Open channel block of human heart hKv1.5 by the beta-subunit hKv beta 1.2.
Voltage-gated K+ currents in human heart are likely to derive from multisubunit complexes of pore-forming alpha-subunits with one or more auxiliary beta-subunits. We recently cloned a novel beta-subunit from human atrium, hKv beta 1.2 (K. Majumder, M. De Biasi, Z. Wang, and B. A. Wible. FEBS Lett. 361: 13-16, 1995), and showed that it interacts with channels in the Kv1 family. Here we characterize the interaction of hKv beta 1.2 with hKv1.5 in terms of a two-closed-state and one-open-state open channel block model. After coexpression in Xenopus oocytes, hKv1.5 currents were reduced in the presence of hKv beta 1.2, and at positive potentials an inactivation process was introduced. Deactivation kinetics of hKv1.5 were slowed, and there was an increased steepness with a -14-mV hyperpolarizing shift in the midpoint of steady-state activation. The model was able to predict all the above features of the interaction of hKv1.5 and hKv beta 1.2 as a result of rapid open channel block of activated channels. Understanding the mechanism of hKv beta 1.2 action on heart K+ channels will further aid the development of the functional and pharmacological characterization of native cardiac K+ currents.


Coaxially electrospun axon-mimicking fibers for diffusion magnetic resonance imaging.
The study of brain structure and connectivity using diffusion magnetic resonance imaging (dMRI) has recently gained substantial interest. However, the use of dMRI still faces major challenges because of the lack of standard materials for validation. The present work reports on brain tissue-mimetic materials composed of hollow microfibers for application as a standard material in dMRI. These hollow fibers were fabricated via a simple and one-step coaxial electrospining (co-ES) process. Poly(ε-caprolactone) (PCL) and polyethylene oxide (PEO) were employed as shell and core materials, respectively, to achieve the most stable co-ES process. These co-ES hollow PCL fibers have different inner diameters, which mainly depend on the flow rate of the core solution and have the potential to cover the size range of the brain tissue we aimed to mimic. Co-ES aligned hollow PCL fibers were characterized using optical and electron microscopy and tested as brain white matter mimics on a high-field magnetic resonance imaging (MRI) scanner. To the best of our knowledge, this is the first time that co-ES hollow fibers have been successfully used as a tissue mimic or phantom in diffusion MRI. The results of the present study provide evidence that this phantom can mimic the dMRI behavior of cellular barriers imposed by axonal cell membranes and myelin; the measured diffusivity is compatible with that of in vivo biological tissues. Together these results suggest the potential use of co-ES hollow microfibers as tissue-mimicking phantoms in the field of medical imaging.


Defensins HNP1 and HBD2 stimulation of wound-associated responses in human conjunctival fibroblasts.
To study the responses of human conjunctival fibroblasts (HCFs) to stimulation by human neutrophil defensin 1 (HNP1) and beta defensin2 (HBD2). Defensin-stimulated gene expression in primary cultures of HCFs was analyzed by real-time PCR after exposure to various concentrations of HNP1 or HBD2. Gene and protein expression for selected collagens, matrix metalloproteinases, and tissue inhibitors of metalloproteinases were determined by real-time PCR and ELISA analysis. Activation of p42/44 mitogen-activated protein (MAP) and Akt was analyzed by Western blot. HCFs did not express significant levels of the genes for HNP1 or HBD1-3. However, HNP1 and HBD2 stimulated HCF proliferation, the activation of p42/44 MAP kinase, and Akt kinase in a dose-dependent manner. HNP1 and HBD2 were not found to be chemotoxic for HCFs. It was demonstrated with the use of U0126 and wortmannin that the activation of p42/44 MAP kinase and Akt was responsible for the increased HCF proliferation observed under HNP1 and HBD2 stimulation. HNP1 stimulated the expression of the genes for collagen I, III, VI, and VIII. In addition, it reduced the secretion of collagen I protein but increased its intracellular retention. HNP1 and HBD2 upregulated the transcription and translation of MMP1. Small increases were observed in MMP14 gene expression after HNP1 stimulation and MMP2 gene expression after HBD2 stimulation. The results of this study suggest that HNP1 and HBD2 have a potential role in the biosynthetic and tissue remodeling responses of conjunctival fibroblasts.


Bleeding complications in immune thrombocytopenia.
Bleeding manifestations in patients with immune thrombocytopenia (ITP) range from mild skin bruises to life-threatening intracranial hemorrhage (ICH). Severe bleeding is distinctly uncommon when the platelet count is >30 × 10(9)/L and usually only occurs when the platelet count falls <10 × 10(9)/L. Based on estimates from clinical studies, ITP registries and administrative databases, the frequency of ICH in patients with ITP is ~0.5% in children and 1.5% in adults. Estimates of severe (non-ICH) bleeding are difficult to obtain because of the lack of standardized case definitions; the lack of a universally accepted, ITP-specific bleeding assessment tool; and the omission of reporting bleeding outcomes in many clinical studies. In practice, the presence of bleeding should dictate whether or not treatment is needed because many patients, especially children, can be safely managed with observation alone. Guiding principles for the management of ITP, based on the bleeding risk are: (1) Decide when treatment is needed and when it can safely be withheld; (2) for patients with chronic ITP, use the least toxic treatment at the lowest dose; (3) emergency treatment of severe thrombocytopenia-associated bleeding requires combination therapy; and (4) early aggressive therapy may result in durable platelet count responses.


Presence of a sarcomatous component outside the ovary is an adverse prognostic factor for primary ovarian malignant mixed mesodermal/mullerian tumors: a clinicopathologic study of 47 cases.
Primary ovarian malignant mixed mesodermal tumors are uncommon. There exist few data in the literature on the significance of the sarcomatous component (SC) in these tumors. Here we investigated this aspect in 47 such tumors, with particular interest in whether the presence of SC outside the ovary confers a worse prognosis. We correlated various features of the SC (homologous vs. heterologous, type of heterologous SC, extent/percentage, mitotic count, necrosis, whether or not SC is present outside the ovary) with disease-specific survival (DSS) using the Kaplan-Meier method and log-rank test. We also correlated other clinicopathologic parameters with DSS: age, stage, tumor size, tumor laterality, type of the carcinomatous component (CC), lymph node status, vascular invasion, and degree of surgical debulking. The mean age was 69.0 years (range, 43 to 89 y). The tumor was located in the left and right ovary in 18 and 24 patients, respectively (laterality could not be determined in 5 cases). The mean tumor size was 13.6 cm. Surgical debulking was optimal in 28, suboptimal in 6, and unclear in 13 patients. FIGO stage was I in 1 patient, II in 5 patients, III in 40 (IIIA in 1, IIIB in 11, IIIC in 28), and IV in 1 patient. Node metastasis and vascular invasion were noted in 6/17 and 29/47 patients, respectively. The mean percentage of SC was 29% (median 20%; range, 1% to 90%). The SC was heterologous in 34 (72%) and homologous in 13 (28%) patients. The mitotic figures per 10 HPF in SC were 33 (0 to 128). Tumor necrosis was present in 45/47 cases (mean 10%; range, 1% to 40%, only in CC in 14, only in SC in 2, in both SC and CC in 29). The CC was high-grade serous in 27 patients, endometrioid in 2, mixed high-grade serous and endometrioid in 17, and mixed high-grade serous and clear cell carcinoma in 1 patient. The extraovarian tumor contained only CC in 17 cases, only SC in 1 case, and both SC and CC in 28 cases. The median follow-up was 29 months (range, 1 to 183 mo): 6 patients were lost to follow-up, 3 died postoperatively, 29 died from disease, 2 died from other causes, and 7 were still alive (14 to 183 mo). The DSS rate at 1, 2, and 5 years was 75%, 56%, and 21%, respectively. Presence of SC outside the ovary was a significant adverse prognostic factor (P=0.03), whereas other parameters were not. After adjusting for FIGO stage, presence of SC outside the ovary was still a significant adverse prognosticator for stage III patients (P=0.003), whereas others were not. Therefore, our findings showed that presence of SC outside the ovary was a significant adverse prognostic factor. We advocate listing the specific extraovarian tumor component (SC and/or CC) in the pathology report for primary ovarian malignant mixed mesodermal tumors.


Sphingomonas ginsengisoli sp. nov. and Sphingomonas sediminicola sp. nov.
Two novel bacteria, designated strains Gsoil 634(T) and Dae 20(T), were isolated in South Korea from soil of a ginseng field and freshwater sediment, respectively and were characterized by a polyphasic approach to clarify their taxonomic positions. Phylogenetic analysis based on 16S rRNA gene sequences indicated that, although they probably represented two distinct species (indicated by a sequence similarity of 96.6 %), both strain Gsoil 634(T) and strain Dae 20(T) belonged to the genus Sphingomonas and were most closely related to 'Sphingomonas humi' PB323 (97.8 % and 96.7 % sequence similarity, respectively), Sphingomonas kaistensis PB56(T) (96.8 % and 96.7 %), Sphingomonas astaxanthinifaciens TDMA-17(T) (96.6 % and 95.4 %) and Sphingomonas jaspsi TDMA-16(T) (95.6 % and 95.8 %). For both novel strains, the major ubiquinone was Q-10, the major polyamine was homospermidine, the major cellular fatty acids included summed feature 7 (C(18 : 1)ω7c, C(18 : 1)ω9t and/or C(18 : 1)ω12t), C(17 : 1)ω6c and C(16 : 0), and the polar lipids included sphingoglycolipid. These chemotaxonomic data supported the affiliation of both strains to the genus Sphingomonas. However, the DNA-DNA relatedness value between strain Gsoil 634(T) and 'Sphingomonas humi' PB323(T) was 31 %. Moreover, the results of physiological and biochemical tests allowed the phenotypic differentiation of strains Gsoil 634(T) and Dae 20(T) from established members of the genus Sphingomonas. Based on these data, the two isolates represent two novel species in the genus Sphingomonas, for which the names Sphingomonas ginsengisoli sp. nov. (type strain Gsoil 634(T) = KCTC 12630(T) = DSM 18094(T) = LMG 23739(T)) and Sphingomonas sediminicola sp. nov. (type strain Dae 20(T) = KCTC 12629(T) = DSM 18106(T) = LMG 23592(T)) are proposed.


Performance Assessment of a Humidity Measurement System and Its Use to Evaluate Moisture Characteristics of Wheelchair Cushions at the User-Seat Interface.
Little is known about the changes in moisture that occur at the body-seat interface during sitting. However, as increased moisture can add to the risk of skin damage, we have developed an array of MEMS (Micro-Electro-Mechanical System) humidity sensors to measure at this interface. Sensors were first evaluated against traceable standards, followed by use in a cross-over field test (n = 11; 20 min duration) using different wheelchair cushions (foam and gel). Relative humidity (RH) was measured at the left mid-thigh, right mid-thigh and coccyx. Sensors were shown to be unaffected by loading and showed highly reliable responses to measured changes in humidity, varying little from the traceable standard (<5%). Field-test data, smoothed through a moving average filter, revealed significant differences between the three chosen locations and between the gel and foam cushions. Maximum RH was attained in less than five minutes regardless of cushion material (foam or gel). Importantly, RH does not appear to distribute uniformly over the body-seat interface; suggesting multiple sensor positions would appear essential for effectively monitoring moisture in this interface. Material properties of the cushions appear to have a significant effect on RH characteristics (profile) at the body-seat interface, but not necessarily the time to peak moisture.


Survey about the potential effects of economic downturn on alcohol consumption, smoking and quality of life in a sample of Central Italy population.
Negative health effects have been associated with the changes in lifestyles in relation with the low income of population. Consequently, in our study we investigated the frequency changes of alcohol and smoke consumption, physical activity, and quality of life in families of Marche Region in Central Italy. In the period 2016-2017, an anonymous questionnaire has been distributed to junior highschool students of Camerino, Fabriano, and Civitanova Marche of Marche Region. The Manchester Short Assessment of Quality of Life (MANSA), was used to assess subjective quality of life. Data obtained in this research were used to analyze lifestyle changes, specifically those involving alcohol consumption, smoking, and physical activity, and to assess perceived general quality of life. In all categories of population, an increase of frequency in alcohol consumption was observed. On the contrary, for the tobacco smoke we observed a reduction in particular in the parents category. The MANSA mean value was 4.5 with a Standard Deviation of 1.3. As underlighted, also, by results of the MANSA test we can hypothesize a reduction in the family income produces a change of lifestyles.


Pacing in lane-based head-to-head competitions: A systematic review on swimming.
Athletes' energy distribution over a race (e.g. pacing behaviour) varies across different sports. Swimming is a head-to-head sport with unique characteristics, such as propulsion through water, a multitude of swimming stroke types and lane-based racing. The aim of this paper was to review the existing literature on pacing behaviour in swimming. According to PRISMA guidelines, 279 articles were extracted using the PubMed and Web of Science databases. After the exclusion process was conducted, 16 studies remained. The findings of these studies indicate that pacing behaviour is influenced by the race distance and stroke type. Pacing behaviours in swimming and time-trial sports share numerous common characteristics. This commonality can most likely be attributed to the lane-based racing set-up. The low efficiency of swimming resulting from propulsion through the water induces a rapid accumulation of blood lactate, prompting a change in swimmers' biomechanical characteristics, with the goal of minimising changes in velocity throughout the race. Although the literature on youth swimmers is scarce, youth swimmers demonstrate more variable pacing profiles and have more difficulty in selecting the most beneficial energy distribution.


Core pertussis transmission groups in England and Wales: A tale of two eras.
The recent resurgence of pertussis in England and Wales has been marked by infant deaths and rising cases in teens and adults. To understand which age cohorts are most responsible for these trends, we employed three separate statistical methods to analyze high-resolution pertussis reports from 1982 to 2012. The fine-grained nature of the time-series allowed us to describe the changes in age-specific incidence and contrast the transmission dynamics in the 1980s and during the resurgence era. Our results identified infants and school children younger than 10 years of age as a core group, prior to 2002: pertussis incidence in these populations was predictive of incidence in other age groups. After 2002, no core groups were identifiable. This conclusion is independent of methodology used. Because it is unlikely that the underlying contact patterns substantially changed over the study period, changes in predictability likely result from the introduction of more stringent diagnostics tests that may have inadvertently played a role in masking the relative contributions of core transmission groups.


Reproducibility of fifteen urinary estrogens and estrogen metabolites over a 2- to 3-year period in premenopausal women.
Endogenous estrogens play an integral role in the etiology of breast, endometrial, and, possibly, ovarian cancers. Estrogen metabolism yields products that are potentially both estrogenic and genotoxic, yet individual metabolic patterns are just beginning to be explored in epidemiologic studies. Within the Nurses' Health Study II, we examined reproducibility of 15 urinary estrogens and estrogen metabolites (EM) among 110 premenopausal women with three luteal-phase urine samples collected over 3 years. EM were measured by a recently developed high-performance liquid chromatography-tandem mass spectrometry (LC-MS(2)) method with high sensitivity, specificity, and precision. We assessed Spearman correlations and intraclass correlation coefficients (ICC) across the three samples. Correlations between urinary estrone or estradiol and EM were only modest (r = 0.1-0.5). The 2- and 4-hydroxylation pathways were highly correlated (r = 0.9) but weakly inversely correlated with the 16-hydroxylation pathway (r = -0.2). Within-woman reproducibility over time was fairly high for the three pathways, with ICCs ranging from 0.52 (16-hydroxylation pathway) to 0.72 (2-hydroxylation pathway). ICCs were similarly high for 2-catechols and the individual catechols (ICCs = 0.58-0.72). Individual and grouped methylated 2-catechols had fairly high ICCs (0.51-0.62), but methylated 4-catechols had low ICCs (0.14-0.27). These data indicate that, in general, urinary EM levels vary substantially among individuals compared with intraindividual variability. Within-person reproducibility over time for most EM measures is comparable to or better than that for well-vetted biomarkers such as plasma cholesterol and, in postmenopausal women, estradiol.


Occurrence of diabetogenic changes in pregnancy among black women in an urban setting.
To find out if pregnancy in black Zimbabwean women is a diabetogenic state using basal blood levels of cortisol, insulin, C-peptide and glucose. 111 women (28 non-pregnant, 29 first trimester, 26 second trimester and 28 third trimester) aged between 18 and 35 years were recruited for the study. Fasting plasma cortisol, insulin, C-peptide and glucose were determined by standard methods. The glucose/insulin ratio was used as an index of insulin sensitivity and the C-peptide/glucose ratio as well as the homeostasis assessment model (HOMA) as an index of insulin resistance. The means of fasting plasma cortisol levels were significantly elevated, p < 0.0001 among the four groups (non-pregnant, first, second and third trimester women). Fasting plasma insulin levels peaked during the third trimester and significant differences were noted among all women, p < 0.05. Similar data was obtained for C-peptide levels (a better indicator of beta-cell insulin secretory activity) among the groups, p < 0.01. The means of fasting plasma glucose levels were significantly decreased with advancing gestation, p < 0.0001. Significantly lower glucose/insulin ratios, a measure of insulin sensitivity and elevated C-peptide/glucose ratios, an index of insulin resistance, were demonstrated among the women, (p < 0.05 and < 0.01 respectively). The basal data presented in this paper clearly demonstrates that the diabetogenic effects of pregnancy are also expressed by Zimbabwean black women, especially in late gestation.


All-metal self-supported THz metamaterial--the meta-foil.
Modern metamaterials face functional constraints as they are commonly embedded in or deposited on dielectric materials. We provide a new solution by microfabricating a completely free-standing all-metal self-supported metamaterial. Using upright S-string architecture with the distinctive feature of metallic transverse interconnects, we form a locally stiff, globally flexible space-grid. Infrared Fourier transform interferometry reveals the typical double-peak structure of a magnetically excited left-handed and an electrically excited right-handed pass-band that is maintained under strong bending and heating, and is sensitive to dielectrics. Exploiting UV/X-ray lithography and ultimately plastic moulding, meta-foils can be mass manufactured cost-effectively to serve as optical elements.


Emergency department throughput, crowding, and financial outcomes for hospitals.
Emergency department (ED) crowding has been identified as a major public health problem in the United States by the Institute of Medicine. ED crowding not only is associated with poorer patient outcomes, but it also contributes to lost demand for ED services when patients leave without being seen and hospitals must go on ambulance diversion. However, somewhat paradoxically, ED crowding may financially benefit hospitals. This is because ED crowding allows hospitals to maximize occupancy with well-insured, elective patients while patients wait in the ED. In this article, the authors propose a more holistic model of hospital flow and revenue that contradicts this notion and offer suggestions for improvements in ED and hospital management that may not only reduce crowding and improve quality, but also increase hospital revenues. Also proposed is that increased efficiency and quality in U.S. hospitals will require changes in systematic microeconomic and macroeconomic incentives that drive the delivery of health services in the United States. Finally, the authors address several questions to propose mutually beneficial solutions to ED crowding that include the realignment of hospital incentives, changing culture to promote flow, and several ED-based strategies to improve ED efficiency.


The role of the cerebellopontine angle cistern area and trigeminal nerve length in the pathogenesis of trigeminal neuralgia: a prospective case-control study.
The aim of this prospective study was to evaluate whether the cerebellopontine angle (CPA) cistern area and trigeminal nerve cisternal length play a role in the pathogenesis of trigeminal neuralgia (TN). High-resolution 1.5 T magnetic resonance imaging of the posterior fossa was performed in 26 patients with TN and 18 age-matched healthy controls. Axial T2-weighted, three-dimensional constructive interference in steady-state (3D-CISS) was used to measure bilaterally the cross-sectional area of the CPA cistern and trigeminal nerve cisternal length. In patients, the cross-sectional area of the CPA cistern and trigeminal nerve cisternal length was smaller on the affected side (p = 0.04). Healthy controls tended to have larger cisternal areas and longer trigeminal nerve lengths than patients (p = 0.059, p = 0.071, respectively). Larger CPA cisternal areas tended to be seen in older patients. There was a strong correlation between the cross-sectional area of the CPA cistern and the length of the trigeminal nerve (p = 0.000). Smaller CPA cisterns and short cisternal trigeminal nerves impact the pathogenesis of essential TN by facilitating the neurovascular conflict, especially in younger patients. Trigeminal nerve cisternal measurement provides an easy and direct estimation of the CPA area. This information can be used for surgical planning and potentially for outcome prediction.


Intake of up to 3 Eggs/Day Increases HDL Cholesterol and Plasma Choline While Plasma Trimethylamine-N-oxide is Unchanged in a Healthy Population.
Eggs are a source of cholesterol and choline and may impact plasma lipids and trimethylamine-N-oxide (TMAO) concentrations, which are biomarkers for cardiovascular disease (CVD) risk. Therefore, the effects of increasing egg intake (0, 1, 2, and 3 eggs/day) on these and other CVD risk biomarkers were evaluated in a young, healthy population. Thirty-eight subjects [19 men/19 women, 24.1 ± 2.2 years, body mass index (BMI) 24.3 ± 2.5 kg/m2] participated in this 14-week crossover intervention. Participants underwent a 2-week washout with no egg consumption, followed by intake of 1, 2, and 3 eggs/day for 4 weeks each. Anthropometric data, blood pressure (BP), dietary records, and plasma biomarkers (lipids, glucose, choline, and TMAO) were measured during each intervention phase. BMI, waist circumference, systolic BP, plasma glucose, and plasma triacylglycerol did not change throughout the intervention. Diastolic BP decreased with egg intake (P < 0.05). Compared to 0 eggs/day, intake of 1 egg/day increased HDL cholesterol (HDL-c) (P < 0.05), and decreased LDL cholesterol (LDL-c) (P < 0.05) and the LDL-c/HDL-c ratio (P < 0.01). With intake of 2-3 eggs/day, these changes were maintained. Plasma choline increased dose-dependently with egg intake (P < 0.0001) while fasting plasma TMAO was unchanged. These results indicate that in a healthy population, consuming up to 3 eggs/day results in an overall beneficial effect on biomarkers associated with CVD risk, as documented by increased HDL-c, a reduced LDL-c/HDL-c ratio, and increased plasma choline in combination with no change in plasma LDL-c or TMAO concentrations.


Glutamate receptor δ2 serum antibodies in pediatric opsoclonus myoclonus ataxia syndrome.
To identify neuronal surface antibodies in opsoclonus myoclonus ataxia syndrome (OMAS) using contemporary antigen discovery methodology. OMAS patient serum immunoglobulin G immunohistochemistry using age-equivalent rat cerebellar tissue was followed by immunoprecipitation, gel electrophoresis, and mass spectrometry. Data are available via ProteomeXchange (identifier PXD009578). This generated a list of potential neuronal surface cerebellar autoantigens. Live cell-based assays were used to confirm membrane-surface antigens and adsorb antigen-specific immunoglobulin Gs. The serologic results were compared to the clinical data. Four of the 6 OMAS sera tested bound rat cerebellar sections. Two of these sera with similar immunoreactivities were used in immunoprecipitation experiments using cerebellum from postnatal rat pups (P18). Mass spectrometry identified 12 cell-surface proteins, of which glutamate receptor δ2 (GluD2), a predominately cerebellar-expressed protein, was found at a 3-fold-higher concentration than the other 11 proteins. Antibodies to GluD2 were identified in 14/16 (87%) OMAS samples, compared with 5/139 (5%) pediatric and 1/38 (2.6%) adult serum controls (p < 0.0001), and in 2/4 sera from patients with neuroblastoma without neurologic features. Adsorption of positive OMAS sera against GluD2-transfected cells substantially reduced but did not eliminate reactivity toward cerebellar sections. Autoantibodies to GluD2 are common in patients with OMAS, bind to surface determinants, and are potentially pathogenic.


IFN-α exerts opposing effects on activation-induced and IL-7-induced proliferation of T cells that may impair homeostatic maintenance of CD4+ T cell numbers in treated HIV infection.
To determine whether IFN-α is a cause of the T cell hyperactivation and IL-7 signaling pathway defects that are observed in some HIV patients receiving antiretroviral therapy, we have investigated the effect of IFN-α on the proliferation of CD4(+) and CD8(+) T cells from healthy donors (n = 30) and treated HIV(+) donors (n = 20). PBMC were cultured for 7 d with staphylococcal enterotoxin B or IL-7 in the absence or presence of 100 U/ml IFN-α8. Total and naive CD4(+) and CD8(+) T cells were assessed for proliferation (via Ki67 expression), CD127 expression, and phosphorylated STAT5 levels using flow cytometry. IFN-α significantly enhanced activation-induced proliferation (via staphylococcal enterotoxin B stimulation) but inhibited homeostatic proliferation (IL-7 induced) of CD4(+) and CD8(+) T cells. Both of these effects may adversely affect CD4(+) T cell homeostasis in HIV patients. CD127 expression was increased in both healthy and HIV(+) donors following culture with IFN-α8, and levels of IL-7-induced phosphorylated STAT5 were increased by IFN-α8 in healthy donors only. Hence, the inhibitory effects of IFN-α on IL-7-induced proliferation of CD4(+) T cells are unlikely to be mediated by downregulation of CD127 expression or inhibition of STAT5 phosphorylation. These data suggest that increased IFN-α activity may promote the loss of T cells by accelerating cell turnover and activation-induced cell death while decreasing the renewal of T cells by inhibiting the proliferative effect of IL-7.


Recovery and management options for spring/summer chinook salmon in the Columbia River basin.
Construction of four dams on the lower Snake River (in northwestern United States) between 1961 and 1975 altered salmon spawning habitat, elevated smolt and adult migration mortality, and contributed to severe declines of Snake River salmon populations. By applying a matrix model to long-term population data, we found that (i) dam passage improvements have dramatically mitigated direct mortality associated with dams; (ii) even if main stem survival were elevated to 100%, Snake River spring/summer chinook salmon (Oncorhynchus tshawytscha) would probably continue to decline toward extinction; and (iii) modest reductions in first-year mortality or estuarine mortality would reverse current population declines.


Present Insights on Cardiomyopathy in Diabetic Patients.
The pathogenesis of diabetic cardiomyopathy (DCM) is partially understood and is likely to be multifactorial, involving metabolic disturbances, hypertension and cardiovascular autonomic neuropathy (CAN). Therefore, an important need remains to further delineate the basic mechanisms of diabetic cardiomyopathy and to apply them to daily clinical practice. We attempt to detail some of these underlying mechanisms, focusing in the clinical features and management. The novelty of this review is the role of CAN and reduction of blood pressure descent during sleep in the development of DCM. Evidence has suggested that CAN might precede left ventricular hypertrophy and diastolic dysfunction in normotensive patients with type 2 diabetes, serving as an early marker for the evaluation of preclinical cardiac abnormalities. Additionally, a prospective study demonstrated that an elevation of nocturnal systolic blood pressure and a loss of nocturnal blood pressure fall might precede the onset of abnormal albuminuria and cardiovascular events in hypertensive normoalbuminuric patients with type 2 diabetes. Therefore, existing microalbuminuria could imply the presence of myocardium abnormalities. Considering that DCM could be asymptomatic for a long period and progress to irreversible cardiac damage, early recognition and treatment of the preclinical cardiac abnormalities are essential to avoid severe cardiovascular outcomes. In this sense, we recommend that all type 2 diabetic patients, especially those with microalbuminuria, should be regularly submitted to CAN tests, Ambulatory Blood Pressure Monitoring and echocardiography, and treated for any abnormalities in these tests in the attempt of reducing cardiovascular morbidity and mortality.


Experiences of the new role of advanced practice nurses in Swedish primary health care--a qualitative study.
Experiences of the new role of advanced practice nurses in Swedish primary health care-A qualitative study The aim of this study was to investigate and describe the experiences of the first advanced practice nurses (APNs), a new profession for Swedish health care, and of their supervising general practitioners (GPs), regarding the new role and scope of practice of APNs in primary health care. Individual interviews were conducted with the four first APNs and one focus group interview was conducted with five supervising physicians. The material was transcribed verbatim and analysed using latent content analysis. The respondents expressed confidence and trust in the new role of APNs. Some opposition to this new role from the GPs and other colleagues was observed, but was nonetheless overcome. The experiences of the APN role indicate that the new role is clearly demarcated from the role of physicians. The APNs were considered an extra resource for both the GPs and other nurses, which contributed to an increased availability of care for patients. The APN role requires an explicit definition and demarcation in relation to responsibility and roles among colleagues. Further development of the APN role presupposes the right to prescribe medication and order treatments, as well as an evaluation of patient, organizational and inter-professional perspectives on the matter.


Binding of N-methylscopolamine to the extracellular domain of muscarinic acetylcholine receptors.
Interaction of orthosteric ligands with extracellular domain was described at several aminergic G protein-coupled receptors, including muscarinic acetylcholine receptors. The orthosteric antagonists quinuclidinyl benzilate (QNB) and N-methylscopolamine (NMS) bind to the binding pocket of the muscarinic acetylcholine receptor formed by transmembrane α-helices. We show that high concentrations of either QNB or NMS slow down dissociation of their radiolabeled species from all five subtypes of muscarinic acetylcholine receptors, suggesting allosteric binding. The affinity of NMS at the allosteric site is in the micromolar range for all receptor subtypes. Using molecular modelling of the M2 receptor we found that E172 and E175 in the second extracellular loop and N419 in the third extracellular loop are involved in allosteric binding of NMS. Mutation of these amino acids to alanine decreased affinity of NMS for the allosteric binding site confirming results of molecular modelling. The allosteric binding site of NMS overlaps with the binding site of some allosteric, ectopic and bitopic ligands. Understanding of interactions of NMS at the allosteric binding site is essential for correct analysis of binding and action of these ligands.


Human enhancer of filamentation 1, a novel p130cas-like docking protein, associates with focal adhesion kinase and induces pseudohyphal growth in Saccharomyces cerevisiae.
Budding in Saccharomyces cerevisiae follows a genetically programmed pattern of cell division which can be regulated by external signals. On the basis of the known functional conservation between a number of mammalian oncogenes and antioncogenes with genes in the yeast budding pathway, we used enhancement of pseudohyphal budding in S. cerevisiae by human proteins expressed from a HeLa cDNA library as a morphological screen to identify candidate genes that coordinate cellular signaling and morphology. In this report, we describe the isolation and characterization of human enhancer of filamentation 1 (HEF1), an SH3-domain-containing protein that is similar in structure to pl30cas, a recently identified docking protein that is a substrate for phosphorylation by a number of oncogenic tyrosine kinases. In contrast to p130cas, the expression of HEF1 appears to be tissue specific. Further, whereas p130cas is localized predominantly at focal adhesions, immunofluorescence indicates that HEF1 localizes to both the cell periphery and the cell nucleus and is differently localized in fibroblasts and epithelial cells, suggesting a more complex role in cell signalling. Through immunoprecipitation and two-hybrid analysis, we demonstrate a direct physical interaction between HEF1 and p130cas, as well as an interaction of the SH3 domain of HEF1 with two discrete proline-rich regions of focal adhesion kinase. Finally, we demonstrate that as with p130cas, transformation with the oncogene v-abl results in an increase in tyrosine phosphorylation on HEF1, mediated by a direct association between HEF1 and v-Abl. We anticipate that HEF1 may prove to be an important linking element between extracellular signalling and regulation of the cytoskeleton.


Volumetric thin-section CT: evaluation of pulmonaryinterlobar fissures.
We aimed to perform an imaging analysis of interlobar fissures and their variations using thin-section computed tomography (CT). Volumetric thin-section CT scanning was performed in 208 subjects. Interlobar fissures were observed on axial images, and reconstructed coronal and sagittal images were observed by multiplanar reformatting (MPR). The vessel distributions were verified by maximal intensity projection (MIP). On the axial images, the interlobar fissures were characterized by lines of hyperattenuation, bands of hyperattenuation, avascular zones, and mixed imaging. The interlobar fissures were divided into seven grades according to the percentage of defects over the entire fissure. On the axial images, of all interlobar fissures without avascular zones, 70.2% of the right oblique fissures (ROFs) and 94.2% of the left oblique fissures (LOFs) appeared as lines, and 83.2% of the horizontal fissures (HFs) appeared as bands. All of the interlobar fissures appeared as lines on the coronal and sagittal images. Of all cases, 17.8% showed fully complete interlobar fissures for all three fissures. Incomplete fissures included 41.3% of ROFs, 58.2% of HFs, and 45.2% of LOFs. In ROFs and LOFs, discontinuity was most frequently below 20%, while in HFs discontinuity was most frequently 41%-60%. The most common classification of incomplete interlobar fissures was a discontinuous avascular zone. Incomplete interlobar fissures are common variations of interlobar fissures. Techniques including volumetric thin-section CT, MPR, and MIP can assist in the diagnosis of incomplete interlobar fissures.


New evidence for chunk-based models in word segmentation.
There is large evidence that infants are able to exploit statistical cues to discover the words of their language. However, how they proceed to do so is the object of enduring debates. The prevalent position is that words are extracted from the prior computation of statistics, in particular the transitional probabilities between syllables. As an alternative, chunk-based models posit that the sensitivity to statistics results from other processes, whereby many potential chunks are considered as candidate words, then selected as a function of their relevance. These two classes of models have proven to be difficult to dissociate. We propose here a procedure, which leads to contrasted predictions regarding the influence of a first language, L1, on the segmentation of a second language, L2. Simulations run with PARSER (Perruchet & Vinter, 1998), a chunk-based model, predict that when the words of L1 become word-external transitions of L2, learning of L2 should be depleted until reaching below chance level, at least before extensive exposure to L2 reverses the effect. In the same condition, a transitional-probability based model predicts above-chance performance whatever the duration of exposure to L2. PARSER's predictions were confirmed by experimental data: Performance on a two-alternative forced choice test between words and part-words from L2 was significantly below chance even though part-words were less cohesive in terms of transitional probabilities than words.


Integrative Conductance of Oxygen During Exercise at Altitude.
In the oxygen (O2) cascade downstream steps can never achieve higher flows of O2 than the preceding ones. At the lung the transfer of O2 is determined by the O2 gradient between the alveolar space and the lung capillaries and the O2 diffusing capacity (DLO2). While DLO2 may be increased several times during exercise by recruiting more lung capillaries and by increasing the oxygen carrying capacity of blood due to higher peripheral extraction of O2, the capacity to enhance the alveolocapillary PO2 gradient is more limited. The transfer of oxygen from the alveolar space to the hemoglobin (Hb) must overcome first the resistance offered by the alveolocapillary membrane (1/DM) and the capillary blood (1/θVc). The fractional contribution of each of these two components to DLO2 remains unknown. During exercise these resistances are reduced by the recruitment of lung capillaries. The factors that reduce the slope of the oxygen dissociation curve of the Hb (ODC) (i.e., lactic acidosis and hyperthermia) increase 1/θVc contributing to limit DLO2. These effects are accentuated in hypoxia. Reducing the size of the active muscle mass improves pulmonary gas exchange during exercise and reduces the rightward shift of the ODC. The flow of oxygen from the muscle capillaries to the mitochondria is pressumably limited by muscle O2 conductance (DmcO2) (an estimation of muscle oxygen diffusing capacity). However, during maximal whole body exercise in normoxia, a higher flow of O2 is achieved at the same pressure gradients after increasing blood [Hb], implying that in healthy humans exercising in normoxia there is a functional reserve in DmcO2. This conclusion is supported by the fact that during small muscle exercise in chronic hypoxia, peak exercise DmcO2 is similar to that observed during exercise in normoxia despite a markedly lower O2 pressure gradient driving diffusion.


Antiinflammatory effect of A3 adenosine receptor agonists in murine autoimmune arthritis models.
CF101, an A3 adenosine receptor (A3AR) agonist, is a small orally bioavailable molecule known to suppress in vitro the production of tumor necrosis factor-alpha (TNF-alpha). We evaluated its therapeutic potential and antiinflammatory effects in 3 murine models of adjuvant induced arthritis (AIA). The antiinflammatory effect of CF101 was examined in rat AIA, in mouse collagen induced arthritis, and in tropomyosin induced arthritis. The clinical effect of another A3AR agonist, Cl-IB-MECA, was examined in rat AIA. The effect of low dose (10 or 100 mg/kg/day) A3AR agonists administered orally once daily on arthritis severity was assessed clinically and histologically. The effect of CF101 on the protein expression level of TNF-alpha in the synovial tissue, draining lymph nodes, and spleen cells was determined by Western blot. CF101 and Cl-IB-MECA markedly ameliorated the clinical and histological features of arthritis in the 3 models when administered orally at a low dose of 10 mg/kg body weight in the 3 autoimmune arthritis models. The lower dose of 10 mg/kg of either CF101 or Cl-IB-MECA had better antiinflammatory effect than the higher 100 mg/kg dose. Decreased expression of TNF-alpha was noted in protein extracts of synovia, draining lymph nodes, and spleen tissues. The results provide evidence that A3AR agonists exert significant antirheumatic effects in different autoimmune arthritis models by suppression of TNF-alpha production. The beneficial activity of the drugs at the low dose demonstrates that the effect is A3AR mediated.


Control of Polar Orientation and Lattice Strain in Epitaxial BaTiO3 Films on Silicon.
Conventional strain engineering of epitaxial ferroelectric oxide thin films is based on the selection of substrates with a suitable lattice parameter. Here, we show that the variation of oxygen pressure during pulsed laser deposition is a flexible strain engineering method for epitaxial ferroelectric BaTiO3 films either on perovskite substrates or on Si(001) wafers. This unconventional growth strategy permits continuous tuning of strain up to high levels (ε > 0.8%) in films greater than one hundred nanometers thick, as well as selecting the polar axis orientation to be either parallel or perpendicular to the substrate surface plane.


Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants.
Childhood/Adult-onset Lysosomal Acid Lipase Deficiency (LAL-D) is a recessive disorder due to loss of function variants of LAL, the enzyme which hydrolyses cholesteryl esters, derived from internalized apoB containing lipoproteins. The disease is characterized by multi-organ involvement including the liver, spleen, intestine and cardiovascular system. The aim of this study was the clinical and molecular characterization of 14 (13 unrelated) previously unreported patients with childhood-onset LAL-D. Data collected included clinical and laboratory investigations, liver imaging, liver biopsy and LIPA gene analysis. The response to lipid-lowering medications, liver transplantation and enzyme replacement therapy (ERT) was reported for some patients. LAL-D was suspected at 4.4 ± 3.3 years of age for the presence of hepatomegaly, elevated serum transaminases and hypercholesterolemia, and was confirmed by liver biopsy/imaging and LAL assay. The follow up period ranged from 3 to 40 years (mean 7.8 ± 4.0 years in 13 cases). Patients treated with statins with or without ezetimibe showed 28% reduction of plasma LDL-cholesterol without a tangible effect on liver enzymes; some patients receiving ERT showed normalized lipoprotein profile and transaminase levels. The common c.894G > A variant was observed in homozygosity or compound heterozygosity in 10 patients. We found seven previously reported variants: p.(Trp140*), p.(Arg218*), p.(Gly266*), p.(Thr288Ile), p.(Leu294Ser), p.(His295Tyr) and p.(Gly342Arg) and two novel variants: p.(Asp345Asn), affecting the LAL catalytic triad, and c.229+3A > C, affecting splicing. Homozygosity for p.(Thr288Ile) or c.229+3A > C was associated with a severe phenotype. This study provides additional data on the features of childhood-onset LAL-D and describes two novel pathogenic variants of the LIPA gene.


Identification and quantitation of clinically relevant microbes in patient samples: Comparison of three k-mer based classifiers for speed, accuracy, and sensitivity.
Infections are a serious health concern worldwide, particularly in vulnerable populations such as the immunocompromised, elderly, and young. Advances in metagenomic sequencing availability, speed, and decreased cost offer the opportunity to supplement or even replace culture-based identification of pathogens with DNA sequence-based diagnostics. Adopting metagenomic analysis for clinical use requires that all aspects of the workflow are optimized and tested, including data analysis and computational time and resources. We tested the accuracy, sensitivity, and resource requirements of three top metagenomic taxonomic classifiers that use fast k-mer based algorithms: Centrifuge, CLARK, and KrakenUniq. Binary mixtures of bacteria showed all three reliably identified organisms down to 1% relative abundance, while only the relative abundance estimates of Centrifuge and CLARK were accurate. All three classifiers identified the organisms present in their default databases from a mock bacterial community of 20 organisms, but only Centrifuge had no false positives. In addition, Centrifuge required far less computational resources and time for analysis. Centrifuge analysis of metagenomes obtained from samples of VAP, infected DFUs, and FN showed Centrifuge identified pathogenic bacteria and one virus that were corroborated by culture or a clinical PCR assay. Importantly, in both diabetic foot ulcer patients, metagenomic sequencing identified pathogens 4-6 weeks before culture. Finally, we show that Centrifuge results were minimally affected by elimination of time-consuming read quality control and host screening steps.


Mechanistic Dissection of PARP1 Trapping and the Impact on In Vivo Tolerability and Efficacy of PARP Inhibitors.
Poly(ADP-ribose) polymerases (PARP1, -2, and -3) play important roles in DNA damage repair. As such, a number of PARP inhibitors are undergoing clinical development as anticancer therapies, particularly in tumors with DNA repair deficits and in combination with DNA-damaging agents. Preclinical evidence indicates that PARP inhibitors potentiate the cytotoxicity of DNA alkylating agents. It has been proposed that a major mechanism underlying this activity is the allosteric trapping of PARP1 at DNA single-strand breaks during base excision repair; however, direct evidence of allostery has not been reported. Here the data reveal that veliparib, olaparib, niraparib, and talazoparib (BMN-673) potentiate the cytotoxicity of alkylating agents. Consistent with this, all four drugs possess PARP1 trapping activity. Using biochemical and cellular approaches, we directly probe the trapping mechanism for an allosteric component. These studies indicate that trapping is due to catalytic inhibition and not allostery. The potency of PARP inhibitors with respect to trapping and catalytic inhibition is linearly correlated in biochemical systems but is nonlinear in cells. High-content imaging of γH2Ax levels suggests that this is attributable to differential potentiation of DNA damage in cells. Trapping potency is inversely correlated with tolerability when PARP inhibitors are combined with temozolomide in mouse xenograft studies. As a result, PARP inhibitors with dramatically different trapping potencies elicit comparable in vivo efficacy at maximum tolerated doses. Finally, the impact of trapping on tolerability and efficacy is likely to be context specific. Understanding the context-specific relationships of trapping and catalytic inhibition with both tolerability and efficacy will aid in determining the suitability of a PARP inhibitor for inclusion in a particular clinical regimen.


Omega-3 Fatty Acids for Depression in Multiple Sclerosis: A Randomized Pilot Study.
Multiple sclerosis is the most common chronic disabling disease in the central nervous system in young to middle aged adults. Depression is common in multiple sclerosis (MS) affecting between 50–60% of patients. Pilot studies in unipolar depression report an improvement in depression when omega-3 fatty acids are given with antidepressants. The objective of this study was to investigate whether omega-3 fatty acid supplementation, as an augmentation therapy, improves treatment-resistant major depressive disorder (MDD) in people with MS. We performed a randomized, double-blind, placebo-controlled pilot study of omega-3 fatty acids at six grams per day over three months. The primary outcome was a 50% or greater improvement on the Montgomery-Asberg Depression Rating Scale (MADRS). Thirty-nine participants were randomized and thirty-one completed the 3-month intervention. Improvement on MADRS between groups was not significantly different at the 3-month end point with 47.4% in the omega-3 fatty acid group and 45.5% in the placebo group showing 50% or greater improvement (p = 0.30). Omega-3 fatty acids as an augmentation therapy for treatment-resistant depression in MS was not significantly different than placebo in this pilot trial. Omega-3 fatty acid supplementation at the dose given was well-tolerated over 3 months. ClinicalTrials.gov NCT00122954.


Empirical treatment of highly suspected nontuberculous mycobacteria infections following aesthetic procedures.
Infection caused by nontuberculous mycobacteria (NTM) has been increasing. Awareness of this infection is crucial yet problematic. Delayed management may lead to destructive results. We empirically treated a series of patients with clinical suspicion of NTM infection prior to the identification of the pathogen. A total of 12 patients who developed surgical site infections between January 2011 and February 2014 were reviewed. Patients with a skin and subcutaneous infection resistant to standard management over two weeks, and previous history of aesthetic procedures within three months were regarded as highly suspected of having an NTM infection. A variety of diagnostic modalities were examined simultaneously, along with starting empirical treatment including a combination of clarithromycin and moxifloxacin, and surgical debridement. All wounds healed completely within 4 weeks. The mean follow-up duration was 7.2 months, and none of the patients developed relapse. Specific NTM pathogens were identified in six patients. Eight patients showed caseating granuloma implying an NTM infection. One patient showed an uncommon Stenotrophomonas infection, which was successfully treated. Three patients had no evidence of a pathogen despite repeated microbial tests. Complications such as scarring, pigmentation, and disfigurement were common in all the patients. NTM should be considered in the differential diagnosis of an unusual skin and soft-tissue infection. We propose an empirical regimen of clarithromycin and moxifloxacin as an efficient treatment option for an NTM infection.


Combination vaccine use and vaccination quality in a managed care population.
To evaluate the impact of a pentavalent combination vaccine on childhood immunization coverage rates and timeliness within a managed care organization. Retrospective matched-cohort analysis of encounter data from administrative claims and a state immunization registry. Children were stratified into 2 demographically matched cohorts (combination and reference), based on receipt of the DTaP/HepB/IPV combination vaccine. Children were followed until 24 months of age, and coverage rates and on-time rates were assessed. Outcomes were measured for the HEDIS Combination 2 vaccine series (4 doses of diphtheria/tetanus/pertussis, 3 doses of polio, 1 dose of measles/mumps/rubella, 3 doses of Haemophilus influenzae type b, 3 doses of hepatitis B, and 1 dose of varicella) and each vaccine series individually. Children in the combination cohort were significantly more likely to be fully vaccinated for the HEDIS Combination 2 series by 2 years of age and to be vaccinated within the recommended age ranges. In the combination cohort 86.9% (752/865) of patients were fully covered compared with only 74.1% (641/865) of the reference cohort (P <.001). In the combination cohort 45.2% (391/865) of patients received vaccinations on time versus 37.5% (324/865) of the reference cohort, P = .001. Receipt of DTaP/HepB/IPV was associated with improved coverage and age-appropriate immunization in a managed care population.


Pyrithione-based ruthenium complexes as inhibitors of aldo-keto reductase 1C enzymes and anticancer agents.
Four ruthenium complexes of clinically used zinc ionophore pyrithione and its oxygen analog 2-hydroxypyridine N-oxide were prepared and evaluated as inhibitors of enzymes of the aldo-keto reductase subfamily 1C (AKR1C). A kinetic study assisted with docking simulations showed a mixed type of inhibition consisting of a fast reversible and a slow irreversible step in the case of both organometallic compounds 1A and 1B. Both compounds also showed a remarkable selectivity towards AKR1C1 and AKR1C3 which are targets for breast cancer drug design. The organoruthenium complex of ligand pyrithione as well as pyrithione itself also displayed toxicity on the hormone-dependent MCF-7 breast cancer cell line with EC50 values in the low micromolar range.


Implementing the TARGET Model in Physical Education: Effects on Perceived Psychobiosocial and Motivational States in Girls.
Grounded in achievement goal and self-determination theories, the purpose of this study was to investigate the effects of mastery and performance climate interventions on students' psychobiosocial (PBS) states and self-determined motivation. A first study was conducted to determine the validity of the measures. In a second study, two groups of female students (N = 65, 14-15 years of age) took part in the investigation. A mastery-performance group participated in eight task-involving lessons and then in another set of eight ego-involving lessons. A performance-mastery group participated in ego-involving lessons and then in task-involving lessons. Findings revealed that the program was effective in changing PBS states and self-determined motivation in the performance-mastery group. In particular, participants in this group reported lower scores on pleasant/functional PBS states and self-determined motivation after the first phase of the intervention. Furthermore, lower levels of self-determined motivation were maintained after the second phase of the intervention, thereby suggesting detrimental carryover effects.


Dental surgery in ancient Egypt.
Many different surgical procedures have over the years been attributed to the ancient Egyptians. This is also true regarding the field of dental surgery. The existence of dentists in ancient Egypt is documented and several recipes exist concerning dental conditions. However, no indications of dental surgery are found in the medical papyri or in the visual arts. Regarding the osteological material/mummies, the possible indications of dental surgery are few and weak. There is not a single example of a clear tooth extraction, nor of a filling or of an artificial tooth. The suggested examples of evacuation of apical abscesses can be more readily explained as outflow sinuses. Regarding the suggested bridges, these are constituted of one find likely dating to the Old Kingdom, and one possibly, but perhaps more likely, dating to the Ptolemaic era. Both seem to be too weak to have served any possible practical purpose in a living patient, and the most likely explanation would be to consider them as a restoration performed during the mummification process. Thus, while a form of dentistry did certainly exist in ancient Egypt, there is today no evidence of dental surgery.


Gonadal-independent activation of enhanced afternoon luteinizing hormone release during pubertal development in the female rat.
In the present study we investigated the extent to which expression of the diurnal pattern of LH secretion in prepubertal female rats is driven by an ovarian-independent neuroendocrine mechanism. To remove gonadal influences, rats were ovariectomized (OVX) during early juvenile, late juvenile, or peripubertal phases of development (20-22, 26-27, and 32-33 days of age, respectively), and blood samples were collected throughout the day (every 30-60 min) 2 or 4 days after surgery. Morning plasma LH levels were relatively low 2 days after ovariectomy (30-120 ng/ml), but rose during the afternoon to reach levels ranging from 180-300 ng/ml. This afternoon elevation was sustained both in late juvenile and peripubertal rats, but not in early juvenile rats. The predominant change observed 4 days after ovariectomy was an overall 3- to 6-fold increase in plasma LH levels, which masked the afternoon elevation. Analysis of plasma LH profiles from individual rats, however, revealed that at each of the three ages studied the peak plasma LH levels occurred in the afternoon, and these were most pronounced in the peripubertal animals. To further clarify the existence of such a diurnal pattern of LH release in the 4-day OVX animals pulsatile LH release profiles were obtained from individual animals, using a 5-min bleeding paradigm, at either 24 days (in the morning) or 36 days of age (in either the morning or the afternoon). LH release was episodic in all of the animals studied, with pulses occurring on average of about once every 30 min. Analysis of the plasma LH profiles using the PULSAR algorithm revealed that the overall mean plasma LH levels of the peripubertal animals was enhanced during the afternoon, compared to that in the morning or to the afternoon LH levels in the early juvenile rats. Mean nadir and mean peak LH levels were also greater. No differences in LH pulse amplitude and only marginal differences in LH pulse frequency were detected among the three groups studied. The enhancement of afternoon LH secretion in the OVX rats could not be attributed to age-related or diurnal changes in adenohypophyseal responsiveness to LHRH. The results suggest that the initiation of enhanced afternoon LH secretion, previously shown to occur in intact female rats during the juvenile-peripubertal transition period, results primarily from the activation of a central neuroendocrine mechanism. Although the ovaries might play a role in the development of this diurnal pattern, it is clear that its activation is ovarian independent.


De-novo Inflammatory Bowel Disease After Bariatric Surgery: A Large Case Series.
Case reports of inflammatory bowel diseases [IBD] have been reported in patients with a history of bariatric surgery. Our aim was to characterize patients who were diagnosed with IBD after having undergone bariatric surgery. Electronic medical records were reviewed at two institutions to identify patients who developed de-novo Crohn's disease or ulcerative colitis [UC] after bariatric surgery. Data on demographics, type of bariatric surgical procedure, IBD subtype, phenotype and medication usage were obtained. The incidence rate of de-novo IBD after bariatric surgery [per 100000 person-years] and standardized incidence ratio [SIR] were estimated from a prospective bariatric surgery database. A total of 44 patients with de-novo IBD after bariatric surgery were identified [31 Crohn's disease, 12 UC, one IBD unclassified]. Most patients were female [88.6%], with median age at IBD onset of 44 years [IQR, 37-52] and median time to IBD diagnosis after bariatric surgery of 7 years [IQR, 3-10]. Sixty-eight per cent underwent Roux-en-Y gastric bypass. In the prospective database, the incidence of IBD in patients who underwent bariatric surgery was 26.7 per 100000 person-years [4.5 for UC and 22.3 for Crohn's disease]. The age-adjusted SIR ranged from 3.56 in the 40-49 year age group to 4.73 in the 30-39 year age group. We described a case series of patients developing de-novo IBD after bariatric surgery. There appears to be a numerically higher incidence of Crohn's disease in this population. Confirmation of causality is required in larger patient cohorts.


New insights into the electrochemistry of magnesium molybdate hierarchical architectures for high performance sodium devices.
Magnesium molybdate (MgMoO4), which possesses synergistic features combining both hierarchical plate-like nanomaterials and porous architectures, has been successfully synthesized through a facile combustion synthesis at a low temperature. The hierarchical architecture is characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), scanning transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS) analyses. The as-obtained MgMoO4 nanoplates showed a porous structure with a pore-size distribution ranging from 50 to 70 nm. This porosity provides an electron transport pathway and enhanced surface reaction kinetics. The binding energies measured for Mg 2p, Mo 3d, 3p and O 1s are consistent with the literature, and with the metal ions being present as M(ii) and M(vi) states, respectively. This indicates that the oxidation states of the metal cations are as expected. The electrochemical behaviour of MgMoO4 was investigated using aqueous (NaOH) and non-aqueous solvents (NaClO4 in EC : DMC : FEC) for supercapacitor and battery applications. The sodium-ion capacitor involves ion absorption and insertion into the MgMoO4 electrodes resulting in superior power and energy densities. However, the cycling stability was found to be stable only for an aqueous system. The formation of a solid electrolyte surface layer restricted the reversible capacity of the MgMoO4 in the sodium-battery. Nevertheless, it does offer some promise as an anode material for storing energy with high rate performance and excellent capacity retention. Detailed comparative analyses of various electrolytes in storage devices such as hybrid sodium-ion capacitors and sodium-ion batteries are vital for the integration of hierarchical structured materials into practical applications. The reaction mechanisms are postulated.


MicroRNA-155 coordinates the immunological landscape within murine melanoma and correlates with immunity in human cancers.
miR-155 has recently emerged as an important promoter of antitumor immunity through its functions in T lymphocytes. However, the impact of T cell-expressed miR-155 on immune cell dynamics in solid tumors remains unclear. In the present study, we used single-cell RNA sequencing to define the CD45+ immune cell populations at different time points within B16F10 murine melanoma tumors growing in either wild-type or miR-155 T cell conditional knockout (TCKO) mice. miR-155 was required for optimal T cell activation and reinforced the T cell response at the expense of infiltrating myeloid cells. Further, myeloid cells from tumors growing in TCKO mice were defined by an increase in wound healing genes and a decreased IFN-γ-response gene signature. Finally, we found that miR-155 expression predicted a favorable outcome in human melanoma patients and was associated with a strong immune signature. Moreover, gene expression analysis of The Cancer Genome Atlas (TCGA) data revealed that miR-155 expression also correlates with an immune-enriched subtype in 29 other human solid tumors. Together, our study provides an unprecedented analysis of the cell types and gene expression signatures of immune cells within experimental melanoma tumors and elucidates the role of miR-155 in coordinating antitumor immune responses in mammalian tumors.


The evolution of interacting phenotypes: genetics and evolution of social dominance.
Although the argument over genetic influences on social dominance is contentious, genetic models of interacting phenotypes provide a theoretical framework for heritable effects on, and therefore evolution of, social behavior. Here we adapt the interacting phenotype model to show how social dominance can evolve. Our model makes a number of predictions: rapid evolution of behavior, strong correlated responses in associated traits (such as a badge of status), and, because context is important for social dominance, integrated evolution of both dominant and subordinate behavior reflecting direct and indirect genetic effects and social selection. We also describe the results of empirical work, artificial selection based on social status within a hierarchy in the cockroach Nauphoeta cinerea, that we used to test the predictions of our model. There was little change within selection lines in the expression of agonistic behavior, but by just generation 7 of selection, in comparisons between lines, high-line males consistently dominated low and control males, while low-line males were consistently subordinate to high-line and control males. There was a strong correlated response to selection in the pheromonal badge of status. Some correlated responses to selection differed among replicate lines, with the compound that makes males subordinate changed in one replicate, while the compound that confers dominance was altered in the other. Overall, our results are consistent with predictions from models of interacting phenotypes: social dominance is influenced by additive genetic variation, can evolve as a result of social selection, and evolution of social interactions appears to be rapid. Finally, different responses in the replicates allowed us to test very specific predictions regarding the role of the social pheromone in N. cinerea, highlighting the value of artificial selection experiments as a tool in evolutionary behavioral genetic studies.


Triton X-100 extraction of P815 tumor cells: evidence for a plasma membrane skeleton structure.
It has been shown that a Triton X-100-insoluble protein matrix can be isolated from the plasma membranes of P815 tumor cells and murine lymphoid cells (Mescher, M. F., M. J. L. Jose and S. P. Balk, 1981, Nature (Lond.), 289:139-144). The properties of the matrix suggested that this set of proteins might form a membrane skeletal structure, stable in the absence of the lipid bilayer. Since purification of plasma membrane results in yields of only 20 to 40%, it was not clear whether the matrix was associated with the entire plasma membrane. To determine if a detergent-insoluble structure was present over the entire cell periphery and stable in the absence of the membrane bilayer or cytoskeletal components, we have examined extraction of whole cells with Triton X-100. Using the same conditions as those used for isolation of the matrix from membranes, we found that extraction of intact cells resulted in structures consisting of a continuous layer of protein at the periphery, a largely empty cytoplasmic space, and a nuclear remnant. Little or no lipid bilayer structure was evident in association with the peripheral layer, and no filamentous cytoskeletal structures could be seen in the cytoplasmic space by thin-section electron microscopy. Analysis of these Triton shells showed them to retain approximately 15% of the total cell protein, most of which was accounted for by low molecular weight nuclear proteins. 5'-Nucleotidase, a cell surface enzyme that remains associated with the plasma membrane matrix, was quantitatively recovered with the shells. Included among the polypeptides present in the shells was a set with mobilities identical to those of the set that makes up the plasma membrane matrix. The polypeptide composition of the shells further confirmed that cytoskeletal proteins were present to a very low extent, if at all, after the extraction. The results demonstrate that a detergent-insoluble protein matrix associated with the periphery of these cells forms a continuous, intact macrostructure whose stability is independent of the membrane bilayer or filamentous cytoskeletal elements, and thus has the properties of a membrane skeletal structure. Although not yet directly demonstrated, the results also strongly suggest that this peripheral layer is composed of the previously described set of plasma membrane matrix proteins. This article discusses possible roles for this proposed membrane skeletal structure in stabilizing the membrane bilayer and affecting the dynamics of other membrane proteins.


Epidemiology, Ventilation Management and Outcomes of COPD Patients Receiving Invasive Ventilation for COVID-19-Insights from PRoVENT-COVID.
Chronic obstructive pulmonary disease (COPD) is a risk factor for death in patients admitted to intensive care units (ICUs) for respiratory support. Previous reports suggested higher mortality in COPD patients with COVID-19. It is yet unknown whether patients with COPD were treated differently compared to non-COPD patients. We compared the ventilation management and outcomes of invasive ventilation for COVID-19 in COPD patients versus non-COPD patients. This was a post hoc analysis of a nation-wide, observational study in the Netherlands. COPD patients were compared to non-COPD patients with respect to key ventilation parameters. The secondary endpoints included adjunctive treatments for refractory hypoxemia, and 28-day mortality. Of a total of 1090 patients, 88 (8.1%) were classified as having COPD. The ventilation parameters were not different between COPD patients and non-COPD patients, except for FiO2, which was higher in COPD patients. Prone positioning was applied more often in COPD patients. COPD patients had higher 28-day mortality than non-COPD patients. COPD had an independent association with 28-day mortality. In this cohort of patients who received invasive ventilation for COVID-19, only FiO2 settings and the use of prone positioning were different between COPD patients and non-COPD patients. COPD patients had higher mortality than non-COPD patients.


Peer stressors and gender differences in adolescents' mental health: the TRAILS study.
This study tested two hypotheses about gender-specific mental health effects of peer stressors during early adolescence: (1) boys and girls are sensitive to different types of peer stressors, and (2) peer stress is associated with different mental health problems in boys and girls. These two hypotheses were tested in a prospective large population cohort of 2,084 Dutch young adolescents. Internalizing and externalizing problems were measured at baseline and follow-up, whereas stressful life events in the period between baseline and follow-up were measured retrospectively at follow-up. We performed the analyses with two types of peer stressors; victimization at school and relationship losses. Relationship losses were more strongly associated with internalizing and externalizing problems in girls than boys, supporting the first hypothesis. Peer victimization at school was also associated with both types of mental health problems, but equally strong in boys and girls. Peer stress is unlikely to be associated with different mental health problems in boys and girls. Instead, boys and girls are more likely to be susceptible to different types of peer stressors.


Altered peptide ligands: prospects for immune intervention in autoimmune disease.
It has long been accepted that the response of T cells to a protein antigen is strongly influenced by parameters governing processing and presentation of the immunodominant epitopes. Recent evidence has suggested, however, that subtle changes in the nature of the ligand itself may also affect the outcome of T-cell receptor (TCR) ligation, necessitating a re-evaluation of previously accepted paradigms of T-cell activation. In particular, activation may no longer be regarded as an all-or-nothing event, but appears to involve both quantitative and qualitative dimensions. This revolution in our understanding has emanated from the recent discovery that analogues of immunogenic peptides, so-called altered peptide ligands (APLs), may elicit a subset of normal activation events, or profoundly influence responses to the wild-type epitope. As such, the potential offered by APLs for modifying the outcome of deleterious immune responses involved in autoimmunity has not passed unnoticed. Indeed, the design and exploitation of novel reagents based on the structure of autoantigenic epitopes has enjoyed some measure of success in the treatment of experimental models of autoimmune disease and holds promise for their exploitation within the clinical arena.


Invasive bacterial infections in neonates and young infants born outside hospital admitted to a rural hospital in Kenya.
Bacterial sepsis is thought to be a major cause of young infant deaths in low-income countries, but there are few precise estimates of its burden or causes. We studied invasive bacterial infections (IBIs) in young infants, born at home or in first-level health units ("outborn") who were admitted to a Kenyan rural district hospital during an 8-year period. Clinical and microbiologic data, from admission blood cultures and cerebrospinal fluid cultures on all outborn infants aged less than 60 days admitted from 2001 to 2009, were examined to determine etiology of IBI and antimicrobial susceptibilities. Of the 4467 outborn young infants admitted, 748 (17%) died. Five hundred five (11%) had IBI (10% bacteremia and 3% bacterial meningitis), with a case fatality of 33%. The commonest organisms were Klebsiella spp., Staphylococcus aureus, Streptococcus pneumoniae, Group B Streptococcus, Acinetobacter spp., Escherichia coli, and Group A Streptococcus. Notably, some blood culture isolates were seen in outborn neonates in the first week of life but not in inborns: Salmonella, Aeromonas, and Vibrio spp. Eighty-one percent of isolates were susceptible to penicillin and/or gentamicin and 84% to ampicillin and/or gentamicin. There was a trend to increasing in vitro antimicrobial resistance to these combinations from 2008 but without a worse outcome. IBI is common in outborn young infants admitted to rural African hospitals with a high mortality. Presumptive antimicrobial use is justified for all young infants admitted to the hospital.


Bromine-rich complexes of bismuth: experimental and theoretical studies.
Three novel polybromide complexes of bismuth(iii) - (2,6-MePyH)3[BiBr5(Br3)] (1), (H2bpp){[BiBr5](Br2)} (2) and (3-ClPyH)2{[BiBr5](Br2)} (3) - were synthesized. The results of an extended screening involving a set of organic cations resulting in the formation/non-formation of Bi(iii) polybromides are presented and discussed. The nature of BrBr interactions in Bi(iii) polybromides was investigated by theoretical methods, enabling the estimation of their energies.


Effects of dry needling (DNHS technique) on the contractile properties of spastic muscles in a patient with stroke: a case report.
Dry needling for hypertonia and spasticity (DNHS) is a technique used for decreasing hypertonia and spasticity and for the improvement of function in patients with damage to the central nervous system. There is limited evidence supporting the effectiveness of this technique on the basis of objective assessments. The aim of the present case report was to quantify the effects of dry needling (DNHS technique) on the contractile properties of spastic muscles in an individual with stroke. The DNHS technique was applied to a 50-year-old male 2.5 years after stroke who had a complaint of spasticity. The treated muscles were biceps brachii, triceps brachii, rectus femoris, semitendinosus, biceps femoris, medial gastrocnemius, and lateral gastrocnemius. Tensiomyography was used to assess maximal displacement (Dm) of treated muscles. We performed a preintervention and postintervention measurement and a follow-up measurement 3 weeks after intervention. After the application of the DNHS technique, a decrease in the level of local muscle stiffness was observed for all muscles after intervention and at the 3-week follow-up, quantified by an increase in Dm. The usefulness of tensiomyography for detecting changes in patients with spasticity correlated with clinical measures in this field requires further research to establish the reliability of the different parameters provided by the equipment.


Depth enhancement of multi-layer light field display using polarization dependent internal reflection.
A technique to enhance the depth range of the multi-layer light field three-dimensional display is proposed. A set of the optical plates are stacked in front of the conventional multi-layer light field display, creating additional internal reflection for one polarization state. By switching between two orthogonal polarization states in synchronization with the displayed three-dimensional images, the depth range of the display can be doubled. The proposed method is verified experimentally, confirming its feasibility.


Acute dialysis risk in living kidney donors.
Reduced kidney function confers a higher risk of acute kidney injury at the time of an inciting event, such as sepsis. Whether the same is true in those with reduced renal mass from living kidney donation is unknown. We conducted a population-based matched cohort study of all living kidney donors in the province of Ontario, Canada who underwent donor nephrectomy from 1992 to 2009. We manually reviewed the medical records of these living kidney donors and linked this information to provincial health care databases. Non-donors were selected from the healthiest segment of the general population. There were 2027 donors and 20 270 matched non-donors. The median age was 43 years (interquartile range 34-50) and individuals were followed for a median of 6.6 years (maximum 17.7 years). The primary outcome was acute dialysis during any hospital stay. Reasons for hospitalization included infectious diseases, cardiovascular diseases and hematological malignancies. Only one donor received acute dialysis in follow-up (6.5 events per 100 000 person-years), a rate which was statistically no different than 14 non-donors (9.4 events per 100 000 person-years). These results are reassuring for the practice of living kidney donation. Longer follow-up of this and other donor cohorts will provide more precise estimates about this risk.


Quantitative Microbial Risk Assessment for Escherichia coli O157:H7 in Fresh-Cut Lettuce.
Leafy green vegetables, including lettuce, are recognized as potential vehicles for foodborne pathogens such as Escherichia coli O157:H7. Fresh-cut lettuce is potentially at high risk of causing foodborne illnesses, as it is generally consumed without cooking. Quantitative microbial risk assessments (QMRAs) are gaining more attention as an effective tool to assess and control potential risks associated with foodborne pathogens. This study developed a QMRA model for E. coli O157:H7 in fresh-cut lettuce and evaluated the effects of different potential intervention strategies on the reduction of public health risks. The fresh-cut lettuce production and supply chain was modeled from field production, with both irrigation water and soil as initial contamination sources, to consumption at home. The baseline model (with no interventions) predicted a mean probability of 1 illness per 10 million servings and a mean of 2,160 illness cases per year in the United States. All intervention strategies evaluated (chlorine, ultrasound and organic acid, irradiation, bacteriophage, and consumer washing) significantly reduced the estimated mean number of illness cases when compared with the baseline model prediction (from 11.4- to 17.9-fold reduction). Sensitivity analyses indicated that retail and home storage temperature were the most important factors affecting the predicted number of illness cases. The developed QMRA model provided a framework for estimating risk associated with consumption of E. coli O157:H7-contaminated fresh-cut lettuce and can guide the evaluation and development of intervention strategies aimed at reducing such risk.


Insights into the hyperthermostability and unusual region-specificity of archaeal Pyrococcus abyssi tRNA m1A57/58 methyltransferase.
The S-adenosyl-L-methionine dependent methylation of adenine 58 in the T-loop of tRNAs is essential for cell growth in yeast or for adaptation to high temperatures in thermophilic organisms. In contrast to bacterial and eukaryotic tRNA m(1)A58 methyltransferases that are site-specific, the homologous archaeal enzyme from Pyrococcus abyssi catalyzes the formation of m(1)A also at the adjacent position 57, m(1)A57 being a precursor of 1-methylinosine. We report here the crystal structure of P. abyssi tRNA m(1)A57/58 methyltransferase ((Pab)TrmI), in complex with S-adenosyl-L-methionine or S-adenosyl-L-homocysteine in three different space groups. The fold of the monomer and the tetrameric architecture are similar to those of the bacterial enzymes. However, the inter-monomer contacts exhibit unique features. In particular, four disulfide bonds contribute to the hyperthermostability of the archaeal enzyme since their mutation lowers the melting temperature by 16.5°C. His78 in conserved motif X, which is present only in TrmIs from the Thermococcocales order, lies near the active site and displays two alternative conformations. Mutagenesis indicates His78 is important for catalytic efficiency of (Pab)TrmI. When A59 is absent in tRNA(Asp), only A57 is modified. Identification of the methylated positions in tRNAAsp by mass spectrometry confirms that (Pab)TrmI methylates the first adenine of an AA sequence.


Detection of submucosal gastric fundal varices with multi-detector row CT angiography.
The diagnosis of submucosal fundal varices is challenging. Currently, endoscopy and endoscopic ultrasound (EUS) are considered most useful for this purpose. The aim of this study was to evaluate if multi-detector row CT (MDCT) angiography contributes to the diagnosis of submucosal fundal varices. Twenty two patients with endoscopically suspected fundal varices were prospectively included in the study. All patients underwent EUS and MDCT angiography. Levels of agreement between EUS and MDCT angiography for the detection of submucosal and perigastric fundal varices were evaluated by three blinded independent readers. In addition, variceal size and location, as well as afferent and efferent vessels of the submucosal varices, were determined. Good or excellent image quality of MDCT angiography was obtained in 21/22 patients (95%). Based on EUS, submucosal varices were detected in 16 of 22 patients (73%) and perigastric varices in 22/22 patients (100%). Using MDCT angiography, the presence of submucosal varices was confirmed in all of these 16 patients by all three readers. Perigastric varices were also confirmed in all 22 patients by all three readers. In addition, all three readers noted the presence of a submucosal varix in an additional patient which was not detected on initial EUS. MDCT angiography showed an excellent interobserver reliability with regard to variceal diameter (kappa=0.90) and variceal location (kappa=0.94). Based on MDCT angiography, afferent and efferent vessels of submucosal varices included the left gastric vein in 11 (65%), the posterior/short gastric veins in 15 (88%), gastrorenal shunts in 10 (59%), the left inferior phrenic vein in six (35%), and the left pericardiophrenic vein in six (35%) of 17 patients. MDCT angiography is equivalent to EUS in terms of detection and characterisation of fundal varices, in particular with regard to the distinction between submucosal and perigastric fundal varices.


Bisphosphonates: The role of chemistry in understanding their biological actions and structure-activity relationships, and new directions for their therapeutic use.
The bisphosphonates ((HO)2P(O)CR1R2P(O)(OH)2, BPs) were first shown to inhibit bone resorption in the 1960s, but it was not until 30 years later that a detailed molecular understanding of the relationship between their varied chemical structures and biological activity was elucidated. In the 1990s and 2000s, several potent bisphosphonates containing nitrogen in their R2 side chains (N-BPs) were approved for clinical use including alendronate, risedronate, ibandronate, and zoledronate. These are now mostly generic drugs and remain the leading therapies for several major bone-related diseases, including osteoporosis and skeletal-related events associated with bone metastases. The early development of chemistry in this area was largely empirical and only a few common structural features related to strong binding to calcium phosphate were clear. Attempts to further develop structure-activity relationships to explain more dramatic pharmacological differences in vivo at first appeared inconclusive, and evidence for mechanisms underlying cellular effects on osteoclasts and macrophages only emerged after many years of research. The breakthrough came when the intracellular actions on the osteoclast were first shown for the simpler bisphosphonates, via the in vivo formation of P-C-P derivatives of ATP. The synthesis and biological evaluation of a large number of nitrogen-containing bisphosphonates in the 1980s and 1990s led to the key discovery that the antiresorptive effects of these more complex analogs on osteoclasts result mostly from their potency as inhibitors of the enzyme farnesyl diphosphate synthase (FDPS/FPPS). This key branch-point enzyme in the mevalonate pathway of cholesterol biosynthesis is important for the generation of isoprenoid lipids that are utilized for the post-translational modification of small GTP-binding proteins essential for osteoclast function. Since then, it has become even more clear that the overall pharmacological effects of individual bisphosphonates on bone depend upon two key properties: the affinity for bone mineral and inhibitory effects on biochemical targets within bone cells, in particular FDPS. Detailed enzyme-ligand crystal structure analysis began in the early 2000s and advances in our understanding of the structure-activity relationships, based on interactions with this target within the mevalonate pathway and related enzymes in osteoclasts and other cells have continued to be the focus of research efforts to this day. In addition, while many members of the bisphosphonate drug class share common properties, now it is more clear that chemical modifications to create variations in these properties may allow customization of BPs for different uses. Thus, as the appreciation for new potential opportunities with this drug class grows, new chemistry to allow ready access to an ever-widening variety of bisphosphonates continues to be developed. Potential new uses of the calcium phosphate binding mechanism of bisphosphonates for the targeting of other drugs to the skeleton, and effects discovered on other cellular targets, even at non-skeletal sites, continue to intrigue scientists in this research field.


Periodic vestibulocerebellar ataxia, an autosomal dominant ataxia with defective smooth pursuit, is genetically distinct from other autosomal dominant ataxias.
Periodic vestibulocerebellar ataxia is an autosomal dominant disorder characterized by defective smooth pursuit, gaze-evoked nystagmus, ataxia, and vertigo. The age of onset ranges from the third to the sixth decade. To date, all patients have originated from North Carolina, suggesting a single common founder. To clarify the classification of periodic vestibulocerebellar ataxia by determining whether it is allelic to other autosomal dominant cerebellar ataxias for which genes have been either localized or identified. Blood was collected and DNA isolated from 66 subjects (19 affected individuals) in two multigenerational families. The microsatellite markers used in the analysis either flanked or were tightly linked to the disease gene regions. Two-point and multipoint linkage analyses were performed to define the limits of exclusion. Periodic vestibulocerebellar ataxia was excluded from loci linked to spinocerebellar ataxia type 1 (chromosome 6p), type 2 (chromosome 12q) type 3/Machado/Joseph disease (chromosome 14q), type 4 (chromosome 16q), and type 5 (11cent) as well as to episodic ataxia with myokymia (chromosome 12p), episodic ataxia with nystagmus (chromosome 19p), acetazolamide-responsive hereditary paroxysmal cerebellar ataxia (chromosome 19p), and dentatorubral-pallidoluysian atrophy/Haw River syndrome (chromosome 12p). Periodic vestibulocerebellar ataxia is genetically distinct from those autosomal dominant ataxias for which chromosomal localization has been established.


The Widmark formula for alcohol quantification.
In 1932 the Swedish scientist Eric P Widmark developed two formulae commonly used for the calculation of the amount of alcohol ingested and for assessing the concentration of alcohol at some time prior to the sampling. The most important statement in the respect to these calculations is to stress the unreliability and inaccuracy of attempting back-calculations in either direction. Only gross approximations can be achieved and no pretence at accuracy must be offered.


Recurrent rearrangement during adaptive evolution in an interspecific yeast hybrid suggests a model for rapid introgression.
Genome rearrangements are associated with eukaryotic evolutionary processes ranging from tumorigenesis to speciation. Rearrangements are especially common following interspecific hybridization, and some of these could be expected to have strong selective value. To test this expectation we created de novo interspecific yeast hybrids between two diverged but largely syntenic Saccharomyces species, S. cerevisiae and S. uvarum, then experimentally evolved them under continuous ammonium limitation. We discovered that a characteristic interspecific genome rearrangement arose multiple times in independently evolved populations. We uncovered nine different breakpoints, all occurring in a narrow ~1-kb region of chromosome 14, and all producing an "interspecific fusion junction" within the MEP2 gene coding sequence, such that the 5' portion derives from S. cerevisiae and the 3' portion derives from S. uvarum. In most cases the rearrangements altered both chromosomes, resulting in what can be considered to be an introgression of a several-kb region of S. uvarum into an otherwise intact S. cerevisiae chromosome 14, while the homeologous S. uvarum chromosome 14 experienced an interspecific reciprocal translocation at the same breakpoint within MEP2, yielding a chimaeric chromosome; these events result in the presence in the cell of two MEP2 fusion genes having identical breakpoints. Given that MEP2 encodes for a high-affinity ammonium permease, that MEP2 fusion genes arise repeatedly under ammonium-limitation, and that three independent evolved isolates carrying MEP2 fusion genes are each more fit than their common ancestor, the novel MEP2 fusion genes are very likely adaptive under ammonium limitation. Our results suggest that, when homoploid hybrids form, the admixture of two genomes enables swift and otherwise unavailable evolutionary innovations. Furthermore, the architecture of the MEP2 rearrangement suggests a model for rapid introgression, a phenomenon seen in numerous eukaryotic phyla, that does not require repeated backcrossing to one of the parental species.


Management of newborns exposed to maternal HIV infection.
The management of infants whose mothers are infected with the human immunodeficiency virus (HIV) involves minimizing the risk of vertical transmission of HIV, recognizing neonatal HIV infection early, preventing opportunistic infections, and addressing psychosocial issues. Maternal antiretroviral drug therapy during pregnancy and labor, followed by six weeks of neonatal zidovudine therapy, can significantly decrease the risk of vertical transmission. Additional antiretroviral drugs may be needed in some high-risk newborns. Elective cesarean section also may prevent vertical transmission of HIV. Virologic tests allow early diagnosis of HIV infection, facilitating the timely initiation of aggressive treatment and the prevention of opportunistic infections. Even when tests are negative, infants must be closely monitored until age 18 months to completely rule out HIV infection. Prophylaxis for Pneumocystis carinii pneumonia should be initiated when HIV-exposed infants are six weeks old and should be continued for at least four months, regardless of negative virologic tests, because P. carinii pneumonia is often the initial presentation of HIV infection in infants. Laboratory monitoring, screening for perinatal infections, appropriate social support, and other modifications of standard infant care are also necessary.


How can mobile phones be used to improve nutrition service delivery in rural Bangladesh?
Nutrition has been integrated within the health services in Bangladesh as it is an important issue for health and development. High penetration of mobile phones in the community and favourable policy and political commitment of the Government of Bangladesh has created possibilities of using Information Communication Technology such as mobile phones for nutrition programs. In this paper the implementation of nutrition services with a specific focus on infant and young child feeding was explored and the potential for using mobile phones to improve the quality and coverage of nutrition services was assessed. A qualitative study was conducted in Mirzapur and Chakaria sub-districts, Bangladesh from February-April 2014. We conducted 24 in-depth interviews (mothers of young children), 8 focus group discussions (fathers and grandmothers); and 13 key informant interviews (community health workers or CHWs). We also observed 4 facilities and followed 2 CHWs during their work day. The data was analyzed manually using pre-existing themes. In this community, mothers demonstrated gaps in knowledge about IYCF. They depended on their social network and media for IYCF information. Although CHWs were trusted in the community, mothers and their family members did not consider them a good source of nutrition information as they did not talk about nutrition. In terms of ICTs, mobile phones were the most available and used by both CHWs and mothers. CHWs showed willingness to incorporate nutrition counselling through mobile phone as this can enhance their productivity, reduce travel time and improve service quality. Mothers were willing to receive voice calls from CHWs as long as the decision makers in the households were informed. Our study indicated that there are gaps in IYCF related service delivery and there is a potential for using mobile phones to both strengthen the quality of service delivery as well as reaching out to the mothers in the community. It is important however, to consider the community readiness to accept the technology during the design and delivery of the intervention.


Folding in and out: passive morphing in flapping wings.
We present a new mechanism for passive wing morphing of flapping wings inspired by bat and bird wing morphology. The mechanism consists of an unactuated hand wing connected to the arm wing with a wrist joint. Flapping motion generates centrifugal accelerations in the hand wing, forcing it to unfold passively. Using a robotic model in hover, we made kinematic measurements of unfolding kinematics as functions of the non-dimensional wingspan fold ratio (2-2.5) and flapping frequency (5-17 Hz) using stereo high-speed cameras. We find that the wings unfold passively within one to two flaps and remain unfolded with only small amplitude oscillations. To better understand the passive dynamics, we constructed a computer model of the unfolding process based on rigid body dynamics, contact models, and aerodynamic correlations. This model predicts the measured passive unfolding within about one flap and shows that unfolding is driven by centrifugal acceleration induced by flapping. The simulations also predict that relative unfolding time only weakly depends on flapping frequency and can be reduced to less than half a wingbeat by increasing flapping amplitude. Subsequent dimensional analysis shows that the time required to unfold passively is of the same order of magnitude as the flapping period. This suggests that centrifugal acceleration can drive passive unfolding within approximately one wingbeat in small and large wings. Finally, we show experimentally that passive unfolding wings can withstand impact with a branch, by first folding and then unfolding passively. This mechanism enables flapping robots to squeeze through clutter without sophisticated control. Passive unfolding also provides a new avenue in morphing wing design that makes future flapping morphing wings possibly more energy efficient and light-weight. Simultaneously these results point to possible inertia driven, and therefore metabolically efficient, control strategies in bats and birds to morph or recover within a beat.