Italian recombinants, which are characterized by three different recombination patterns, probably represent less fitted strains, because they were less viable with respect to their recombinant parents.


Substantial changes in mastery perceptions of dementia caregivers with the placement of a care recipient.
The current study examined how a key component of caregiving stress processes, global mastery perceptions, changes with placing the care recipient in a nursing home or institution. We also explored the role of primary stressors in accounting for mastery changes with placement and whether characteristics of the caregiver and care recipient moderate reactions to placement. We applied multiphase growth curve models to prospective longitudinal data from 271 caregivers in the Caregiver Stress and Coping Study who experienced placement of their care recipient. Using a time-to/from-placement metric, we found that caregivers typically experienced declines in mastery preceding placement, followed by a significant increase within 1 year after placement and further increases thereafter. Corresponding changes in primary stressors (role overload) mediated the placement-related increase in mastery. Caregivers who reported more depressive symptoms and activities of daily living/instrumental activities of daily living dependencies of the care recipient were more likely to experience larger placement-related increases in mastery perceptions. Our findings suggest that placement alters psychological resources of caregivers and this effect is driven by corresponding changes in primary stressors. Findings also underscore the importance of examining change processes across salient life events and transitions.


Why has COVID-19 not hit the countries like Nepal yet?
Noble CORONA Virus (COVID-19) is an infectious disease similar form of pneumonia/ SARS-CoV-2- impacting globally. The fear of coronavirus looks pandemic, but its severity is uncertain. Nepal was one of the first nine countries outside of China to report a COVID-19 case. Also, its unpredictability of mode or range of surface, the lifespan of the virus, objects of transmission (a distance of air/air currents, living duration in air, humidity, duration on objects, surface). The first case was found in Wuhan in December 2019 in China. The purpose is to summarize the current information about COVID-19 and to explore in terms of why Nepal is not hitting severely, while other countries are on death toll? We summarized the published articles form the web sources and news, Academic Journals, Ministry of health and population Nepal, WHO/CDC update reports/guidelines, Google search engine. Thematic analysis is made to explore the situation. Although, Nepal has a lack of health services, testing kits, advance lab and protecting equipment (PPE), why COVID-19 does not hit Nepal than China, Europe and North America, it still tremendous uncertainty. Is lockdown, isolation, social distance and quarantine the best ways of prevention? The hypothesis is floating globally - do BCG vaccinated countries are safer than non-user OR due to not having enough kits to screen populations at risk for the virus - while lack of testing a big cause for missing case OR Nepalese have better immune systems? It has attracted global attention. We believe that the COVID-19 is still evolving and it is too early to predict of an outbreak in Nepal. The government needs to increase funding for local health departments, begin planning for future epidemics and be prepared to bolster the economy by supporting consumer spending the midst of a serious outbreak. COVID-19 is a serious health challenge for Nepal, but so far the number of death has been lower than was foretell. It is, therefore essential to carry out more scientific evidence to explore results. Nepalese health services need to maintain up than today and follow lockdown, isolation, social distance and an advance screening test kit through the country.


The effect of distant malignancy upon quantitative cytologic assessment of normal oral mucosa.
In 1962 Nieburgs et al. reported specific changes within cells taken from normal buccal mucosa, in those with malignant disease distant from the oral cavity. Few have attempted to confirm these findings. Given the potential application of the observations of Nieburgs et al., a quantitative investigation seemed necessary. Two groups were studied: 40 patients with malignant disease outside the oral cavity and 40 healthy patients attending for routine dental treatment. Both groups were matched for age and sex, with anemia excluded. Quantitative cytologic assessment of nuclear (NA) and cytoplasmic area (CA) and DNA distribution (using DNA cytophotometric study) were calculated from cells in normal buccal mucosal smears. No significant difference in NA (P = 0.28) was found between the two groups. However, a significant reduction in CA (P = 0.005) was found within the distant malignancy group. DNA distribution was invariably diploid. Previous studies on the effect of distant malignancy and nutritional deficiency have concentrated on examination of the nucleus, with exclusion of the cytoplasm. Important changes, such as the one reported, may therefore have gone unrecorded, particularly since oral smears have rarely been quantitatively assessed. The cause of this decrease in CA in distant malignancy patients is discussed with regard to the patients' nutritional state. The buccal smear may yet prove of value in assessing nutritional deficiency consequent to internal malignancy.


Rapid versus standard intravenous rehydration in paediatric gastroenteritis: pragmatic blinded randomised clinical trial.
To determine if rapid rather than standard intravenous rehydration results in improved hydration and clinical outcomes when administered to children with gastroenteritis. Single centre, two arm, parallel randomised pragmatic controlled trial. Blocked randomisation stratified by site. Participants, caregivers, outcome assessors, investigators, and statisticians were blinded to the treatment assignment. Paediatric emergency department in a tertiary care centre in Toronto, Canada. 226 children aged 3 months to 11 years; complete follow-up was obtained on 223 (99%). Eligible children were aged over 90 days, had a diagnosis of dehydration secondary to gastroenteritis, had not responded to oral rehydration, and had been prescribed intravenous rehydration. Children were excluded if they weighed less than 5 kg or more than 33 kg, required fluid restriction, had a suspected surgical condition, or had an insurmountable language barrier. Children were also excluded if they had a history of a chronic systemic disease, abdominal surgery, bilious or bloody vomit, hypotension, or hypoglycaemia or hyperglycaemia. Rapid (60 mL/kg) or standard (20 mL/kg) rehydration with 0.9% saline over an hour; subsequent fluids administered according to protocol. clinical rehydration, assessed with a validated scale, two hours after the start of treatment. prolonged treatment, mean clinical dehydration scores over the four hour study period, time to discharge, repeat visits to emergency department, adequate oral intake, and physician's comfort with discharge. Data from all randomised patients were included in an intention to treat analysis. 114 patients were randomised to rapid rehydration and 112 to standard. One child was withdrawn because of severe hyponatraemia at baseline. There was no evidence of a difference between the rapid and standard rehydration groups in the proportions of participants who were rehydrated at two hours (41/114 (36%) v 33/112 (30%); difference 6.5% (95% confidence interval -5.7% to 18.7%; P=0.32). The results did not change after adjustment for weight, baseline dehydration score, and baseline pH (odds ratio 1.8, 0.90 to 3.5; P=0.10). The rates of prolonged treatment were similar (52% rapid v 43% standard; difference 8.9%, 21% to -5%; P=0.19). Although dehydration scores were similar throughout the study period (P=0.96), the median time to discharge was longer in the rapid group (6.3 v 5.0 hours; P=0.03). There are no relevant clinical benefits from the administration of rapid rather than standard intravenous rehydration to haemodynamically stable children deemed to require intravenous rehydration. Trail registration Clinical Trials NCT00392145.


Effects of jazz on postoperative pain and stress in patients undergoing elective hysterectomy.
Anesthesiologists use various medications to provide surgical patients with pain relief in the postoperative period. Other modalities, such as music, could be used in conjunction with opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) to decrease pain and lower heart rate and blood pressure. Our hypothesis was that patients listening to jazz in a postanesthesia care unit (PACU) would have lower heart rates and blood pressures and reduced pain and anxiety. The study objective was to determine if listening to jazz music in the PACU, when compared to wearing noise-canceling headphones with no music playing, would decrease heart rate, blood pressure, pain, or anxiety in patients undergoing a hysterectomy. The research design was a prospective, randomized study. The study was conducted in the PACU at the Penn State Hershey Medical Center in Hershey, PA, USA. A total of 56 patients, aged 18-75 y, who were categorized as status 1 or 2 according to the American Society of Anesthesiologists (ASA) Physical Status Classification System, and who were undergoing elective laparoscopic or abdominal hysterectomies, were enrolled in the study. Patients were randomly assigned either to listen to jazz music where the beats per min (BPM) was <100 (experimental group, n = 28) or to wear noise-canceling headphones (control group, n = 28) for 30 min while in the PACU after their surgery. Heart rate was the primary outcome, and secondary outcomes included systolic and diastolic blood pressure, an anxiety score, and a pain score. All outcome measures were initially recorded at baseline upon the patient's arrival in the PACU. Heart rate and blood pressure were recorded postoperatively every 5 min for the initial 30 min that a patient was in the PACU. Pain was checked every 10 min during the 30-min period; anxiety was checked at 30 min. Heart rates of patients in the noise-cancellation group were significantly lower when compared with baseline (P < .05), at all time points. For patients in the jazz group, heart rates were significantly lower at 15, 20, 25, and 30 min when compared with baseline. The pain scores were significantly lower (P < .05) in the noise-cancellation group compared with the jazz group at 10 min into the recovery period. Overall, the results showed that patients responded not only to music but also to silence in the PACU. Using music and/or noise reduction could decrease opioid administration, promote relaxation, and improve patient satisfaction.


Food protein-induced enterocolitis syndrome: case presentations and management lessons.
Enterocolitis induced in infants by cow's milk and/or soy protein has been recognized for decades. Symptoms typically begin in the first month of life in association with failure to thrive and may progress to acidemia and shock. Symptoms resolve after the causal protein is removed from the diet but recur with a characteristic symptom pattern on re-exposure. Approximately 2 hours after reintroduction of the protein, vomiting ensues, followed by an elevation of the peripheral blood polymorphonuclear leukocyte count, diarrhea, and possibly lethargy and hypotension. The disorder is generally not associated with detectable food-specific IgE antibody. There are increasing reports of additional causal foods, prolonged clinical courses, and onset outside of early infancy, leading to description of a food protein-induced enterocolitis syndrome. The disorder poses numerous diagnostic and therapeutic challenges. The purpose of this report is to delineate the characteristic clinical features and review the possible pathophysiologic basis to frame a rational strategy toward management.


Different types of dietary advice for women with gestational diabetes mellitus.
Dietary advice is the main strategy for managing gestational diabetes mellitus (GDM). It remains unclear what type of advice is best. To assess the effects of different types of dietary advice for women with GDM for improving health outcomes for women and babies. We searched Cochrane Pregnancy and Childbirth's Trials Register (8 March 2016), PSANZ's Trials Registry (22 March 2016) and reference lists of retrieved studies. Randomised controlled trials comparing the effects of different types of dietary advice for women with GDM. Two authors independently assessed study eligibility, risk of bias, and extracted data. Evidence quality for two comparisons was assessed using GRADE, for primary outcomes for the mother: hypertensive disorders of pregnancy; caesarean section; type 2 diabetes mellitus; and child: large-for-gestational age; perinatal mortality; neonatal mortality or morbidity composite; neurosensory disability; secondary outcomes for the mother: induction of labour; perineal trauma; postnatal depression; postnatal weight retention or return to pre-pregnancy weight; and child: hypoglycaemia; childhood/adulthood adiposity; childhood/adulthood type 2 diabetes mellitus. In this update, we included 19 trials randomising 1398 women with GDM, at an overall unclear to moderate risk of bias (10 comparisons). For outcomes assessed using GRADE, downgrading was based on study limitations, imprecision and inconsistency. Where no findings are reported below for primary outcomes or pre-specified GRADE outcomes, no data were provided by included trials. Primary outcomes Low-moderate glycaemic index (GI) versus moderate-high GI diet (four trials): no clear differences observed for: large-for-gestational age (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.22 to 2.34; two trials, 89 infants; low-quality evidence); severe hypertension or pre-eclampsia (RR 1.02, 95% CI 0.07 to 15.86; one trial, 95 women; very low-quality evidence); eclampsia (RR 0.34, 95% CI 0.01 to 8.14; one trial, 83 women; very low-quality evidence) or caesarean section (RR 0.66, 95% CI 0.29 to 1.47; one trial, 63 women; low-quality evidence). Energy-restricted versus no energy-restricted diet (three trials): no clear differences seen for: large-for-gestational age (RR 1.17, 95% CI 0.65 to 2.12; one trial, 123 infants; low-quality evidence); perinatal mortality (no events; two trials, 423 infants; low-quality evidence); pre-eclampsia (RR 1.00, 95% CI 0.51 to 1.97; one trial, 117 women; low-quality evidence); or caesarean section (RR 1.12, 95% CI 0.80 to 1.56; two trials, 420 women; low-quality evidence). DASH (Dietary Approaches to Stop Hypertension) diet versus control diet (three trials): no clear differences observed for: pre-eclampsia (RR 1.00, 95% CI 0.31 to 3.26; three trials, 136 women); however there were fewer caesarean sections in the DASH diet group (RR 0.53, 95% CI 0.37 to 0.76; two trials, 86 women). Low-carbohydrate versus high-carbohydrate diet (two trials): no clear differences seen for: large-for-gestational age (RR 0.51, 95% CI 0.13 to 1.95; one trial, 149 infants); perinatal mortality (RR 3.00, 95% CI 0.12 to 72.49; one trial, 150 infants); maternal hypertension (RR 0.40, 95% CI 0.13 to 1.22; one trial, 150 women); or caesarean section (RR 1.29, 95% CI 0.84 to 1.99; two trials, 179 women). High unsaturated fat versus low unsaturated fat diet (two trials): no clear differences observed for: large-for-gestational age (RR 0.54, 95% CI 0.21 to 1.37; one trial, 27 infants); pre-eclampsia (no cases; one trial, 27 women); hypertension in pregnancy (RR 0.54, 95% CI 0.06 to 5.26; one trial, 27 women); caesarean section (RR 1.08, 95% CI 0.07 to 15.50; one trial, 27 women); diabetes at one to two weeks (RR 2.00, 95% CI 0.45 to 8.94; one trial, 24 women) or four to 13 months postpartum (RR 1.00, 95% CI 0.10 to 9.61; one trial, six women). Low-GI versus high-fibre moderate-GI diet (one trial): no clear differences seen for: large-for-gestational age (RR 2.87, 95% CI 0.61 to 13.50; 92 infants); caesarean section (RR 1.91, 95% CI 0.91 to 4.03; 92 women); or type 2 diabetes at three months postpartum (RR 0.76, 95% CI 0.11 to 5.01; 58 women). Diet recommendation plus diet-related behavioural advice versus diet recommendation only (one trial): no clear differences observed for: large-for-gestational age (RR 0.73, 95% CI 0.25 to 2.14; 99 infants); or caesarean section (RR 0.78, 95% CI 0.38 to 1.62; 99 women). Soy protein-enriched versus no soy protein diet (one trial): no clear differences seen for: pre-eclampsia (RR 2.00, 95% CI 0.19 to 21.03; 68 women); or caesarean section (RR 1.00, 95% CI 0.57 to 1.77; 68 women). High-fibre versus standard-fibre diet (one trial): no primary outcomes reported. Ethnic-specific versus standard healthy diet (one trial): no clear differences observed for: large-for-gestational age (RR 0.14, 95% CI 0.01 to 2.45; 20 infants); neonatal composite adverse outcome (no events; 20 infants); gestational hypertension (RR 0.33, 95% CI 0.02 to 7.32; 20 women); or caesarean birth (RR 1.20, 95% CI 0.54 to 2.67; 20 women). Secondary outcomes For secondary outcomes assessed using GRADE no differences were observed: between a low-moderate and moderate-high GI diet for induction of labour (RR 0.88, 95% CI 0.33 to 2.34; one trial, 63 women; low-quality evidence); or an energy-restricted and no energy-restricted diet for induction of labour (RR 1.02, 95% CI 0.68 to 1.53; one trial, 114 women, low-quality evidence) and neonatal hypoglycaemia (average RR 1.06, 95% CI 0.48 to 2.32; two trials, 408 infants; very low-quality evidence).Few other clear differences were observed for reported outcomes. Longer-term health outcomes and health services use and costs were largely not reported. Evidence from 19 trials assessing different types of dietary advice for women with GDM suggests no clear differences for primary outcomes and secondary outcomes assessed using GRADE, except for a possible reduction in caesarean section for women receiving a DASH diet compared with a control diet. Few differences were observed for secondary outcomes.Current evidence is limited by the small number of trials in each comparison, small sample sizes, and variable methodological quality. More evidence is needed to assess the effects of different types of dietary advice for women with GDM. Future trials should be adequately powered to evaluate short- and long-term outcomes.


Pancreatic Gastrointestinal Stromal Tumor after Upper Gastrointestinal Hemorrhage and Performance of Whipple Procedure: A Case Report and Literature Review.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal system. These types of tumors originate from any part of the tract as well as from the intestine, colon, omentum, mesentery or retroperitoneum. GIST is a rare tumor compared to other types of tumors, accounting for less than 1% of all gastrointestinal tumors. A 56-year-old male patient was hospitalized due to an upper gastrointestinal hemorrhage and the start of abdominal pain on the same day. In the upper gastrointestinal endoscopy that was performed, a solitary mass was found in the second section of the duodenum and a blood vessel (Forrest type 2a) was seen. The extent and location of the mass was detected by abdominal tomography. After hemodynamic recovery, a Whipple procedure was performed without any complications. A subsequent histopathological examination detected a c-kit-positive (CD117) pancreatic GIST with high mitotic index. The most effective treatment method for GISTs is surgical resection. In patients with a head of pancreatic GIST, the Whipple procedure can be used more safely and effectively.


Octimibate inhibition of platelet aggregation: stimulation of adenylate cyclase through prostacyclin receptor activation.
Octimibate inhibited ADP- and collagen-induced platelet aggregation in human, rabbit and rat platelet-rich plasma. Washed human platelets treated with octimibate had elevated cyclic AMP (cAMP) levels and cAMP-dependent protein kinase activity. When whole platelets were incubated with radiolabeled phosphate, octimibate produced an increase in the phosphorylation of platelet proteins with relative molecular weights of 22, 26, 50 and 80 kilodaltons. This pattern of protein phosphorylation is identical to that observed when the platelets were treated with forskolin, phosphodiesterase inhibitors or other compounds that elevate platelet cAMP levels. Octimibate also inhibited the rise in intracellular Ca++ caused by thrombin, as measured using Fura-2-loaded platelets, which is consistent with octimibate's ability to elevate platelet cAMP levels. When isolated platelet plasma membranes were treated with octimibate, adenylate cyclase activity was stimulated, reaching maximal activation at 1 microM octimibate. (The maximal activation of adenylate cyclase observed with octimibate is 70-75% of that observed with 10 microM PGE1.) This stimulation of platelet adenylate cyclase activity was enhanced by GTP. Octimibate competed for radiolabeled prostaglandin E1 and lloprost binding to isolated platelet membranes at submicromolar concentrations, but did not compete with radiolabeled prostaglandin D2 binding. These studies suggest that octimibate inhibits platelet aggregation by activating platelet adenylate cyclase through stimulation of platelet prostacyclin receptors.


Ice core records of atmospheric CO2 around the last three glacial terminations
Air trapped in bubbles in polar ice cores constitutes an archive for the reconstruction of the global carbon cycle and the relation between greenhouse gases and climate in the past. High-resolution records from Antarctic ice cores show that carbon dioxide concentrations increased by 80 to 100 parts per million by volume 600 +/- 400 years after the warming of the last three deglaciations. Despite strongly decreasing temperatures, high carbon dioxide concentrations can be sustained for thousands of years during glaciations; the size of this phase lag is probably connected to the duration of the preceding warm period, which controls the change in land ice coverage and the buildup of the terrestrial biosphere.


Empty mast cell syndrome: fallacy or fact?
Post-anaphylaxis mast cell anergy (PAMA), commonly referred to as 'empty mast cell (MC) syndrome', is a state of temporary loss of cutaneous MC reactivity in the immediate aftermath of anaphylaxis. Data relating to this condition are sparse and the incidence rate is currently unknown. PAMA has been described only in a few published case reports in the context of hymenoptera venom allergy and perioperative anaphylaxis. Best practice guidelines regarding optimal timing for performing skin tests postanaphylaxis are largely based on expert opinion, and allergy work-up has been recommended after 4-6 weeks postanaphylaxis to avoid false-negative results.This article provides a review of clinical literature surrounding PAMA, critically evaluates intracellular events in MCs from in vitro data and hypothesises regarding plausible immune mechanisms. There are no published data to directly explain molecular mechanisms underlying this phenomenon. Although not evidence based, PAMA has been attributed to depletion of MC granules following anaphylaxis. It is also plausible that exposure to high allergen concentrations in anaphylaxis can induce a temporary shift in MCs towards dominance of inhibitory signalling pathways, thus contributing to a state of transient hyporesponsiveness observed in some patients. Other potential contributory factors for reduced MC reactivity include downregulation of FcεRI expression, cross-linking of FcεRI to the inhibitory, low-affinity IgG receptors and administration of pharmacotherapeutic agents for anaphylaxis treatment. It is likely that this interesting phenomenon can be explained by a combination of these proposed mechanisms in addition to other genetic/host factors that have not yet been identified.


Extinction processes in hot spots of avian biodiversity and the targeting of pre-emptive conservation action.
Hot spots of endemism are regarded as important global sites for conservation as they are rich in threatened endemic species and currently experiencing extensive habitat loss. Targeting pre-emptive conservation action to sites that are currently relatively intact but which would be vulnerable to particular human activities if they occurred in the future is, however, also valuable but has received less attention. Here, we address this issue by using data on Endemic Bird Areas (EBAs). First, we identify the ecological factors that affect extinction risk in the face of particular human activities, and then use these insights to identify EBAs that should be priorities for pre-emptive conservation action. Threatened endemic species in EBAs are significantly more likely to be habitat specialists or relatively large-bodied than non-threatened species, when compared across avian families. Increasing habitat loss causes a significant increase in extinction risk among habitat specialists, but we found no evidence to suggest that the presence of alien species/human exploitation causes a significant increase in extinction risk among large-bodied species. This suggests that these particular human activities are contributing to high extinction risk among habitat specialists, but not among large-bodied species. Based on these analyses, we identify 39 EBAs containing 570 species (24% of the total in EBAs) that are not currently threatened with severe habitat loss, but would be ecologically vulnerable to future habitat loss should it occur. We show that these sites tend to be poorly represented in existing priority setting exercises involving hot spots, suggesting that vulnerability must be explicitly included within these exercises if such sites are to be adequately protected.


The aftermath of Angie's overdose: is soap (opera) damaging to your health?
In a study designed to evaluate the behavioural impact of a fictional parasuicide--namely, Angie's overdose on the popular television soap opera EastEnders--information about cases of deliberate overdose treated in accident and emergency departments in 63 hospitals throughout Britain was obtained for the week after the televised overdose (experimental period) and the week before the overdose (control period). After adjusting for trends in the equivalent weeks in a control year (1985) the increase in the cases of parasuicide treated by hospitals during the experimental week was not found to be significant. A significant increase (31%) was found among people aged greater than or less than 45, but this is not thought to be reliable. The increase among women alone (21%) was significant with a one tailed test. Contrary to expectations there was a positive association between trends in overdose and distance from London--that is, the further the distance of the region from London the greater the increase in cases of overdose during the experimental period--and a negative association between trends in overdose and viewing figures--that is, the higher the viewing figure the less the impact on the incidence of overdoses. These findings do not lend support to the claim that there was a strong imitation effect after this televised parasuicide.


Assessment of the use of industrial by-products to remediate a copper- and arsenic-contaminated soil.
Two water treatment sludges (WTS-A, WTS-B), two red muds (RM), and red gypsum (RG), all rich in iron oxy-hydroxides, were added to a soil highly polluted with As and Cu at 2% (w/w) to reduce metal bioavailability. Because the amendments increased soil pH to approximately 6, a lime treatment to the same pH and an unamended treatment were included for comparison. All the amendments had significant positive effects on the soil microbial biomass and growth of ryegrass (Lolium multiflorum Lam. cv. Avance), but only WTS-A improved lettuce (Lactuca sativa L. cv. Tom Thumb) growth. The mineralization of added ammonium nitrogen was not significantly affected by the treatments, while a physiologically based extraction test (PBET) showed that bioaccessibility of As was low (< 5%) and decreased only in the WTS-A treatment. Concentrations of As in soil pore water and extractable As only decreased in the WTS and RG treatments. In contrast, Cu concentrations in soil pore water and extractable Cu decreased in all treatments, by more than 84% in the WTS, RM, and RG treatments. Non-isotopically exchangeable As and Cu were present in colloids in the soil pore water. Untreated soil had < 4% isotopically exchangeable As and this decreased by approximately 50%, with WTS, RM, and RG. The labile Cu pool represented a large proportion (34%) of the total Cu pool, and the isotopically exchangeable and soluble Cu were strongly correlated with soil pH. Acidification of the treated soils showed that the labile As and Cu both increased in the treated soils compared with untreated soils. The significance of the treatment effects on soil fertility and potential off-site transport of As and Cu to ground water are discussed.


Genetic susceptibility, colony size, and water temperature drive white-pox disease on the coral Acropora palmata.
Outbreaks of coral diseases are one of the greatest threats to reef corals in the Caribbean, yet the mechanisms that lead to coral diseases are still largely unknown. Here we examined the spatial-temporal dynamics of white-pox disease on Acropora palmata coral colonies of known genotypes. We took a Bayesian approach, using Integrated Nested Laplace Approximation algorithms, to examine which covariates influenced the presence of white-pox disease over seven years. We showed that colony size, genetic susceptibility of the coral host, and high-water temperatures were the primary tested variables that were positively associated with the presence of white-pox disease on A. palmata colonies. Our study also showed that neither distance from previously diseased individuals, nor colony location, influenced the dynamics of white-pox disease. These results suggest that white-pox disease was most likely a consequence of anomalously high water temperatures that selectively compromised the oldest colonies and the most susceptible coral genotypes.