Evaluation of the association of length of stay in hospital and outcomes.
There exist wide variations in healthcare quality within the National Health Service (NHS). A shorter hospital length of stay (LOS) has been implicated as premature discharge, that may in turn lead to adverse consequences. We tested the hypothesis that a short LOS might be associated with increased risk of readmissions within 28 days of hospital discharge and also post-discharge mortality. We conducted a single-centred study of 32 270 (46.1% men) consecutive alive-discharge episodes (mean age = 64.0 years, standard deviation = 20.5, range = 18-107 years), collected between 01/04/2017 and 31/03/2019. Associations of LOS tertiles (middle tertile as a reference) with readmissions and mortality were assessed using observed/expected ratios, and logistic and Cox regressions to estimate odds (OR) and hazard ratios (HR) (adjusted for age, sex, patients' severity of underlying health status and index admissions), with 95% confidence intervals (CIs). The observed numbers of readmissions within 28 days of hospital discharge or post-discharge mortality were lower than expected (observed: expected ratio < 1) in patients in the bottom tertile (<1.2 days) and middle tertile (1.2-4.3 days) of LOS, whilst higher than expected (observed: expected ratio > 1) in patients in the top tertile (>4.3 days), amongst all ages. Patients in the top tertile of LOS had increased risks for one readmission: OR = 2.32 (95% CI = 1.86-2.88) or ≥2 readmissions: OR = 6.17 (95% CI = 5.11-7.45), death within 30 days: OR = 2.87 (95% CI = 2.34-3.51), and within six months of discharge: OR = 2.52 (95% CI = 2.23-2.85), and death over a two-year period: HR = 2.25 (95% CI = 2.05-2.47). The LOS explained 7.4% and 15.9% of the total variance (r2) in one readmission and ≥2 readmissions, and 9.1% and 10.0% of the total variance in mortality with 30 days and within six months of hospital discharge, respectively. Within the bottom, middle and top tertiles of the initial LOS, the median duration from hospital discharge to death progressively shortened from 136, 126 to 80 days, whilst LOS during readmission lengthened from 0.4, 0.9 to 2.8 days, respectively. Short LOS in hospital was associated with favourable post-discharge outcomes such as early readmission and mortality, and with a delay in time interval from discharge to death and shorter LOS in hospital during readmission. These findings indicate that timely discharge from our hospital meets the aims of the NHS-generated national improvement programme, Getting It Right First Time.


Use of dietary supplements in the United States, 1988-94.
This report presents estimates of the prevalence of use of dietary supplements among the U.S. population by various demographic and descriptive characteristics, the number of products taken, and types of supplements taken by broad product-type categories. The third National Health and Nutrition Examination Survey (NHANES III) is a nationally representative survey of the civilian, noninstitutionalized U.S. population, 2 months of age or over. Participants were asked about their use of vitamin and/or mineral supplements in the past month. Many also reported use of other dietary supplements. Approximately 40 percent of the population took dietary supplements during the month prior to the interview. Females (44 percent) were more likely to take a supplement than males (35 percent). Non-Hispanic white persons (43 percent) were more likely to take supplements than non-Hispanic black persons (30 percent) and Mexican American persons (29 percent). Children 1-5 years of age were major users of supplements. Among adults 20 years of age and older, there was a trend toward increasing use of dietary supplements with age. Higher levels of education, income, and self-reported health status were all positively related to supplement use. Sixty-seven percent of supplement users took only one supplement, with the majority of them taking a combination vitamin/mineral product (46 percent). A substantial proportion of the U.S. population takes vitamins, minerals, and/or other dietary supplements.


Heart Performance Determination by Visualization in Larval Fishes: Influence of Alternative Models for Heart Shape and Volume.
Understanding cardiac function in developing larval fishes is crucial for assessing their physiological condition and overall health. Cardiac output measurements in transparent fish larvae and other vertebrates have long been made by analyzing videos of the beating heart, and modeling this structure using a conventional simple prolate spheroid shape model. However, the larval fish heart changes shape during early development and subsequent maturation, but no consideration has been made of the effect of different heart geometries on cardiac output estimation. The present study assessed the validity of three different heart models (the "standard" prolate spheroid model as well as a cylinder and cone tip + cylinder model) applied to digital images of complete cardiac cycles in larval mahi-mahi and red drum. The inherent error of each model was determined to allow for more precise calculation of stroke volume and cardiac output. The conventional prolate spheroid and cone tip + cylinder models yielded significantly different stroke volume values at 56 hpf in red drum and from 56 to 104 hpf in mahi. End-diastolic and stroke volumes modeled by just a simple cylinder shape were 30-50% higher compared to the conventional prolate spheroid. However, when these values of stroke volume multiplied by heart rate to calculate cardiac output, no significant differences between models emerged because of considerable variability in heart rate. Essentially, the conventional prolate spheroid shape model provides the simplest measurement with lowest variability of stroke volume and cardiac output. However, assessment of heart function-especially if stroke volume is the focus of the study-should consider larval heart shape, with different models being applied on a species-by-species and developmental stage-by-stage basis for best estimation of cardiac output.


Post-stress changes in the gut microbiome composition in rats with different levels of nervous system excitability.
The gut-brain axis is a critical communication system influencing the interactions between the gastrointestinal tract (GI) and the central nervous system (CNS). The gut microbiota plays a significant role in this axis, affecting the development and function of the nervous system. Stress-induced psychopathologies, such as depression and anxiety, have been linked to the gut microbiota, but underlying mechanisms and genetic susceptibility remain unclear. In this study, we examined stress-induced changes in the gut microbiome composition in two rat strains with different levels of nervous system excitability: high threshold (HT strain) and low threshold (LT strain). Rats were exposed to long-term emotional and painful stress using the Hecht protocol, and fecal samples were collected at multiple time points before and after stress exposure. Using 16S rRNA amplicon sequencing, we assessed the qualitative and quantitative changes in the gut microbiota. Our results revealed distinct microbial diversity between the two rat strains, with the HT strain displaying higher diversity compared to the LT strain. Notably, under prolonged stress, the HT strain showed an increase in relative abundance of microorganisms from the genera Faecalibacterium and Prevotella in fecal samples. Additionally, both strains exhibited a decrease in Lactobacillus abundance following stress exposure. Our findings provide valuable insights into the impact of hereditary nervous system excitability on the gut microbiome composition under stress conditions. Understanding the gut-brain interactions in response to stress may open new avenues for comprehending stress-related psychopathologies and developing potential therapeutic interventions targeted at the gut microbiota. However, further research is needed to elucidate the exact mechanisms underlying these changes and their implications for stress-induced disorders. Overall, this study contributes to the growing body of knowledge on the gut-brain axis and its significance in stress-related neurobiology.


GRP78 compartmentalized redistribution in Pb-treated glia: role of GRP78 in lead-induced oxidative stress.
Glucose-regulated protein of 78 kDa (GRP78) is an endoplasmic reticulum (ER) molecular chaperone functioning in protein folding, assembly and trafficking. GRP78 also plays a role in protection against cytotoxicity and apoptosis induced by environmental insults. Our previous study showed that lead (Pb) directly targets GRP78 by binding to the protein and increasing GRP78 levels. In this study, the effect of Pb on compartmentalized distribution of GRP78 in living cells was examined. A rat GRP78-EGFP fusion protein and EGFP were transiently expressed in astrocytoma cells exposed to 5 microM Pb acetate or 50 microM CuSO4 and fluorescence signals were captured. Control cells expressing EGFP showed a homogeneous distribution of EGFP that was not changed by Pb or Cu treatment. Cells expressing GRP78-EGFP showed a compartmentalized, non-homogeneous distribution of GRP78-EGFP in the cytosol. The redistribution of GRP78-EGFP fluorescent bodies was observed in cells exposed to Pb for 10 h, but not 5 h. Redistribution was also observed in cells exposed to 50 microM Cu for 5 or 10 h. To assess GRP78 function, GRP78 was depleted with dsRNAi oligos in rat C6 glioma cells. GRP78 depletion significantly increased the sensitivity of cells to Pb exposure as indicated by the generation of reactive oxygen species (ROS). These data suggest that Pb directly targets GRP78 and induces its compartmentalized redistribution in living cells and that GRP78 plays a protective role in Pb neurotoxicity.


Emotional contagion in nonhuman animals: A review.
Emotional contagion, the emotional state-matching of an individual with another, seems to be crucial for many social species. In recent years evidence on emotional contagion in different animal species has accumulated. However, despite its adaptative advantages and its presumed simplicity, the study and direct demonstration of this phenomenon present more complexities than previously thought. For these reasons, a review of the literature on emotional contagion in nonhuman species is timely to integrate current findings. In this paper thus, we carry out a comprehensive review of the most relevant studies on emotional contagion in animals and discuss the main problems and challenges of the field. We conclude that more research is needed to broaden our understanding of the mechanisms and functions of emotional contagion and the extent to which this process is present in a wide variety of species. Furthermore, the comparative study of emotional contagion would benefit from the use of systematized paradigms including both behavioral and physiological measures and the simultaneous recording of the responses of the interacting individuals to reliably assess an emotional state-matching between them and reliable controls. This article is categorized under: Cognitive Biology > Evolutionary Roots of Cognition Psychology > Comparative Psychology Psychology > Emotion and Motivation.


Pancreaticoduodenal artery aneurysms associated with celiac axis stenosis: report of two cases and review of the literature.
We have endeavored to define the incidence of pancreaticoduodenal artery aneurysm associated with stenosis of the celiac axis and to address modalities in this setting. This association was found in 23 of 34 cases. Aneurysmal dilation of the pancreatic arteries associated with celiac axis stenosis is not accidental and seems to be due to increased flow through the peripancreatic arteries. Hemorrhagic complications, i.e., peripancreatic hematoma, hemoperitoneum, ductal hemorrhage, were the initial manifestation in 16 of 34 cases. Isolated aneurysms were treated by resection, exclusion or embolization without any complications. For associated aneurysms, resection and exclusion were employed. Pancreatoduodenectomy was required in three cases in which bleeding was uncontrollable. In six cases, the celiac axis was restored either by arterial reconstruction, aortohepatic bypass, or division of the arcuate ligament. Four patients died. All had been operated on for ruptured aneurysm. None of the deaths was directly due to ischemic compromise of the celiac artery bed. Because of the risk of rupture, all pancreaticoduodenal artery aneurysms should be treated surgically after appropriate investigation to detect associated celiac axis stenosis. Revascularization of the celiac axis is indicated whenever blood flow is reduced or, routinely, to reduce high peripancreatic collateral flow, particularly when collaterality is due to arcuate ligament-related stenosis.


Treatment of advanced Hodgkin's disease with chemotherapy--comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD: a report from the National Cancer Institute of Canada clinical trials group.
This randomized, prospective trial compares outcomes for patients with advanced Hodgkin's disease treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, and vinblastine (ABV) hybrid regimen or alternating MOPP/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Three hundred one patients with advanced Hodgkin's disease were randomized to receive MOPP/ ABV hybrid regimen or alternating MOPP/ABVD after stratification for prior treatment, B symptoms, and treatment center. Eligible patients were either previously untreated and found to have stage IIIB, IVA, or IVB disease or previously treated with wide-field irradiation. Responding patients received a minimum of eight cycles of chemotherapy. Those with residual disease in a localized region received irradiation between the sixth and seventh cycle of treatment. Response rates to the two regimens were similar. Five-year overall survival rates were 81% and 83% for MOPP/ABV hybrid and alternating MOPP/ ABVD, respectively (P = .74; 95% confidence interval [CI] for the difference, -11% to 7%). Five-year failure-free survivals were 71% and 67% for MOPP/ABV hybrid and alternating MOPP/ABVD, respectively (P = .87; 95% CI for the difference, -9% to 17%). Significantly more episodes of febrile neutropenia and stomatitis were observed with the MOPP/ABV hybrid regimen; there was no significant difference in fatal toxicity. Patients with predefined, high-quality partial responses (PR-1s) had results similar to those with complete responses (CRs). Planned subset analysis showed no significant difference in outcome between the two arms of the trial for patients with newly diagnosed disease (5-year failure-free survival rates were 70% for MOPP/ABV hybrid and 59% for alternating MOPP/ABVD; P = .180), but superiority of alternating MOPP/ABVD for patients with prior irradiation (5-year failure-free survival 94% v 73%; P = .017). MOPP/ABV hybrid and alternating MOPP/ABVD regimens are equally effective for patients with advanced Hodgkin's disease.


Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin.
The aspartic proteinase renin plays an important physiological role in the regulation of blood pressure. It catalyses the first step in the conversion of angiotensinogen to the hormone angiotensin II. In the past, potent peptide inhibitors of renin have been developed, but none of these compounds has made it to the end of clinical trials. Our primary aim was to develop novel nonpeptide inhibitors. Based on the available structural information concerning renin-substrate interactions, we synthesized inhibitors in which the peptide portion was replaced by lipophilic moieties that interact with the large hydrophobic S1/S3-binding pocket in renin. Crystal structure analysis of renin-inhibitor complexes combined with computational methods were employed in the medicinal-chemistry optimisation process. Structure analysis revealed that the newly designed inhibitors bind as predicted to the S1/S3 pocket. In addition, however, these compounds interact with a hitherto unrecognised large, distinct, sub-pocket of the enzyme that extends from the S3-binding site towards the hydrophobic core of the enzyme. Binding to this S3(sp) sub-pocket was essential for high binding affinity. This unprecedented binding mode guided the drug-design process in which the mostly hydrophobic interactions within subsite S3(sp) were optimised. Our design approach led to compounds with high in vitro affinity and specificity for renin, favourable bioavailability and excellent oral efficacy in lowering blood pressure in primates. These renin inhibitors are therefore potential therapeutic agents for the treatment of hypertension and related cardiovascular diseases.


Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma.
Steroidogenesis-mediated production of neurosteroids is important for brain homeostasis. Cytochrome P450 17A1 (CYP17A1), which converts pregnenolone to dehydroepiandrosterone (DHEA) in endocrine organs and the brain, is required for prostate cancer progression and acquired chemotherapeutic resistance. However, whether CYP17A1-mediated DHEA synthesis is involved in brain tumor malignancy, especially in glioma, the most prevalent brain tumor, is unknown. To investigate the role of CYP17A1 in glioma, we determined that CYP17A1 expression is significantly increased in gliomas, which secrete more DHEA than normal astrocytes. We found that as gliomas became more malignant, both CYP17A1 and DHEA were significantly upregulated in temozolomide (TMZ)-resistant cells and highly invasive cells. In particular, the increase of CYP17A1 was caused by Sp1-mediated DNA demethylation, whereby Sp1 competed with DNMT3a for binding to the CYP17A1 promoter in TMZ-resistant glioma cells. CYP17A1 was required for the development of glioma cell invasiveness and resistance to TMZ-induced cytotoxicity. In addition, DHEA markedly attenuated TMZ-induced DNA damage and apoptosis. Together, our results suggest that components of the Sp1-CYP17A1-DHEA axis, which promotes the development of TMZ resistance, may serve as potential biomarkers and therapeutic targets in recurrent glioma.


p53/p21(CIP1) cooperate in enforcing rapamycin-induced G(1) arrest and determine the cellular response to rapamycin.
The relationship between G(1) checkpoint function and rapamycininduced apoptosis was examined using two human rhabdomyosarcoma cell lines, Rh1 and Rh30, that express mutated p53 alleles. Serum-starved tumor cells became apoptotic when exposed to rapamycin, but were completely protected by expression of a rapamycin-resistant mutant mTOR. Exposure to rapamycin (100 ng/ml) for 24 h significantly increased the proportion of Rh1 and Rh30 cells in G(1) phase, although there were no significant changes in expression of cyclins D1, E, or A in drug-treated cells. To determine whether apoptosis was associated with continued slow progression through G(1) to S phase, cells were exposed to rapamycin for 24 h, then labeled with bromodeoxyuridine (BrdUrd). Histochemical analysis showed that >90% of cells with morphological signs of apoptosis had incorporated BRDURD: To determine whether restoration of G(1) arrest could protect cells from rapamycin-induced apoptosis, cells were infected with replication-defective adenovirus expressing either p53 or p21(CIP1). Infection of Rh30 cells with either Ad-p53 or Ad-p21, but not control virus (Ad-beta-gal), induced G(1) accumulation, up-regulation of p21(CIP1), and complete protection of cells from rapamycin-induced apoptosis. Within 24 h of infection of Rh1 cells with Ad-p21, expression of cyclin A was reduced by >90%. Similar results were obtained after Ad-p53 infection of Rh30 cells. Consistent with these data, incorporation of [(3)H]thymidine or BrdUrd into DNA was significantly inhibited, as was cyclin-dependent kinase 2 activity. These data indicate that rapamycin-induced apoptosis in tumor cells is a consequence of continued G(1) progression during mTOR inhibition and that arresting cells in G(1) phase, by overexpression of p53 or p21(CIP1), protects against apoptosis. The response to rapamycin was next examined in wild-type or murine embryo fibroblasts nullizygous for p53or p21(CIP1). Under serum-free conditions, rapamycin-treated wild-type MEFs showed no increase in apoptosis compared to controls. In contrast, rapamycin significantly induced apoptosis in cells deficient in p53 ( approximately 2.4-fold) or p21(CIP1) ( approximately 5.5-fold). Infection of p53(-/-) MEFs with Ad-p53 or Ad-p21 completely protected against rapamycin-induced apoptosis. Under serum-containing conditions, rapamycin inhibited incorporation of BrdUrd significantly more in wild-type murine embryo fibroblasts (MEFs) than in those lacking p53 or p21(CIP1). When BrdUrd was added 24 h after rapamycin, almost 90% and 70% of cells lacking p53 or p21(CIP1), respectively, incorporated nucleoside. In contrast, only 19% of wild-type cells incorporated BrdUrd in the presence of rapamycin. Western blot analysis of cyclin levels showed that rapamycin had little effect on levels of cyclins D1 or E in any MEF strain. However, cyclin A was reduced to very low levels by rapamycin in wild-type cells, but remained high in cells lacking p53 or p21(CIP1). Taken together, the data suggest that p53 cooperates in enforcing G(1) cell cycle arrest, leading to a cytostatic response to rapamycin. In contrast, in tumor cells, or MEFs, having deficient p53 function the response to this agent may be cell cycle progression and apoptosis.


A dominant population of optically invisible massive galaxies in the early Universe.
Our current knowledge of cosmic star-formation history during the first two billion years (corresponding to redshift z > 3) is mainly based on galaxies identified in rest-frame ultraviolet light1. However, this population of galaxies is known to under-represent the most massive galaxies, which have rich dust content and/or old stellar populations. This raises the questions of the true abundance of massive galaxies and the star-formation-rate density in the early Universe. Although several massive galaxies that are invisible in the ultraviolet have recently been confirmed at early epochs2-4, most of them are extreme starburst galaxies with star-formation rates exceeding 1,000 solar masses per year, suggesting that they are unlikely to represent the bulk population of massive galaxies. Here we report submillimetre (wavelength 870 micrometres) detections of 39 massive star-forming galaxies at z > 3, which are unseen in the spectral region from the deepest ultraviolet to the near-infrared. With a space density of about 2 × 10-5 per cubic megaparsec (two orders of magnitude higher than extreme starbursts5) and star-formation rates of 200 solar masses per year, these galaxies represent the bulk population of massive galaxies that has been missed from previous surveys. They contribute a total star-formation-rate density ten times larger than that of equivalently massive ultraviolet-bright galaxies at z > 3. Residing in the most massive dark matter haloes at their redshifts, they are probably the progenitors of the largest present-day galaxies in massive groups and clusters. Such a high abundance of massive and dusty galaxies in the early Universe challenges our understanding of massive-galaxy formation.


Fusion Genes and RNAs in Cancer Development.
Fusion RNAs are a hallmark of some cancers. They result either from chromosomal rearrangements or from splicing mechanisms that are non-chromosomal rearrangements. Chromosomal rearrangements that result in gene fusions are particularly prevalent in sarcomas and hematopoietic malignancies; they are also common in solid tumors. The splicing process can also give rise to more complex RNA patterns in cells. Gene fusions frequently affect tyrosine kinases, chromatin regulators, or transcription factors, and can cause constitutive activation, enhancement of downstream signaling, and tumor development, as major drivers of oncogenesis. In addition, some fusion RNAs have been shown to function as noncoding RNAs and to affect cancer progression. Fusion genes and RNAs will therefore become increasingly important as diagnostic and therapeutic targets for cancer development. Here, we discuss the function, biogenesis, detection, clinical relevance, and therapeutic implications of oncogenic fusion genes and RNAs in cancer development. Further understanding the molecular mechanisms that regulate how fusion RNAs form in cancers is critical to the development of therapeutic strategies against tumorigenesis.


[The role of the phytogenic field of larch of the pre-fire generation in forming edaphic conditions in burned-out forest areas].
It is shown that larch of the prefire generation is the main edificator at the early stages of restorative successions in burned-out areas. Its environment-forming effect manifests itself most strongly in the phytogenic field of living trees, where edaphic conditions similar to those in primary larch forests are formed within ten years after the fire. This is accompanied by an increase in the numbers of microorganisms utilizing organic and mineral nitrogen, as well as in the rate of nitrogen mineralization in plant microgroups of this zone. Hence, living trees remaining in a burned-out area promote restoration of the initial edaphic conditions.


Paradoxical enhancement of fear extinction memory and synaptic plasticity by inhibition of the histone acetyltransferase p300.
It is well established that the coordinated regulation of activity-dependent gene expression by the histone acetyltransferase (HAT) family of transcriptional coactivators is crucial for the formation of contextual fear and spatial memory, and for hippocampal synaptic plasticity. However, no studies have examined the role of this epigenetic mechanism within the infralimbic prefrontal cortex (ILPFC), an area of the brain that is essential for the formation and consolidation of fear extinction memory. Here we report that a postextinction training infusion of a combined p300/CBP inhibitor (Lys-CoA-Tat), directly into the ILPFC, enhances fear extinction memory in mice. Our results also demonstrate that the HAT p300 is highly expressed within pyramidal neurons of the ILPFC and that the small-molecule p300-specific inhibitor (C646) infused into the ILPFC immediately after weak extinction training enhances the consolidation of fear extinction memory. C646 infused 6 h after extinction had no effect on fear extinction memory, nor did an immediate postextinction training infusion into the prelimbic prefrontal cortex. Consistent with the behavioral findings, inhibition of p300 activity within the ILPFC facilitated long-term potentiation (LTP) under stimulation conditions that do not evoke long-lasting LTP. These data suggest that one function of p300 activity within the ILPFC is to constrain synaptic plasticity, and that a reduction in the function of this HAT is required for the formation of fear extinction memory.


Hepatitis C virus stabilizes hypoxia-inducible factor 1alpha and stimulates the synthesis of vascular endothelial growth factor.
Hepatitis C virus (HCV) infection is one of the major causes of chronic hepatitis, liver cirrhosis, which subsequently leads to hepatocellular carcinoma (HCC). The overexpression of the angiogenic factors has been demonstrated in HCC. In this study, we investigated the potential of HCV gene expression in inducing angiogenesis. Our results show that HCV infection leads to the stabilization of hypoxia-inducible factor 1alpha (HIF-1alpha). We further show that this stabilization was mediated via oxidative stress induced by HCV gene expression. The activation of NF-kappaB, STAT-3, PI3-K/AkT, and p42/44 mitogen-activated protein kinase was necessary for HIF-1alpha stabilization. HIF-1alpha induction in turn led to the stimulation of vascular endothelial growth factor. By using the chick chorioallantoic membrane assay, we show that HCV-infected cells released angiogenic cytokines, leading to neovascularization in vivo. These results indicate the potential of HCV gene expression in angiogenesis.


Alcohol inhibits T-cell glucose metabolism and hepatitis in ALDH2-deficient mice and humans: roles of acetaldehyde and glucocorticoids.
Aldehyde dehydrogenase 2 (ALDH2), a key enzyme to detoxify acetaldehyde in the liver, exists in both active and inactive forms in humans. Individuals with inactive ALDH2 accumulate acetaldehyde after alcohol consumption. However, how acetaldehyde affects T-cell hepatitis remains unknown. Wild-type (WT) and Aldh2 knockout (Aldh2-/-) mice were subjected to chronic ethanol feeding and concanavalin A (ConA)-induced T-cell hepatitis. Effects of acetaldehyde on T-cell glucose metabolism were investigated in vitro. Human subjects were recruited for binge drinking and plasma cortisol and corticosterone measurement. Ethanol feeding exacerbated ConA-induced hepatitis in WT mice but surprisingly attenuated it in Aldh2-/- mice despite higher acetaldehyde levels in Aldh2-/- mice. Elevation of serum cytokines and their downstream signals in the liver post-ConA injection was attenuated in ethanol-fed Aldh2-/- mice compared to WT mice. In vitro exposure to acetaldehyde inhibited ConA-induced production of several cytokines without affecting their mRNAs in mouse splenocytes. Acetaldehyde also attenuated interferon-γ production in phytohaemagglutinin-stimulated human peripheral lymphocytes. Mechanistically, acetaldehyde interfered with glucose metabolism in T cells by inhibiting aerobic glycolysis-related signal pathways. Finally, compared to WT mice, ethanol-fed Aldh2-/- mice had higher levels of serum corticosterone, a well-known factor that inhibits aerobic glycolysis. Blockade of corticosterone partially restored ConA-mediated hepatitis in ethanol-fed Aldh2-/- mice. Acute alcohol drinking elevated plasma cortisol and corticosterone levels in human subjects with higher levels in those with inactive ALDH2 than those with active ALDH2. ALDH2 deficiency is associated with elevated acetaldehyde and glucocorticoids post-alcohol consumption, thereby inhibiting T-cell activation and hepatitis.


"Riding High on Low Fuel" - Our Experience with Endogenous Hyperinsulinemic Hypoglycemia.
Endogenous hyperinsulinemic hypoglycemia (EHH) is a condition in which the insulin levels are inappropriately high in the presence of low plasma glucose. We did a retrospective analysis of case records of those patients admitted and evaluated for EHH from June 2004 to June 2016 in our center, excluding those that were diagnosed with reactive hypoglycemia. We collected data regarding demographics, clinical presentation, laboratory results, localization techniques, and treatment administered. Sixteen patients who were admitted for evaluation based on history suggestive of repeated hypoglycemic episodes were included in the study. All but one pregnant patient was subjected to a supervised fast in the hospital. All patients developed hypoglycemia (defined using Whipple's triad) within the first 24 h. Three patients had autoimmune hypoglycemia which differed significantly from insulinoma-mediated hypoglycemia in certain clinical and laboratory parameters. They were older in age with marked fluctuations in the 24 h glucose profile ranging from frank hypoglycemia to frank hyperglycemia. The insulin levels were markedly elevated in this group of patients along with a significantly elevated insulin C peptide molar ratio (ICMR) when compared with patients with insulinoma-mediated hypoglycemia. Although insulinoma is the most common cause of EHH, autoimmune hypoglycemia should be considered as a differential diagnosis, particularly in older individuals with plasma glucose values increasing to the hyperglycemic range. Degree of elevation of insulin levels and ICMR may provide additional clues. Overall, the survival and prognosis of patients with EHH are excellent.


[Cervical abscess by Streptococcus anginosus-milleri after foreign body ingestion and suspicion of esophageal perforation].
We report a case of cervical abscess after the ingestion of foreign body (chicken bone) secondary to probable esophageal perforation that it was sent to us with suspicion of mediastinal complication. The girl, 17 years-old, nothing else to arrive our hospitalary center required entrance in ICU due to her severe clinical process: High fever, intense neck-thoracic pain, laterocervical diffuse and progressive left inflammation and bad general state. The CT showed the presence of a well defined abscess and abundant aerial component that dissected the cervical muscles that made necessary to perform drainage verifying intraoperatively no mediastinal involvement. The culture of the purulent collection revealed Streptococcus anginosus/milleri resistant to clindamicine but sensible to penicilina and derivatives. We exposed a serie of considerations at respect of such microorganism and its clinical signification.


Evolution in fertility-preserving options for early-stage cervical cancer: radical trachelectomy, simple trachelectomy, neoadjuvant chemotherapy.
Fertility preservation is of paramount importance for young women diagnosed with early-stage cervical cancer. The radical trachelectomy procedure was developed to preserve uterine/reproductive function. The procedure has evolved significantly over the last 25 years. This review focuses on the various surgical techniques (vaginal, abdominal, laparoscopic, and robotic), highlighting advantages and disadvantages of each in relation to their respective obstetrical and oncologic outcomes. A trend toward even more conservative surgery (simple trachelectomy/large cone) has recently been advocated for patients with low-risk early lesions. Conversely, the option of neoadjuvant chemotherapy followed by fertility-preserving surgery for patients with larger-size lesions has also been proposed. Emerging data are presented.


The Nurse Anesthetists' Adherence to Swedish National Recommendations to Maintain Normothermia in Patients During Surgery.
The aim of this study was to determine if nurse anesthetists (NAs) have access, knowledge, and adhere to recommended guidelines to maintain normal body temperature during the perioperative period. A descriptive survey design. Questionnaires were sent to heads of the department (n = 56) and NAs in the operating departments in Sweden. The level of access to the recommendations is high, but only one third of the operating departments have included the recommendations in their own local guidelines. The NAs' adherence was low, between 5% and 67%, and their knowledge levels were 57% to 60%. A high level of knowledge, access, and adherence are important for the organization of operating departments to prevent barriers against implementation of new recommendations or guidelines. There are needs for education about patients' heat loss due to redistribution and clear recommendations.


Dibutyryl cyclic AMP does not influence glomerular collagen or basement membrane production in vitro.
Glomeruli isolated from normal rat renal cortex were incubated for 3 hr with radiolabeled proline in the presence or absence of dibutyryl cyclic AMP. Following incubation, glomerular basement membranes were purified with osmotic lysis followed by selective solubilization of the cell membranes and intracellular proteins with detergents. This technique permitted quantitative recovery of radiolabeled membranes synthesized under different incubational conditions. Dibutyryl cyclic AMP did not affect the incorporation of radioactive precursor glomerular basement membrane (control = 14.72 +/- 1.08 cpm/microgram of membrane protein; cyclic AMP = 14.43 +/- 1.13). Nondialyzable [14C]protein and hydroxy[14C]proline were also measured in the media and in the various glomerular cell fractions obtained during isolation of the basement membranes. Protein ([14C]proline) and collagen (OH[14C]proline) secretion into the media in incubations with cyclic AMP did not differ from that in control incubations. OH[14C]proline content was greatest (congruent to 23% in the water-soluble fraction recovered after osmotic lysis, but significant amounts of OH[14C]proline were also associated with the detergent-solubilized cell fractions. Dibutyryl cyclic AMP had no effect on either glomerular protein or collagen synthesis in these experiments. The results suggest that total glomerular basement membrane production in mixed cell populations is not modulated via a cyclic AMP--coordinated mechanism but do not exclude the possibility that cyclic AMP modulates the amount or kind of collagen synthesis by individual glomerular cell types.


Potential molecular semiconductor devices: cyclo-Cn (n = 10 and 14) with higher stabilities and aromaticities than acknowledged cyclo-C18.
The successful synthesis and isolation of cyclo-C18 in experiments is a ground-breaking development in carbon rings. Herein, we studied the thermodynamic stabilities of cyclo-Cn (4 ≤ n ≤ 34) with hybrid density functional theory. When n = 4N + 2 (N is an integer), cyclo-Cn were thermodynamically stable. In particular, cyclo-C10 and cyclo-C14 were more thermodynamically, kinetically, dynamically, and optically stable compared with the acknowledged cyclo-C18, and were potential candidates for zero-dimensional carbon rings. Cyclo-Cn (n = 10 and 14) show similar molecular semiconductor characteristics to the acknowledged cyclo-C18. The carbon atoms were sp hybridized in cyclo-C10, cyclo-C14, and cyclo-C18. Cyclo-C14 and cyclo-C18 had alternating abnormal single and triple bonds, but cyclo-C10 had equal bonds. Cyclo-C10, cyclo-C14, and cyclo-C18 with large aromaticities had out-of-plane and in-plane π systems, which were perpendicular to each other. The number of π electrons in the out-of-plane and in-plane π systems, respectively, followed the standard Hückel aromaticity rule. Simulated UV-vis-NIR spectra indicated similar electronic structures of cyclo-C14 and cyclo-C18.


Colorimetric Band-aids for Point-of-Care Sensing and Treating Bacterial Infection.
Sensing bacterial infections and monitoring drug resistance are very important for the selection of treatment options. However, the common methods of sensing resistance are limited by time-consuming, the requirement for professional personnel, and expensive instruments. Moreover, the abuse of antibiotics causes the accelerated process of bacterial resistance. Herein, we construct a portable paper-based band-aid (PBA) which implements a selective antibacterial strategy after sensing of drug resistance. The colors of PBA indicate bacterial infection (yellow) and drug resistance (red), just like a bacterial resistance colorimetric card. On the basis of color, antibiotic-based chemotherapy and Zr-MOF PCN-224-based photodynamic therapy (PDT) are used on site to treat sensitive and resistant strains, respectively. Eventually, it takes 4 h to sense, and the limit of detection is 104 CFU/mL for drug-resistant E. coli. Compared with traditional PDT-based antibacterial strategies, our design can alleviate off-target side effects, maximize therapeutic efficacy, and track the drug resistance in real time with the naked eye. This work develops a new way for the rational use of antibiotics. Given the low cost and easy operation of this point-of-care device, it can be developed for practical applications.


microRNA172 plays a crucial role in wheat spike morphogenesis and grain threshability.
Wheat domestication from wild species involved mutations in the Q gene. The q allele (wild wheats) is associated with elongated spikes and hulled grains, whereas the mutant Q allele (domesticated wheats) confers subcompact spikes and free-threshing grains. Previous studies showed that Q encodes an AP2-like transcription factor, but the causal polymorphism of the domestication traits remained unclear. Here, we show that the interaction between microRNA172 (miR172) and the Q allele is reduced by a single nucleotide polymorphism in the miRNA binding site. Inhibition of miR172 activity by a miRNA target mimic resulted in compact spikes and transition from glumes to florets in apical spikelets. By contrast, overexpression of miR172 was sufficient to induce elongated spikes and non-free-threshing grains, similar to those observed in three Q loss-of-function mutations. These lines showed transitions from florets to glumes in the basal spikelets. These localized homeotic changes were associated with opposing miR172/Q gradients along the spike. We propose that the selection of a nucleotide change at the miR172 binding site of Q contributed to subcompact spikes and free-threshing grains during wheat domestication.


Occurrence of tongue worm, Linguatula cf. serrata (Pentastomida: Linguatulidae) in wild canids and livestock in south-eastern Australia.
Pentastomids are obligate zoonotic arthropod parasites utilising canids and vulpids as their definitive hosts and several herbivorous species as their intermediate hosts. Reported only 10 times in Australia over the last 150 years as incidental findings, adult Pentastomids referred to as Linguatula serrata have been encountered in nasal cavities of domestic and wild dogs, and foxes. Nymphs have been reported in cattle and rabbits. In the present study, a number of potential definitive hosts, including red foxes (Vulpes vulpes), wild dogs (Canis lupus dingo and C.l. dingo x C. familiaris) and feral cats (Felis catus), and intermediate hosts cattle (Bos taurus), sheep (Ovis aries), feral pigs (Sus scrofa), rabbits (Oryctolagus cuniculus), goats (Capra hircus) and a European hare (Lepus europaeus), from the highlands of south-eastern Australia were examined. Of the animals examined 67.6% of wild dogs (n = 37), 14.5% of red foxes (n = 55) and 4.3% of cattle (n = 164) were found to be infected with Pentastomids, herein identified as Linguatula cf. serrata. The common occurrence of the parasite in wild dogs and less frequently in foxes suggests these wild canids have potential to act as a reservoir for infection of livestock, wildlife, domestic dogs and possibly humans. The unexpected high frequency of the parasite in wild dogs and foxes in south-eastern Australia suggests the parasite is more common than previously realised. Of the potential intermediate hosts in the region, only 4.3% of cattle were found to be infected with pentastomid nymphs which suggest the search for the host(s) acting as the main intermediate host in the region should continue. Future studies should investigate transmission patterns, health impacts on hosts and whether the parasite has zoonotic significance in Australia.


Targeting protein kinase C (PKC) in physiology and cancer of the gastric cell system.
Protein kinase C (PKC) family members are multifunctional kinases that have been implicated in many cell biological and physiological tasks including acid, pepsinogen, and mucous production. Through the use of small-molecule PKC modulators, PKC has been found to be involved in gene expression, the control of cytoskeleton, membrane and secretagogue-dependent signal transduction for secretion of acid. Gastric carcinoma and adenocarcinoma cells often show dysregulated PKC-dependent cell signal transduction compared to normal gastric cells. Moreover, PKC was the first known target of tumor promoting phorbol esters. These findings support PKC as a potential chemotherapy target in gastric cancer. Various approaches have been launched in directly targeting PKC for chemotherapy of gastric cancer. The macrocyclic lactone bryostatin-1 is a promising agent that acts as a modulator of PKC activity, and enhances the effect of chemotherapeutic agents such as paclitaxel. This article provides an overview of the findings to date regarding the physiological role of PKC in the gastric cell system by various pharmacological approaches and examines PKC as a target in gastric (adeno-)carcinoma chemotherapy.


Smart Environments and Social Robots for Age-Friendly Integrated Care Services.
The world is facing major societal challenges because of an aging population that is putting increasing pressure on the sustainability of care. While demand for care and social services is steadily increasing, the supply is constrained by the decreasing workforce. The development of smart, physical, social and age-friendly environments is identified by World Health Organization (WHO) as a key intervention point for enabling older adults, enabling them to remain as much possible in their residences, delay institutionalization, and ultimately, improve quality of life. In this study, we survey smart environments, machine learning and robot assistive technologies that can offer support for the independent living of older adults and provide age-friendly care services. We describe two examples of integrated care services that are using assistive technologies in innovative ways to assess and deliver of timely interventions for polypharmacy management and for social and cognitive activity support in older adults. We describe the architectural views of these services, focusing on details about technology usage, end-user interaction flows and data models that are developed or enhanced to achieve the envisioned objective of healthier, safer, more independent and socially connected older people.


Breaking bad news in the emergency department: a comparative analysis among residents, patients and family members' perceptions.
Our main objective was to assess patient and family members' perception of bad news communication in the emergency department (ED) and compare these with physicians' perceptions. This is a cross-sectional study carried out at the ED of a tertiary teaching hospital. To compare physicians' and receivers' (patient and/or family member) perceptions, we created a survey based on the six attributes derived from the SPIKES protocol. The surveys were applied immediately after communication of bad news occurred in the ED. We analyzed agreement among participants using κ-statistics and the χ-test to compare proportions. A total of 73 bad news communication encounters were analyzed. The survey respondents were 73 physicians, 69 family members, and four patients. In general, there is a low level of agreement between physicians' and receivers' perceptions of how breaking bad news transpired. The satisfaction level of receivers, in terms of breaking bad news by doctors, presented a mean of 3.7±0.6 points. In contrast, the physicians' perception of the communication was worse (2.9±0.6 points), with P value less than 0.001. Doctors and receivers disagree in relation to what transpired throughout bad news communications. Discrepancies were more evident in issues involving emotion, invitation, and privacy. An important agreement between perceptions was found in technical and knowledge-related aspects of the communication.


Chromosome-level genome assembly of the Asian spongy moths Lymantria dispar asiatica.
The Asian spongy moth, Lymantria dispar asiatica, is one of the most devastating forestry defoliators. The absence of a high-quality genome limited the understanding of its adaptive evolution. Here, we conducted the first chromosome-level genome assembly of L. dispar asiatica using PacBio HIFI long reads, Hi-C sequencing reads and transcriptomic data. The total assembly size is 997.59 Mb, containing 32 chromosomes with a GC content of 38.91% and a scaffold N50 length of 35.42 Mb. The BUSCO assessment indicated a completeness estimate of 99.4% for this assembly. A total of 19,532 protein-coding genes was predicted. Our study provides a valuable genomics resource for studying the mechanisms of adaptive evolution and facilitate an efficient control of L. dispar asiatica.


Ecological transition from natural forest to tea plantations: effect on the dynamics of malaria vectors in the highlands of Cameroon.
From October 2002 to September 2003, an entomological survey was carried out in a rural forested fringed village in the highlands of Mount Cameroon region to determine the temporal dynamics of the anopheline population and the intensity of malaria transmission. A total of 2387 Anopheles spp. were collected, with A. funestus predominating (59.9%), followed by A. hancocki (24.4%) and A. gambiae s.l. (15.7%). Considerable differences were observed in the nocturnal biting cycles of parous mosquitoes, with peak activity in the latter part of the night. PCR revealed that all specimens of the A. funestus group were A. funestus s.s. and all specimens from the A. gambiae complex were A. gambiae s.s. of the S molecular form. Plasmodium falciparum sporozoite rates of 17.3% and 8.5% were recorded for A. funestus and A. hancocki, respectively, with an anthropophilic rate of 96.3%. A strong positive correlation (r=0.996) was found between the human-biting rate and the entomological inoculation rate (EIR). Malaria transmission was very high and perennial, with an estimated annual EIR of 460.1 infective bites per person per year. These results confirm that in high agricultural activity areas, A. funestus can be by far the major malaria vector responsible for malaria transmission.


Amyand's hernia with perforated appendix in a neonate.
Inguinal hernia with acute appendicitis known as Amyand's hernia is uncommon. It occurs mostly in adults, older children and infants. The appendix inside the hernial sac is rarely perforated. The authors describe in a neonate aged 14 days an unusual case of inguinal hernia containing a perforated appendix that was clinically considered as a strangulated inguinal hernia. Surgery performed with an inguinal approach permitted us to remove the appendix and close the hernial sac. The postoperative course was uneventful after a follow-up of 1 year.


Using Healthcare Databases to Refine Understanding of Exploratory Associations Between Drugs and Progression of Open-Angle Glaucoma.
We sought to refine understanding about associations identified in prior studies between angiotensin-II receptor blockers, metformin, selective serotonin reuptake inhibitors, fibric-acid derivatives, or calcium channel blockers and progression to glaucoma filtration surgery for open-angle glaucoma (OAG). We used new-initiator, active-comparator cohort designs to investigate these drugs in two data sources. We adjusted for confounders using stabilized inverse-probability-of-treatment weights and evaluated results using "intention-to-treat" and "as-treated" follow-up approaches. In both data sources, Kaplan-Meier curves showed trends for more rapid progression to glaucoma filtration surgery in patients taking calcium channel blockers compared with thiazides with as-treated (MarketScan P = 0.15; Medicare P = 0.03) and intention-to-treat follow-up (MarketScan P < 0.01; Medicare P = 0.10). There was suggestion of delayed progression for selective serotonin reuptake inhibitor compared with tricyclic antidepressants in Medicare, which was not observed in MarketScan. Our study provided support for a relationship between calcium channel blockers and OAG progression but not for other investigated drugs.


Repression of the Drosophila proliferating-cell nuclear antigen gene promoter by zerknüllt protein.
A 631-bp fragment containing the 5'-flanking region of the Drosophila melanogaster proliferating-cell nuclear antigen (PCNA) gene was placed upstream of the chloramphenicol acetyltransferase (CAT) gene of a CAT vector. A transient expression assay of CAT activity in Drosophila Kc cells transfected with this plasmid and a set of 5'-deletion derivatives revealed that the promoter function resided within a 192-bp region (-168 to +24 with respect to the transcription initiation site). Cotransfection with a zerknüllt (zen)-expressing plasmid specifically repressed CAT expression. However, cotransfection with expression plasmids for a nonfunctional zen mutation, even-skipped, or bicoid showed no significant effect on CAT expression. RNase protection analysis revealed that the repression by zen was at the transcription step. The target sequence of zen was mapped within the 34-bp region (-119 to -86) of the PCNA gene promoter, even though it lacked zen protein-binding sites. Transgenic flies carrying the PCNA gene regulatory region (-607 to +137 or -168 to +137) fused with lacZ were established. When these flies were crossed with the zen mutant, ectopic expression of lacZ was observed in the dorsal region of gastrulating embryos carrying the transgene with either construct. These results indicate that zen indirectly represses PCNA gene expression, probably by regulating the expression of some transcription factor(s) that binds to the PCNA gene promoter.


A review of dietary and environmental correlates of obesity with emphasis on developing countries.
The relationships between dietary and environmental factors and obesity are reviewed. Findings from selected population studies of diet and body weight are presented. In general, the results from population studies of diet and obesity have been inconsistent and marked with methodological weaknesses, especially the use of cross-sectional study design. Apart from the diet, several social and economic factors appear to be important correlates of obesity in the population. However, most studies have focused on the socioeconomic status as a broad, composite measure. The relationships between income, education, occupation, place of residence, and obesity are reviewed here, with emphasis on the developing countries. In many developing countries, the changing dietary pattern, along with rising life expectancy and changing socioeconomic environment, has contributed to the increasing problems of obesity and other diet-related chronic diseases that will have an enormous impact on the health and health care resource of these countries in the near future.


Is arcA3 a possible mediator in the signal transduction pathway during agonist cell cycle arrest by salicylic acid and UV irradiation?
Progression of BY-2 tobacco cells through the cell cycle was followed after treatments with ultra violet (UV) and salicylic acid (SA) used as a potent inhibitor of the octadecanoid pathway which can mediate response to UV irradiation. Cells in S phase were more sensitive than G0/G1 or G2 cells to UV irradiation. Although SA efficiently blocked cells in G0/G1 or G2, it did not block S phase synchronized cells. UV and SA applied simultaneously to cells in G0/G1 delayed the cell cycle progression more than each one separately. Therefore UV irradiation and SA act as agonists to arrest BY-2 cells at cell cycle entry. To further investigate the signalling pathway mediating UV response, we complemented a UV-sensitive Escherichia coli strain with a Nicotiana xanthi cDNA expression library. A cDNA (arcA3) whose coding sequence is identical to the 2,4-D induced arcA cDNA cloned by Ishida et al. (1993) was isolated. We show that arcA3 transcription is induced at cell cycle entry but not directly by the 2,4-D treatment. Moreover, arcA3 transcription is induced prior to the restriction point as shown with the CDK inhibitor roscovitine. The arcA3 transcription level is increased by UV irradiation but prevented by SA. Indeed, addition of SA prior to UV irradiation blocks the induction of arcA3 transcription. This suggests that arcA3 gene is modulated in both UV and SA responses, the SA effect preceding the UV step. Since arcA3 is 67% similar to RACK1 (functional homology), a rat intracellular receptor for protein kinase C, and possesses identical PKC fixation motifs, it is hypothesised that the arcA3 gene is involved in UV and SA cell cycle arrest.


Pomegranate leaf attenuates lipid absorption in the small intestine in hyperlipidemic mice by inhibiting lipase activity.
Pomegranate leaf (PGL) has a definite role in regulating lipid metabolism. However, pharmacokinetic results show the main active ingredient, ellagic acid, in PGL has lower oral bioavailability, suggesting that the lipid-lowering effect of PGL may act through inhibiting lipid absorption in the small intestine. Our results demonstrated that pomegranate leaf and its main active ingredients (i.e., ellagic acid, gallic acid, pyrogallic acid and tannic acid) were capable of inhibiting pancreatic lipase activity in vitro. In computational molecular docking, the four ingredients had good affinity for pancreatic lipase. Acute lipid overload experiments showed that a large dosage of PGL significantly reduced serum total cholesterol (TG) and triglycerides (TC) levels in addition to inhibiting intestinal lipase activity, which demonstrated that PGL could inhibit lipase activity and reduce the absorption of lipids. We also found that PGL could reverse the reduced tight-junction protein expression due to intestinal lipid overload, promote Occludin and Claudin4 expression in the small intestine, and enhance the intestinal mucosal barrier. In conclusion, we demonstrated that PGL can inhibit lipid absorption and reduce blood TG and TC by targeting pancreatic lipase, promoting tight-junction protein expression and thereby preventing intestinal mucosa damage from an overload of lipids in the intestine.


The beta 1 subunit of L-type voltage-gated Ca2+ channels independently binds to and inhibits the gating of large-conductance Ca2+-activated K+ channels.
Large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels encoded by the Slo1 gene are ubiquitously expressed, and they play a role in regulation of many cell types. In excitable cells, BK(Ca) channels and voltage-activated Ca(2+) channels often form functional complexes that allow the cytoplasmic domains of BK(Ca) channels to lie within spatially discrete calcium microdomains. Here, we report a novel protein interaction between the beta1-subunit of L-type voltage-activated calcium channels (Ca(v)beta1) and critical regulatory domains of Slo1 that can occur in the absence of other proteins. This interaction was identified by a yeast two-hybrid screen, and it was confirmed by confocal microscopy in native neurons, by coimmunoprecipitation, and by direct binding assays. The Ca(v)beta1 subunit binds within the calcium bowl domain of Slo1 that mediates a portion of high-affinity Ca(2+) binding to BK(Ca) channels and also to a noncanonical Src homology 3 (SH3) domain-binding motif within Slo1. Binding of Ca(v)beta1 markedly slows Slo1 activation kinetics, and it causes a significant decrease in Ca(2+) sensitivity in inside-out and in dialyzed cells, even in the absence of pore-forming subunits of voltage-gated Ca(2+) channels. The guanylate kinase domain of Ca(v)beta1 mediates Slo1 regulation through its binding to calcium bowl domains, and this domain of Ca(v)beta1 is necessary and sufficient for the observed effects on BK(Ca) activation. Binding of Ca(v)beta1 to SH3-binding motifs may stabilize the interaction with Slo1, or it may contribute to formation of other complexes, but it does not seem to affect Ca(2+)-dependent gating of Slo1. Binding of Ca(v)beta1 does not affect cell surface expression of Slo1 in human embryonic kidney 293T cells.


Aortic valve sclerosis is associated with preclinical cardiovascular disease in hypertensive adults: the Hypertension Genetic Epidemiology Network study.
Aortic valve sclerosis (AVS) has been associated with atherosclerosis and increased all-cause and cardiovascular death. However, whether AVS is associated with preclinical cardiovascular disease among adults at high risk because of hypertension has not been determined in a population-based sample. Clinical and echocardiographic parameters were measured in 1624 hypertensive participants (54 +/- 11 years, 65% women, 63% black, 17% diabetic, 19% smokers) without significant valvular or cardiovascular diseases in the population-based Hypertension Genetic Epidemiology Network study. The 152 participants with AVS (9.4%), compared with participants without AVS, were older, more often white, male, treated for hypertension or hypercholesteromia (all P < 0.05) and had longer duration and worse hypertension, but did not differ in diabetes status, smoking or fenfluramine use. Adjusting for age, gender and race, the AVS group had higher total cholesterol/high-density lipoprotein-cholesterol (P < 0.05). Controlling for age, gender, race and other clinical covariates, AVS was independently associated with higher septal, posterior and relative wall thicknesses, isovolumic relaxation time and left atrial diameter, and with mild aortic regurgitation and mitral annular calcification (all P < 0.05). In a population-based sample of hypertensive adults, AVS was prevalent (9.4%) and associated with a proatherogenic clinical profile and abnormal left ventricular geometry and filling, increased left atrial size and mitral annular calcification, which may contribute to the adverse prognosis associated with AVS.


Self-perceived Income Sufficiency and Self-reported Income Level among a Health Inequity Population.
This study presents a dynamic approach to collecting income information. We conducted a cross-sectional survey of 2,022 residents of historically underserved Appalachian Kentucky, an ideal location due to pervasive low income and our ability to control for potential confounders such as race/ethnicity and residential heterogeneity. In unadjusted analyses, nearly half of the sample indicated they struggled to meet their needs; 43% said they made just enough to get by; and 10% indicated they had more than they needed to live well. Adjusting for socio-demographic characteristics, proportionately more of those with lower self-rated health and a higher number of morbidities reported struggling to make ends meet. Less than 1% refused to respond to the question on self-perceived income sufficiency, compared with 20% who refused to report income levels. We conclude that self-perceived income sufficiency is a useful question to assess resources, both theoretically and practically, in an underserved population.


Chromosomal recombination in Haemophilus influenzae.
Haemophilus influenzae cultures doubly lysogenic for defective phage HP1, with a prophage marker sequence +b+/a+c, always contained some free wild-type phage. Single ultraviolet-irradiated cells produced either no wild-type phage or large numbers of them. This suggested that the phage was not released by the original double lysogen but by internal recombinants, i.e., by double lysogens with altered prophage marker sequence such as +++/abc or +b+/++c. Thirty-one wild-type phage-producing clones have been isolated independently from cultures of this double lysogen and identified. They fell in five classes. Two classes, still possessing all three prophage markers, can be explained by Campbell's (1963) prophage recombination model. The other classes had lost one or more markers. They can be explained by interchromosomal double-strand DNA breakage and rejoining. A single-DNA-strand gene conversion model is discussed in view of the fact that genetic transformation involves single-DNA-strand exchanges. A number of potentially interesting mutants has been analyzed of which only the derivatives of rec1 mutant DB117 (obtained from Dr. J. Setlow) were incapable of internal recombination.


Twelve tips to facilitate the transition between research and clinical training in physician scientist education.
This article was migrated. The article was marked as recommended. Medical scientist trainees who take extended scholarly time in the middle of their training experience challenges during transitions in training. As they complete their dissertation and re-enter the clinical years of medical school, there is marked by a loss of clinical knowledge and skills over a prolonged hiatus from medicine and mismatched expectations. We have developed a re-entry pathway including guidance, support, and a course to provide clinical skills and knowledge training to align expectations, dispel myths, and allow advanced planning to meet milestones. Students reporting satisfaction with their transition from PhD to MD3 and 90% of students reported that the pathway was valuable. We provide 12 tips on how to improve the transition from research to clinical training. Here we demonstrate that a planned pathway for the transition back to medical training can improve the student-mentor experience, reduce anxiety, and create a more seamless and successful transition.


Altered L-arginine metabolism results in increased nitric oxide release from uraemic endothelial cells.
Results regarding the nitric oxide (NO) system in uraemia are contradictory. L-arginine, the precursor of NO, is also metabolized by arginase to form ornithine and urea. In the present study, endothelial NO production and arginine metabolism in uraemia were assessed. In addition an in vivo model was used to examine excess consumption of NO in uraemia. NO and amino acid measurements were made from basal and stimulated (by bradykinin) uraemic and control endothelial cells. Reverse-transcriptase PCR was used to assess endothelial NO synthase (eNOS) and inducible NOS (iNOS) expression. Finally, aortae of uraemic rats were stained for nitrotyrosine (a marker of peroxynitrite). Basal uraemic cells produced more NO than the control cells. L-arginine levels were greater in uraemic (supernatants/cells), but ornithine levels were higher in control (supernatants/cells). Following stimulation, NO levels in supernatants were similar, but the rise in NO production was greater in control compared with uraemic cells; l-arginine levels still remained higher in uraemic supernatants/cells. Differences in ornithine concentration (supernatants/cells) disappeared following bradykinin stimulation, due to a rise in ornithine levels in the uraemic group. There was no difference in eNOS expression, nor was iNOS detected in either group. Only aortae from uraemic rats showed evidence for nitrotyrosine staining. These studies demonstrated increased basal NO release in uraemic endothelial cells, perhaps by inhibition of arginase and hence diversion of arginine to the NO pathway. The increased NO produced under basal conditions may be inactive due to excessive consumption, resulting in peroxynitrite formation. Interestingly, bradykinin appears to restore arginase activity in uraemia, resulting in normalization of NO production.


DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson's disease.
In the brain, programmed cell death (PCD) serves to adjust the numbers of the different types of neurons during development, and its pathological reactivation in the adult leads to neurodegeneration. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) is a pleiotropic kinase involved in neural proliferation and cell death, and its role during brain growth is evolutionarily conserved. Human DYRK1A lies in the Down syndrome critical region on chromosome 21, and heterozygous mutations in the gene cause microcephaly and neurological dysfunction. The mouse model for DYRK1A haploinsufficiency (the Dyrk1a(+/-) mouse) presents neuronal deficits in specific regions of the adult brain, including the substantia nigra (SN), although the mechanisms underlying these pathogenic effects remain unclear. Here we study the effect of DYRK1A copy number variation on dopaminergic cell homeostasis. We show that mesencephalic DA (mDA) neurons are generated in the embryo at normal rates in the Dyrk1a haploinsufficient model and in a model (the mBACtgDyrk1a mouse) that carries three copies of Dyrk1a. We also show that the number of mDA cells diminishes in postnatal Dyrk1a(+/-) mice and increases in mBACtgDyrk1a mice due to an abnormal activity of the mitochondrial caspase9 (Casp9)-dependent apoptotic pathway during the main wave of PCD that affects these neurons. In addition, we show that the cell death induced by 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), a toxin that activates Casp9-dependent apoptosis in mDA neurons, is attenuated in adult mBACtgDyrk1a mice, leading to an increased survival of SN DA neurons 21 days after MPTP intoxication. Finally, we present data indicating that Dyrk1a phosphorylation of Casp9 at the Thr125 residue is the mechanism by which this kinase hinders both physiological and pathological PCD in mDA neurons. These data provide new insight into the mechanisms that control cell death in brain DA neurons and they show that deregulation of developmental apoptosis may contribute to the phenotype of patients with imbalanced DYRK1A gene dosage.


Validation of the zebrafish pentylenetetrazol seizure model: locomotor versus electrographic responses to antiepileptic drugs.
Zebrafish have recently emerged as an attractive in vivo model for epilepsy. Seven-day-old zebrafish larvae exposed to the GABA(A) antagonist pentylenetetrazol (PTZ) exhibit increased locomotor activity, seizure-like behavior, and epileptiform electrographic activity. A previous study showed that 12 out of 13 antiepileptic drugs (AEDs) suppressed PTZ-mediated increases in larval movement, indicating the potential utility of zebrafish as a high-throughput in vivo model for AED discovery. However, a question remained as to whether an AED-induced decrease in locomotion is truly indicative of anticonvulsant activity, as some drugs may impair larval movement through other mechanisms such as general toxicity or sedation. We therefore carried out a study in PTZ-treated zebrafish larvae, to directly compare the ability of AEDs to inhibit seizure-like behavioral manifestations with their capacity to suppress epileptiform electrographic activity. We re-tested the 13 AEDs of which 12 were previously reported to inhibit convulsions in the larval movement tracking assay, administering concentrations that did not, on their own, impair locomotion. In parallel, we carried out open-field recordings on larval brains after treatment with each AED. For the majority of AEDs we obtained the same response in both the behavioral and electrographic assays. Overall our data correlate well with those reported in the literature for acute rodent PTZ tests, indicating that the larval zebrafish brain is more discriminatory than previously thought in its response to AEDs with different modes of action. Our results underscore the validity of using the zebrafish larval locomotor assay as a rapid first-pass screening tool in assessing the anticonvulsant and/or proconvulsant activity of compounds, but also highlight the importance of performing adequate validation when using in vivo models.


Text (Oral) Reading Fluency as a Construct in Reading Development: An Investigation of its Mediating Role for Children from Grades 1 to 4.
In the present study we investigated a developmentally changing role of text reading fluency in mediating the relations of word reading fluency and listening comprehension to reading comprehension. We addressed this question by using longitudinal data from Grades 1 to 4, and employing structural equation models. Results showed that the role of text reading fluency changes over time as children's reading proficiency develops. In the beginning phase of reading development (Grade 1), text reading fluency was not independently related to reading comprehension over and above word reading fluency and listening comprehension. In Grades 2 to 4, however, text reading fluency completely mediated the relation between word reading fluency and reading comprehension whereas it partially mediated the relation between listening comprehension and reading comprehension. These results suggest that text reading fluency is a dissociable construct that plays a developmentally changing role in reading acquisition.


Influence of growth rate and exposure to bulls on age at puberty in beef heifers.
Two experiments were conducted to test the following hypotheses: 1) exposure of beef heifers to sterile bulls increases the proportion of heifers attaining puberty by 14 mo of age and 2) rate of growth interacts with bull exposure to influence age at puberty in beef heifers. In Exp. I, heifers were assigned to one of two treatments: 1) heifers were exposed to bulls (BE; approximately 70-d period of exposure) or 2) heifers were isolated from bulls (NE) and served as controls. In Exp. II, heifers were assigned to either BE or NE treatments (175-d period of exposure to bulls) and were fed to gain at a moderate (MG; .6 kg/d) or high (HG; .8 kg/d) growth rate. Blood samples were collected twice weekly to determine concentrations of progesterone indicative of onset of corpus luteum function and puberty. In Exp. I a greater (P less than .05) proportion of heifers receiving the BE treatment than of heifers receiving the NE treatment initiated corpus luteum function by 14 mo of age. In Exp. II, there was a bull exposure x growth rate interaction (P less than .05). The effect of bull exposure was greater within the HG groups than within the MG groups. However, heifers fed to attain a moderate or high growth rate and exposed to bulls attained puberty at younger ages than heifers not exposed to bulls and fed to attain a moderate or high growth rate. Mean ages at puberty were 375, 422, 428, and 449 (pooled SEM = 8.6) d for heifers in the BE-HG, BE-MG, NE-HG, and NE-MG groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


The biomechanical and histologic effects of platelet-rich plasma on rat rotator cuff repairs.
Rotator cuff tears are common injuries that are often treated with surgical repair. Because of the high concentration of growth factors within platelets, platelet-rich plasma (PRP) has the potential to enhance healing in rotator cuff repairs. Platelet-rich plasma would alter the biomechanical and histologic properties of rotator cuff repair during an acute injury response. Controlled laboratory study. Platelet-rich plasma was produced from inbred donor rats. A tendon-from-bone supraspinatus tear was created surgically and an immediate transosseous repair performed. The control group underwent repair only. The PRP group underwent a repair with PRP augmentation. Rats in each group were sacrificed at 7, 14, and 21 days. The surgically repaired tendons underwent biomechanical testing, including failure load, stiffness, failure strain, and stress relaxation characteristics. Histological analysis evaluated the cellular characteristics of the repair tissue. At 7- and 21-day periods, augmentation with PRP showed statistically significant effects on the biomechanical properties of the repaired rat supraspinatus tear, but failure load was not increased at the 7-, 14-, or 21-day periods (P = .688, .209, and .477, respectively). The control group had significantly higher stiffness at 21 days (P = .006). The control group had higher failure strain at 7 days (P = .02), whereas the PRP group had higher failure strain at 21 days (P = .008). Histologically, the PRP group showed increased fibroblastic response and vascular proliferation at each time point. At 21 days, the collagen fibers in the PRP group were oriented in a more linear fashion toward the tendon footprint. In this controlled, rat model study, PRP altered the tissue properties of the supraspinatus tendon without affecting the construct's failure load. The decreased tendon tissue stiffness acutely and failure to enhance tendon-to-bone healing of repairs should be considered before augmenting rotator cuff repairs with PRP. Further studies will be necessary to determine the role of PRP in clinical practice.


A Cross Sectional Study on Acceptability and Safety of IUCD among Postpartum Mothers at Tertiary Care Hospital, Telangana.
India is world's 2(nd) largest populated country. It is first to introduce family planning services. IUCD is most effective, safe, long acting and do not interfere with coitus. Immediately or within 72 hours after delivery of placenta in a health care facility is convenient for those who are in outreach area, where family planning facilities are less available. To study the socio demographic profile of parturients attended to obstetric ward for delivery. To assess the acceptability and safety of IUCD among study population. A cross-sectional study was conducted among eligible postpartum women at Gandhi hospital secunderabad. Counseling was given about IUCD. After obtaining consent, Cu-T 380 was inserted in a 250 women, followed up to 6 weeks. The reasons for both acceptance and decline were recorded. Mean age of acceptance was 23.70±2.95 years. Majority were from urban area (79.75%). Acceptance was more in those who completed their secondary school level education (23.3%). Women undergoing caesarean section were accepting PPIUCD, more frequently than those who underwent normal vaginal delivery. Majority (67.12%) accepters told that they accepted IUCD because it is a reversible method. Main reported complications were pain abdomen (17.14%), bleeding (14.28%). Expulsion rate was 6.8%. Most common reason (40%) for removal of IUCD was inclination to other methods. Even though expulsion rate high with, acceptance was high IUCD when it is inserted in postpartum period.


[Cigarette smoke extract reduces NOS activity and CX43 expression in the corporal cavernosum].
To study the effects of different doses of cigarette smoke extract (CSE) on the erectile function of male rats and the mechanism of smoking-induced erectile dysfunction (ED). A total of 75 healthy male SD rats were randomly divided into Groups A (control), B (dimethyl sulphoxide [DMSO]), C (low-dose CSE), D (medium-dose CSE) and E (high-dose CSE). CSE models were established in male SD rats by hypodermic injection, and 60 days later observed for penile erection following subcutaneous injection of apomorphine. Then the rats were killed and the penile cavernous body obtained for the examination of NOS activity by chromatometry and the determination of Cx43 expression by laser scanning confocal fluorescence microscopy (LCSM). Compared with the control and DMSO groups, penile erection frequency, NOS activity and Cx43 expression in the penile cavernous tissue were significantly decreased in the CSE groups (P < 0.05), and the decrease was proportional to the increase of the doses of CSE. No statistically significant differences were observed between the control and DMSO groups (P > 0.05). Cigarette smoke obviously reduces NOS activity and Cx43 expression in the penile cavernous tissue and seriously affects penile erection. The higher the dose, the more serious the influence. The decreases of NOS activity and Cx43 expression may be an important mechanism of ED.


Immunity to canine adenovirus respiratory disease: effect of vaccination with an inactivated vaccine.
Nine puppies without maternal antibody to canine adenovirus (CAV) were divided into two groups. The first consisted of six puppies, each of which was given two doses of a commercial inactivated CAV-1 vaccine, 14 days apart. Eight days after administration of the second dose of vaccine, all six puppies, together with the second group, consisting of three unvaccinated controls, were challenged with an aerosol of virulent CAV-2. One dog from each group was killed on the third, fifth and 10th days after challenge and the three additional vaccinates killed at intervening times. All of the dogs developed respiratory signs, mainly coughing and tachypnoea, but the vaccinated dogs made a more rapid recovery. The lungs of both groups were consolidated, the areas affected being more extensive in the controls, and histological examination revealed the main lesion to be a severe necrotising bronchiolitis. Virus was isolated from the respiratory tissues and from throat swabs collected from both groups of dogs. The presence of neutralising antibody in the serum was not, of itself, sufficient to control viral replication and oblate the disease.


The Effects of a 10-wk Outpatient Pulmonary Rehabilitation Program on Exercise Performance, Muscle Strength, Soluble Biomarkers, and Quality of Life in Patients With Pulmonary Hypertension.
Pulmonary arterial hypertension (PAH) is characterized by right ventricular failure, leading to exertional dyspnea, skeletal muscle weakness, and poor quality of life (QOL). Apart from treatment with PAH-specific drugs, guidelines recommend pulmonary rehabilitation (PR). Clinical PR programs have shown improvement in functional capacity and QOL. However, little is known about the effectiveness of an outpatient PR program. The aim of our study was to assess effectiveness of a multidisciplinary outpatient PR program. Patients with PAH or chronic thromboembolic pulmonary hypertension (CTEPH), who were in a stable condition on optimized drug therapy, followed a 10-wk outpatient program in a rehabilitation center. The PR program was designed to improve exercise capacity and health status by means of low load cycling, walking, and muscle training twice a week combined with psychological counseling. QOL was measured by the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) questionnaire. Twenty-one patients (13 women) with PAH (n = 16) or CTEPH (n = 5) completed the study. All patients were in New York Heart Association (NYHA) functional class III, and their mean age was 45 ± 16 yr. After PR, the mean cycling endurance time increased by 4.4 min (P < .001), 6-min walk distance by 12.2 m (P < .05), and maximum inspiratory pressure by 5.8 cm H2O (P = .01). Skeletal muscle function increased significantly. The CAMPHOR questionnaire demonstrated significant decrease in symptoms and improvement in QOL. Soluble biomarkers did not show any change before and after PR. Outpatient PR could be an effective instrument to improve exercise capacity and health status in patients with PAH or CTEPH.


On robust parameter estimation in brain-computer interfacing.
The reliable estimation of parameters such as mean or covariance matrix from noisy and high-dimensional observations is a prerequisite for successful application of signal processing and machine learning algorithms in brain-computer interfacing (BCI). This challenging task becomes significantly more difficult if the data set contains outliers, e.g. due to subject movements, eye blinks or loose electrodes, as they may heavily bias the estimation and the subsequent statistical analysis. Although various robust estimators have been developed to tackle the outlier problem, they ignore important structural information in the data and thus may not be optimal. Typical structural elements in BCI data are the trials consisting of a few hundred EEG samples and indicating the start and end of a task. This work discusses the parameter estimation problem in BCI and introduces a novel hierarchical view on robustness which naturally comprises different types of outlierness occurring in structured data. Furthermore, the class of minimum divergence estimators is reviewed and a robust mean and covariance estimator for structured data is derived and evaluated with simulations and on a benchmark data set. The results show that state-of-the-art BCI algorithms benefit from robustly estimated parameters. Since parameter estimation is an integral part of various machine learning algorithms, the presented techniques are applicable to many problems beyond BCI.


Visual-field-specific heterogeneity within the tecto-rotundal projection of the pigeon.
The organization of the tecto-rotundal projection of the pigeon was investigated by means of anterograde and retrograde tracing techniques. Besides the known organization in tecto-rotundal connectivity, this study additionally demonstrates major variations in the ascending projections of different tectal subfields. We show that the ventral tectum opticum (TO) has significantly more projections onto the nucleus rotundus (Rt) than dorsal tectal areas. This difference coincides with differential innervation densities of afferent fibres within rotundal subregions. While ventral tectal efferents project onto the ventral and central Rt, dorsal tectal efferents mainly arborize within limited areas between the central Rt and its dorsal cap, the nucleus triangularis. Thus, the ventral TO, representing the lower and frontal field of view, exhibits a quantitatively and spatially enhanced projection onto the Rt, as compared with the dorsal TO. The data presented here demonstrate a visual field-dependent projection pattern of ascending tectal outputs onto different rotundal domains. The data are consistent with behavioural studies, demonstrating tectofugal lesions to suppress visual stimulus analysis mainly within the frontal field of view.


Ruled by ubiquitylation: a new order for polycomb recruitment.
Polycomb complexes are found in most cells, but they must be targeted to specific genes in specific cell types in order to regulate pluripotency and differentiation. The recruitment of Polycomb complexes to specific targets has been widely thought to occur in two steps: first, one complex, PRC2, produces histone H3 lysine 27 (H3K27) trimethylation at a specific gene, and then the PRC1 complex is recruited by its ability to bind to H3K27me3. Now, three new articles turn this model upside-down by showing that binding of a variant PRC1 complex and subsequent H2A ubiquitylation of surrounding chromatin is sufficient to trigger the recruitment of PRC2 and H3K27 trimethylation. These studies also show that ubiquitylated H2A is directly sensed by PRC2 and that ablation of PRC1-mediated H2A ubiquitylation impairs genome-wide PRC2 binding and disrupts mouse development.


Neutron beams from protons on beryllium.
Measurements of dose rate and penetration in water have been made for neutron beams produced by 30--75 MeV protons on beryllium. The effects of Polythene filters added on the target side of the collimator have also been studied. A neutron beam comparable with a photon beam from a 4--8 MeV linear accelerator can be produced with p/Be neutrons plus 5 cm Polythene filtrations, with protons in the range 50--75 MeV. This is a more economical method than use of the d/Be reaction.


Polymorphisms of PLIN1 and MOGAT1 genes and their association with feed efficiency in Hu sheep.
Feed cost accounts for a high proportion of sheep production, and improving sheep's utilization of feed will reduce production costs and improve economic benefits. The purpose of this study was to investigate the expression characteristics of PLIN1 and MOGAT1 genes and the relationship between their polymorphisms and feed efficiency traits in Hu sheep, and to find molecular Genetic marker that can be used in breeding. The expression levels of PLIN1 and MOGAT1 genes in various tissues were determined using quantitative real-time PCR (qRT-PCR). The results showed that PLIN1 and MOGAT1 genes were widely expressed in heart, liver, spleen, lungs, kidneys, rumen, duodenum, muscle, lymph, and tail fat. The PLIN1 gene had the highest expression level in in the tail fat compared to the other nine tissues. The expression levels of MOGAT1 gene in liver, tail fat, lung and heart was significantly higher than in kidney, muscle and lymph. The expression level of MOGAT1 was lowest in muscle compared to the other tissues (heart, liver, spleen, lung, rumen and tail fat). We recorded the body weight (BW80 and BW180) and feed intake (FI) information of 985 male Hu sheep at 80 and 180 days of age, and calculated the daily average feed intake (ADFI), average daily gain (ADG), and feed conversion rate (FCR) from 80 to 180 days of age. Two intronic mutations, g.18517910 A > G and g.224856118 G > C, were identified in PLIN1 and MOGAT1 genes by PCR amplification and Sanger sequencing. MassARRAY ® SNP detection technology was used to genotype the DNA of 985 Hu sheep and analyze its association with feed efficiency traits. The results showed that the SNP g.18517910 A > G was significantly associated with BW80, BW180, FI, ADFI and FCR (P < 0.05), while SNP g.2248561118 G > C was significantly associated with FCR (P < 0.05). Meanwhile, significant differences were also observed in different combinations of genotypes (P < 0.05). Therefore, these two polymorphic loci can serve as candidate molecular markers for improving feed utilization efficiency in Hu sheep.


The Ca2+-Permeable Cation Transient Receptor Potential TRPV3 Channel: An Emerging Pivotal Target for Itch and Skin Diseases.
Temperature-sensitive transient receptor potential (TRP) channels such as TRPA1 and TRPV1 have been identified as downstream ion channel targets in the transduction of itch. As a member of the temperature-sensitive TRP family, the Ca2+-permeable nonselective cation channel TRPV3 is expressed abundantly in skin keratinocytes. Recent identification of gain-of-function mutations of human TRPV3 from patients with Olmsted syndrome, which is characterized by severe itching and palmoplantar and periorificial keratoderma, unveils its crucial role in chronic itch and skin diseases. In this review, we will focus on recent progress made in the understanding of TRPV3 that emerges as an attractive target for developing effective antipruritic therapy for chronic itch or skin-related diseases.


New monoclonal antibodies specific for 1-(5-fluoropentyl)-3-(2-iodobenzoyl)indole.
1-(5-fluoropentyl)-3-(2-iodobenzoyl)indole (AM694) is one of the synthetic cannabinoids and an illegal drug in Japan. It is important to generate a monoclonal antibody (MAb) against AM694 for use in the rapid and sensitive detection of the drug. Two monoclonal antibodies, named HN0124 (IgG1) and NK0504 (IgG1), were obtained, which were possibly effective for detecting AM694 and its derivatives. The cross-reactive ability of these MAbs was evaluated using a competitive enzyme-linked immunosorbent assay. In the results, both of these antibodies recognize 1-(5-fluoropentyl)-3-(2-iodobenzoyl)indole, 1-(5-fluoropentyl)-3-(3-iodobenzoyl)indole, 1-(5-fluoropentyl)-3-(4-iodobenzoyl)indole. Forty nmol/L AM694 can be detected using HN0124 MAb. Thus, MAbs produced in this study could be considered a useful tool for the detection of AM694.


Anaesthetic management of the severely injured patient: chest injury.
Life-threatening haemorrhage is common in major chest and abdominal trauma (Figure 1). Management consists of rapid fluid transfusion via large bore intravenous cannulae and early surgical intervention if indicated. Refractory hypoxaemia is frequently present in the chest injured patient (Figure 2). Pneumothorax and haemothorax must be carefully sought, and chest drains used in their management. Hypoxaemia secondary to simple chest injury should be managed with oxygen administration and the provision of analgesia initially. Resistant hypoxaemia may necessitate intubation and ventilation.


Evolutionary implications of the unusual walking mechanics of the common marmoset (C. jacchus).
Several features that appear to differentiate the walking gaits of most primates from those of most other mammals (the prevalence of diagonal-sequence footfalls, high degrees of humeral protraction, and low forelimb vs. hindlimb peak vertical forces) are believed to have evolved in response to requirements of locomotion on thin arboreal supports by early primates that had developed clawless grasping hands and feet. This putative relationship between anatomy, behavior, and ecology is tested here by examining gait mechanics in the common marmoset (Callithrix jacchus), a primate that has sharp claws and reduced pedal grasping, and that spends much of its time clinging on large trunks. Kinematic and kinetic data were collected on three male Callithrix jacchus as they walked across a force platform attached to the ground or to raised horizontal poles. The vast majority of all walking gaits were lateral-sequence. For all steps, the humerus was retracted (<90 degrees relative to a horizontal axis) or held in a neutral (90 degrees ) position at forelimb touchdown. Peak vertical forces on the forelimb were always higher than those on the hindlimb. These three features of the walking gaits of C. jacchus separate it from any other primate studied (including other callitrichids). The walking gaits of C. jacchus are mechanically more similar to those of small, nonprimate mammals. The results of this study support previous models that suggest that the unusual suite of features that typify the walking gaits of most primates are adaptations to the requirements of locomotion on thin arboreal supports. These data, along with data from other primates and marsupials, suggest that primate postcranial and locomotor characteristics are part of a basal adaptation for walking on thin branches.


Isoform-specific role of transforming growth factor-beta2 in the regulation of proliferation and differentiation of murine adrenal chromaffin cells in vivo.
Chromaffin cells, the neuroendocrine cells of the adrenal medulla, play an important role in molecular, cellular, and developmental neurobiology. Unlike the closely related sympathetic neurons, chromaffin cells are able to proliferate throughout their whole life span. Proliferation of chromaffin cells in vivo is thought to be regulated by the interaction of neurogenic and hormonal signals. Previous studies have shown that chromaffin cells synthesize and release transforming growth factor-betas (TGF-betas). In the present study, effects of TGF-betas on proliferation and differentiation of chromaffin cells in mouse adrenal chromaffin cells were investigated in a genetic mouse model. We observed a significant increase in the total number of tyrosine hydroxylase-positive (TH(+)) cells in Tgfbeta2(-/-) knockout mouse embryos at embryonic day (E) 18.5 compared with wild-type animals (Tgfbeta2(+/+)), but no changes in the number of TH(+) cells were observed in Tgfbeta3(-/-) mouse mutants. At E15.5, but not at E18.5, there was a marked increase in the number of proliferative cell nuclear antigen-positive chromaffin cells in Tgfbeta2(-/-) knockout embryos compared with the wild-type group. On the other hand, there was a clear decrease in the ratio of total number of phenylethanolamine-N-methyltransferase-positive cells to the total TH(+) in Tgfbeta2(-/-) mice embryos at E18.5 compared with wild-type animals. This is the first documentation of the physiological significance of the TGF-beta2, an isoform that has been suggested to play a role in the regulation of chromaffin cells proliferation and differentiation based on in vitro experiments.


Risk factors for the initial symptomatic giardia infection in a cohort of young Arab-Bedouin children.
Giardiasis is a common protozoan infection with clinical manifestations in children ranging from asymptomatic carriage to persistent diarrhoea with malabsorption. It can lead to growth and developmental retardation. The study evaluated risk factors for the initial symptomatic giardiasis (SG) episode among Arab-Bedouin children in Israel. A community-based, prospective cohort study was conducted in Rahat, a Bedouin township in southern Israel. Infants (n=238) were followed by weekly visits from birth to age 18 months. Giardia infection was identified by antigen detection in faecal specimens. Approximately 26% of children experienced one or more SG episode. Mean (SD) age for first SG episode was 12.3 (3.3) months, with 95% of episodes occurring in children >6 months of age. Risk for the first SG in children >6 months of age was associated with it being spring or summer [odds ratio (OR) 6.16, p<0.001], exposure to livestock (OR 4.89, p=0.002) and prior infection with entero-aggregative Escherichia coli (EAEC) (OR 1.12 for each additional percentage in stool prevalence, p=0.02). Weight-for-age Z-scores at age 6 months were inversely related to SG risk (OR 0.62 for each unit increase in Z-score, p=0.029). Giardiasis is an important cause of diarrhoea in Bedouin children. Increased risk of SG in spring/summer might be linked to environmental conditions or seasonal dietary practices which increase virulence or transmission. SG in those exposed to livestock suggests that there are zoonotic risk factors or that hygiene is a causal factor. The association between EAEC infection and SG warrants further investigation.


The planar cell polarity pathway drives pathogenesis of chronic lymphocytic leukemia by the regulation of B-lymphocyte migration.
The planar cell polarity (PCP) pathway is a conserved pathway that regulates cell migration and polarity in various contexts. Here we show that key PCP pathway components such as Vangl2, Celsr1, Prickle1, FZD3, FZD7, Dvl2, Dvl3, and casein kinase 1 (CK1)-ε are upregulated in B lymphocytes of patients with chronic lymphocytic leukemia (CLL). Elevated levels of PCP proteins accumulate in advanced stages of the disease. Here, we show that PCP pathway is required for the migration and transendothelial invasion of CLL cells and that patients with high expression of PCP genes, FZD3, FZD7, and PRICKLE1, have a less favorable clinical prognosis. Our findings establish that the PCP pathway acts as an important regulator of CLL cell migration and invasion. PCP proteins represent an important class of molecules regulating pathogenic interaction of CLL cells with their microenvironment.


Looking at the face and seeing the whole body. Neural basis of combined face and body expressions.
In the natural world, faces are not isolated objects but are rather encountered in the context of the whole body. Previous work has studied the perception of combined faces and bodies using behavioural and electrophysiological measurements, but the neural correlates of emotional face-body perception still remain unexplored. Here, we combined happy and fearful faces and bodies to investigate the influence of body expressions on the neural processing of the face, the effect of emotional ambiguity between the two and the role of the amygdala in this process. Our functional magnetic resonance imaging analyses showed that the activity in motor, prefrontal and visual areas increases when facial expressions are presented together with bodies rather than in isolation, consistent with the notion that seeing body expressions triggers both emotional and action-related processes. In contrast, psychophysiological interaction analyses revealed that amygdala modulatory activity increases after the presentation of isolated faces when compared to combined faces and bodies. Furthermore, a facial expression combined with a congruent body enhanced both cortical activity and amygdala functional connectivity when compared to an incongruent face-body compound. Finally, the results showed that emotional body postures influence the processing of facial expressions, especially when the emotion conveyed by the body implies danger.