How phonological reductions sometimes help the listener.
In speech production, high-frequency words are more likely than low-frequency words to be phonologically reduced. We tested in an eye-tracking experiment whether listeners can make use of this correlation between lexical frequency and phonological realization of words. Participants heard prefixed verbs in which the prefix was either fully produced or reduced. Simultaneously, they saw a high-frequency verb and a low-frequency verb with this prefix-plus 2 distractors-on a computer screen. Participants were more likely to look at the high-frequency verb when they heard a reduced prefix than when they heard a fully produced prefix. Listeners hence exploit the correlation of lexical frequency and phonological reduction and assume that a reduced prefix is more likely to belong to a high-frequency word. This shows that reductions do not necessarily burden the listener but may in fact have a communicative function, in line with functional theories of phonology.


Endothelial MAPKs Direct ICAM-1 Signaling to Divergent Inflammatory Functions.
Lymphocyte transendothelial migration (TEM) is critically dependent on intraendothelial signaling triggered by adhesion to ICAM-1. Here we show that endothelial MAPKs ERK, p38, and JNK mediate diapedesis-related and diapedesis-unrelated functions of ICAM-1 in cerebral and dermal microvascular endothelial cells (MVECs). All three MAPKs were activated by ICAM-1 engagement, either through lymphocyte adhesion or Ab-mediated clustering. MAPKs were involved in ICAM-1-dependent expression of TNF-α in cerebral and dermal MVECs, and CXCL8, CCL3, CCL4, VCAM-1, and cyclooxygenase 2 (COX-2) in cerebral MVECs. Endothelial JNK and to a much lesser degree p38 were the principal MAPKs involved in facilitating diapedesis of CD4+ lymphocytes across both types of MVECs, whereas ERK was additionally required for TEM across dermal MVECs. JNK activity was critical for ICAM-1-induced F-actin rearrangements. Furthermore, activation of endothelial ICAM-1/JNK led to phosphorylation of paxillin, its association with VE-cadherin, and internalization of the latter. Importantly ICAM-1-induced phosphorylation of paxillin was required for lymphocyte TEM and converged functionally with VE-cadherin phosphorylation. Taken together we conclude that during lymphocyte TEM, ICAM-1 signaling diverges into pathways regulating lymphocyte diapedesis, and other pathways modulating gene expression thereby contributing to the long-term inflammatory response of the endothelium.


Drug development for metastatic castration-resistant prostate cancer: current status and future perspectives.
Prostate cancer represents a third of all newly diagnosed cancers in men in the USA with an estimated incidence of 192,280 cases and 27,360 deaths in 2009. It continues to be a major cause of cancer-related morbidity and mortality, and there is an urgent need for new treatments. Historically, systemic therapy options were limited after progression on docetaxel-based chemotherapy. This article reviews current data on the novel therapeutics demonstrating activity in metastatic castration-resistant prostate cancer and their future role in the treatment of this disease with a poor prognosis.


Electron transfer by human wild-type and A287P mutant P450 oxidoreductase assessed by transient kinetics: functional basis of P450 oxidoreductase deficiency.
Cytochrome P450 oxidoreductase (POR) is a 2-flavin protein that transfers electrons from NADPH via its FAD and FMN moieties to all microsomal cytochrome P450 enzymes, including steroidogenic and drug-metabolizing P450s. Defects in the POR gene can cause POR deficiency (PORD), manifested clinically by disordered steroidogenesis, genital anomalies and skeletal malformations. We examined the POR mutant A287P, which is the most frequent cause of PORD in patients of European ancestry and partially disrupts most P450 activities in vitro. Flavin content analysis showed that A287P is deficient in FAD and FMN binding, although the mutation site is distant from the binding sites of both flavins. Externally added flavin partially restored the cytochrome c reductase activity of A287P, suggesting that flavin therapy may be useful for this frequent form of PORD. Transient kinetic dissection of the reaction of POR with NADPH and the reduction in cytochrome c by POR using stopped-flow techniques revealed defects in individual electron transfer steps mediated by A287P. A287P had impaired ability to accept electrons from NADPH, but was capable of a fast FMN → cytochrome c electron donation reaction. Thus the reduced rates of P450 activities with A287P may be due to deficient flavin and impaired electron transfer from NADPH.


Real-time quantitative polymerase chain reaction to assess gene transfer.
Accurate quantification of gene transfer (or gene correction) is a universal challenge in the field of gene therapy. In developing a clinical trial of lymphocyte gene therapy for Hunter syndrome (mucopolysaccharidosis type II), methods using Southern blot or automated DNA sequencing technology were employed, but found to be laborious and subject to considerable variation. As an alternative approach, we explored a real-time kinetic PCR assay appropriate to new instrumentation (PE Biosystems model 7700). A TaqMan probe was designed to hybridize directly across the exon 2-exon 3 junction of the iduronate-2-sulfatase transgene cDNA. In this assay system, cDNA from the retroviral vector L2SN generates a PCR product that is 84 nucleotides long and readily quantified by TaqMan probe binding and subsequent cleavage. Evaluation of this method demonstrated sensitivity over at least 5 logs with respect to the standard (vector plasmid pL2SN). There was no detectable signal from genomic DNA from nontransduced cells, thus indicating the specificity of this assay. The sample preparation method used to prepare specimens was a relatively simple cell lysis procedure, without DNA extraction, and represents a significant advancement over the more complex methods of DNA extraction that are typically used for such assays. This specific assay, and comparison to previous methods, illustrates the utility of a new method that is readily generalized to many gene therapy studies, and that has the potential to be extended to measure gene expression by means of quantitative RT-PCR.


Cell-type-specific expression of plant cytochrome c mRNA in developing flowers and roots.
We have used RNA in situ hybridization to analyze the expression of transcripts encoding cytochrome c in different tissues and organs of sunflower (Helianthus annuus). Although northern-blot hybridization experiments indicate that the relative abundance of transcripts does not vary greatly, we have detected important changes in localization during flower development. Enhanced expression is observed in floral meristems as soon as they are discernible from the central portion of the capitulum containing the inflorescence meristem. As flowers develop, labeling is observed in all developing floral organ primordia. Later in development, expression in petals is reduced, and only the central portion of the flower becomes labeled. During the process of stamen formation, hybridization signals were obtained mainly in anthers. Less developed flowers at this stage showed expression through the archesporial tissue. During meiosis, the label was observed mainly in tapetal cells. Specific expression patterns, similar to those obtained for sunflower, were observed when Arabidopsis flowers were analyzed with a homologous cytochrome c probe. Specific patterns of expression were also observed in young sunflower roots. In this case, enhanced expression was detected in developing endodermis and pericycle and in protoxylem initials. We conclude that cell-specific mechanisms operate to regulate the abundance of cytochrome c encoding transcripts in different plant tissues. The overlap between the expression patterns of the nuclear encoded cytochrome c gene and some mitochondrial genes suggests the existence of coordinated mechanisms of expression.


Control in the Hospital by Extensive Clinical rules for Unplanned hospitalizations in older Patients (CHECkUP); study design of a multicentre randomized study.
Due to ageing of the population the incidence of multimorbidity and polypharmacy is rising. Polypharmacy is a risk factor for medication-related (re)admission and therefore places a significant burden on the healthcare system. The reported incidence of medication-related (re)admissions varies widely due to the lack of a clear definition. Some medications are known to increase the risk for medication-related admission and are therefore published in the triggerlist of the Dutch guideline for Polypharmacy in older patients. Different interventions to support medication optimization have been studied to reduce medication-related (re)admissions. However, the optimal template of medication optimization is still unknown, which contributes to the large heterogeneity of their effect on hospital readmissions. Therefore, we implemented a clinical decision support system (CDSS) to optimize medication lists and investigate whether continuous use of a CDSS reduces the number of hospital readmissions in older patients, who previously have had an unplanned probably medication-related hospitalization. The CHECkUP study is a multicentre randomized study in older (≥60 years) patients with an unplanned hospitalization, polypharmacy (≥5 medications) and using at least two medications from the triggerlist, from Zuyderland Medical Centre and Maastricht University Medical Centre+ in the Netherlands. Patients will be randomized. The intervention consists of continuous (weekly) use of a CDSS, which generates a Medication Optimization Profile, which will be sent to the patient's general practitioner and pharmacist. The control group will receive standard care. The primary outcome is hospital readmission within 1 year after study inclusion. Secondary outcomes are one-year mortality, number of emergency department visits, nursing home admissions, time to hospital readmissions and we will evaluate the quality of life and socio-economic status. This study is expected to add evidence on the knowledge of medication optimization and whether use of a continuous CDSS ameliorates the risk of adverse outcomes in older patients, already at an increased risk of medication-related (re)admission. To our knowledge, this is the first large study, providing one-year follow-up data and reporting not only on quality of care indicators, but also on quality-of-life. The trial was registered in the Netherlands Trial Register on October 14, 2018, identifier: NL7449 (NTR7691). https://www.trialregister.nl/trial/7449 .


Characteristic early changes of Glu and Cho in brain regions affected by different types of subjective cognitive decline and their clinical significance.
To discuss the early changes of Glu and Cho in the affected areas of different types of subjective cognitive decline, including amnestic MCI (aMCl), non-amnestic MCI (naMCI) and vascular cognitive impairment no dementia (VCIND), using Proton Magnetic Resonance Spectroscopy (1H-MRS) technology. Routine head MRI and lH-MRS examinations were performed on 50 clearly diagnosed aMCI patients, 44 naMCI patients, 44 VCIND patients, and 44 elderly individuals with normal cognitive function. Measure the volume of the patient bilateral hippocampus. Using the bilateral hippocampus, left posterior cingulate gyrus (PCG), and frontal lobe as regions of interest, the scope under the peak of N-acetylaspartate (NAA), choline complex (Cho), glutamate (Glu), Metabolic Images (mI), and creatine (Cr) was tested. Perform a correlation analysis between the NAA/Cho/Cr values of the VCIND group and the MoCA score. All experimental subjects were right-handed. The NAACr values in both hippocampus of the VCIND were greatly lower than those in control (P < .05). The NAA/Cr values on both sides of the VCIND were correlated with the MoCA score (P < .05). The NAA/Cr values in the LHp and PCG of subjects in the aMCI and naMCI groups were lower than those in the NC group (P < .05). The NAA/Cr values in the left frontal lobe of the aMCI and naMCI showed no obvious decrease compared to the NC. The Glu/Cr of subjects in the aMCI was lower in the left PCG than those in the naMCI and NC (P < .05). The discrepancy between the naMCI and the NC was P > .05. In the LHp and frontal lobe, in contrast with the naMCI and NC, the mI/Cr values in the LHp and PCG of subjects in the aMCI were higher (P < .05). In the left frontal lobe, relative to the aMCI and NC, the mI/Cr values in the naMCI were higher (P < .05). The changes in the concentration of 1H-MRS metabolites in the hippocampus can indicate the presence of hippocampal neuronal damage before morphological changes occur in the hippocampus. 1H-MRS NAA/Cr can reflect the cognitive function changes of patients to a certain extent. There are regional differences in mI and Glu metabolism in the brain between aMCI and naMCI groups. 1H-MRS provides an effective basis for clinical differentiation between aMCI and naMCI.


Functional changes of the primary somatosensory cortex in patients with unilateral cerebellar lesions.
Although cerebellar lesions do not cause evident sensory deficits, it has been suggested recently that the cerebellum might play a role in sensory acquisition and discrimination. To determine whether the cerebellum influences the early phases of cortical somatosensory processing, we recorded cortical somatosensory evoked potentials after median nerve stimulation in five patients with unilateral cerebellar damage. We also performed a dipolar source analysis of traces by means of brain electrical source analysis. In all patients, the amplitude of the frontal N24 and parietal P24 components, as well as the strength of the corresponding dipolar sources, were significantly smaller after stimulation of the symptomatic side. These neurophysiological findings indicate that the primary somatosensory cortical processing is altered after contralateral cerebellar damage. They represent the first indication of a possible substrate for the reduction in cerebral blood flow observed in the parietal cortex after cerebellar lesion. Furthermore, the present data allow characterization of the functional influence of the cerebellar input to the primary somatosensory cortex as specifically acting over the inhibitory components of somatosensory processing.


'I am doing fine only because I have not told anyone': the necessity of concealment in the lives of people living with HIV in India.
In HIV prevention and care programmes, disclosure of status by HIV-positive individuals is generally encouraged to contain the infection and provide adequate support to the person concerned. Lack of disclosure is generally framed as a barrier to preventive behaviours and accessing support. The assumption that disclosure is beneficial is also reflected in studies that aim to identify determinants of disclosure and recommend individual-level measures to promote disclosure. However, in contexts where HIV infection is stigmatised and there is fear of rejection and discrimination among those living with HIV, concealment of status becomes a way to try and regain as much as possible the life that was disrupted by the discovery of HIV infection. In this study of HIV-positive women and children in India, concealment was considered essential by individuals and families of those living with HIV to re-establish and maintain their normal lives in an environment where stigma and discrimination were prevalent. This paper describes why women and care givers of children felt the need to conceal HIV status, the various ways in which people tried to do so and the implications for treatment of people living with HIV. We found that while women were generally willing to disclose their status to their husband or partner, they were very keen to conceal their status from all others, including family members. Parents and carers with an HIV-positive child were not willing to disclose this status to the child or to others. Understanding the different rationales for concealment would help policy makers and programme managers to develop more appropriate care management strategies and train care providers to assist clients in accessing care and support without disrupting their lives.


pH-adjusted solvent extraction and reversed-phase HPLC quantification of isoflavones from soybean (Glycine max (L.) Merr.).
Soybeans, Glycine max (L.) Merr., are among the most important food crops worldwide. Isoflavones are major bioactive phytochemicals in soybeans, and have a variety of health benefits, including antioxidative, antiatherosclerotic, antiinflammatory, and weak estrogen-like effects. The isoflavone content and composition of soybeans vary according to the cultivar and the extraction solvent conditions. Therefore, we investigated the effects of three different solvent pHs (1.0, 5.5, and 10.0) on the isoflavone, total phenolic, and total flavonoid contents and antioxidant capacities of eight soybean cultivars developed in Korea. Twelve isoflavones in soybeans were efficiently separated and identified on a reversed-phase high-performance liquid chromatography (HPLC) system. The percentage distribution of isoflavones measured by HPLC in the eight soybean cultivars at various extraction pHs decreased as follows: malonyl isoflavones (67.2% to 81.3%) > isoflavone glucosides (16.2% to 29.0%; as nonacylated form) > acetyl isoflavones (1.6% to 5.9%). The highest contents of isoflavone glucosides, malonyl derivatives, and acetyl derivatives were extracted at solvent pHs of 10.0, 1.0, and 5.5, respectively. The solvent extraction at pH 1.0 yielded a lower total isoflavone content than those at pHs 5.5 and 10.0. However, the highest total phenolic and flavonoid contents were extracted from soybeans at pH 1.0. Soybeans extracted at pH 10.0 displayed the highest antioxidant capacities in the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical assay. Taken together, these results suggest that proper solvent pH adjustment is needed to maximize the extraction of targeted forms of isoflavones from soybeans. PRACTICAL APPLICATION: Soybeans contain a variety of bioactive compounds, including isoflavones, which function as antioxidants and weak phytoestrogens. Chemical and instrumental analyses can facilitate the selection of soybean cultivars with high amounts of isoflavones for soybean breeding and isoflavone-enriched product development. Proper solvent pH adjustment allows for the efficient extraction of high amounts of targeted isoflavone subgroups (acetyl and malonyl forms) from soybeans for functional food products.


Successful Recovery of Nuclear Protein-Coding Genes from Small Insects in Museums Using Illumina Sequencing.
In this paper we explore high-throughput Illumina sequencing of nuclear protein-coding, ribosomal, and mitochondrial genes in small, dried insects stored in natural history collections. We sequenced one tenebrionid beetle and 12 carabid beetles ranging in size from 3.7 to 9.7 mm in length that have been stored in various museums for 4 to 84 years. Although we chose a number of old, small specimens for which we expected low sequence recovery, we successfully recovered at least some low-copy nuclear protein-coding genes from all specimens. For example, in one 56-year-old beetle, 4.4 mm in length, our de novo assembly recovered about 63% of approximately 41,900 nucleotides in a target suite of 67 nuclear protein-coding gene fragments, and 70% using a reference-based assembly. Even in the least successfully sequenced carabid specimen, reference-based assembly yielded fragments that were at least 50% of the target length for 34 of 67 nuclear protein-coding gene fragments. Exploration of alternative references for reference-based assembly revealed few signs of bias created by the reference. For all specimens we recovered almost complete copies of ribosomal and mitochondrial genes. We verified the general accuracy of the sequences through comparisons with sequences obtained from PCR and Sanger sequencing, including of conspecific, fresh specimens, and through phylogenetic analysis that tested the placement of sequences in predicted regions. A few possible inaccuracies in the sequences were detected, but these rarely affected the phylogenetic placement of the samples. Although our sample sizes are low, an exploratory regression study suggests that the dominant factor in predicting success at recovering nuclear protein-coding genes is a high number of Illumina reads, with success at PCR of COI and killing by immersion in ethanol being secondary factors; in analyses of only high-read samples, the primary significant explanatory variable was body length, with small beetles being more successfully sequenced.


Longitudinal post-radiotherapy plasma Epstein-Barr virus DNA trends inform on optimal risk stratification in endemic nasopharyngeal carcinoma.
To characterize longitudinal changes in Epstein-Barr virus (EBV) DNA post-radiotherapy in nasopharyngeal carcinoma (NPC) patients, and investigate whether an early (0-2 weeks) or delayed (8-12 weeks) EBV DNA result better predicts for disease-free survival (DFS). Histologically-confirmed NPC patients with ≥1 EBV DNA test quantified using the harmonized BamHI-W polymerase chain reaction-based assay at 0-2 and 8-12 weeks post-radiotherapy were included. We identified 302 patients with EBV DNA measured at 0-2 weeks post-radiotherapy; of which, 110 (36.4 %) underwent a repeat test at 8-12 weeks post-treatment. Patients harboring a detectable EBV DNA at 0-2 weeks experienced an inferior DFS (adjusted HR1-264 copies 1.72 [95 %CI: 1.05-2.83], P = 0.031; AHR≥265 copies 4.39 [95 %CI: 1.68-11.44], P = 0.002 relative to 0 copies/mL). At 8-12 weeks, we observed substantial shifts in EBV DNA readings from 0 to 2 weeks; 76/110 (69.1 %) and 34/110 (30.9 %) patients at 0-2 weeks versus 90/110 (81.8 %) and 20/110 (18.2 %) at 8-12 weeks recorded undetectable and detectable EBV DNA, respectively. Positive EBV DNA at 8-12 weeks was strongly associated with relapse (73.3 % [11/15] for 1-264; 80.0 % [4/5] for ≥265 subgroups had relapses versus 15.6 % [14/90] for 0 copies/mL). Area under receiver operating curve values for 2-year relapse rates were 0.817 (95 %CI: 0.725-0.909) for stage + EBV DNA8-12w versus 0.654 (95 %CI: 0.542-0.765) for stage + EBV DNA0-2w. CONCLUSION: EBV DNA is dynamic post-radiotherapy, and delayed EBV DNA testing better enriched for higher-risk NPC patients. This implicates trials investigating adjuvant chemotherapy intensification based on early EBV DNA testing.


Thyroid dysfunction in Down's syndrome: relation to age and thyroid autoimmunity.
The prevalence of thyroid disease is increased in Down's syndrome. Most available data come from cross sectional studies. To study longitudinally thyroid function in patients with Down's syndrome in Uppsala county (85 patients) up to the age of 25 years. Observational study based on yearly follow up in a children's clinic. Thyroid function tests were performed at each visit to the clinic. Hypothyroidism was found in 30 and hyperthyroidism was found in two of the 85 patients. No sex difference was seen. Half of the patients with hypothyroidism acquired the condition before the age of 8 years, but only one of them displayed thyroid autoantibodies at diagnosis. Most patients who developed hypothyroidism after this age had thyroid autoantibodies. In the prepubertal patients with hypothyroidism, growth velocity was lower during the year before the start of thyroxine treatment than during the year after treatment began; it was also lower than that of sex and age matched euthyroidic children with Down's syndrome. Thyroid dysfunction in patients with Down's syndrome is common in childhood. Consequently, annual screening is important. Autoimmune thyroid disease is uncommon in young children with Down's syndrome but is common after 8 years of age.


The experience of blood glucose monitoring in people with type 2 diabetes mellitus (T2DM).
Finger prick blood glucose (BG) monitoring remains a mainstay of management in people with type 2 diabetes (T2DM) who take sulphonylurea (SU) drugs or insulin. We recently examined patient experience of BG monitoring in people with type 1 diabetes (T1DM). There has not been any recent comprehensive assessment of the performance of BG monitoring strips or the patient experience of BG strips in people with T2DM in the UK. An online self-reported questionnaire containing 44 questions, prepared following consultation with clinicians and patients, was circulated to people with T2DM. 186 responders provided completed responses (25.5% return rate). Fixed responses were coded numerically (eg not confident = 0 fairly confident = 1). Of responders, 84% were treated with insulin in addition to other agents. 75% reported having had an HbA1c check in the previous 6 months. For those with reported HbA1c ≥ 65 mmol/mol, a majority of people (70%) were concerned or really concerned about the shorter term consequences of running a high HbA1c This contrasted with those who did not know their recent HbA1c, of whom only 33% were concerned/really concerned and those with HbA1c <65 mmol/mol of whom 35% were concerned. Regarding BG monitoring/insulin adjustment, only 25% of responders reported having sufficient information with 13% believing that the accuracy and precision of their BG metre was being independently checked. Only 9% recalled discussing BG metre accuracy when their latest metre was provided and only 7% were aware of the International Standardisation Organisation (ISO) standards for BG metres. 77% did not recall discussing BG metre performance with a healthcare professional. The group surveyed comprised engaged people with T2DM but even within this group there was significant variation in (a) awareness of shorter term risks, (b) confidence in their ability to implement appropriate insulin dosage (c) awareness of the limitations of BG monitoring technology. There is clearly an area where changes in education/support would benefit many.


Risk factors for traumatic or unsuccessful lumbar punctures in children.
Traumatic and unsuccessful lumbar punctures can cause substantial diagnostic ambiguity that may lead to unnecessary antibiotic use and hospitalization, in addition to patient discomfort. Risk factors for obtaining traumatic and unsuccessful lumbar punctures have been studied in a limited fashion only. We sought to determine patient, physician, and procedural factors associated with traumatic and unsuccessful lumbar punctures in children. The study included a prospective cohort of all children undergoing lumbar punctures in a single emergency department between July 2003 and January 2005. Our main outcome was either a traumatic lumbar puncture (cerebrospinal fluid RBC counts > or = 10,000 cells/mm3) or unsuccessful lumbar puncture (failure of the procedure to yield fluid for cell counts) after the first lumbar puncture attempt. We performed multiple logistic regression analyses to identify independent predictors of traumatic or unsuccessful lumbar punctures. Of the 1,474 eligible lumbar punctures, 1,459 (99%) were included in the analysis. Of these, 513 (35%) were traumatic or unsuccessful on the first attempt. After adjustment for patient characteristics, physician and procedural factors associated with an increased risk of a traumatic or unsuccessful lumbar puncture included less physician experience (adjusted odds ratio for an ordinal decrease in experience 1.08; 95% confidence interval [CI] 1.01 to 1.15), lack of local anesthetic use (adjusted odds ratio 1.6; 95% CI 1.1 to 2.2), advancement of the spinal needle with stylet in place versus stylet removed (adjusted odds ratio 1.3; 95% CI 1.04 to 1.7), and increased patient movement (adjusted odds ratio 2.1; 95% CI 1.6 to 2.6). Of the factors associated with traumatic or unsuccessful lumbar punctures in children, advancement of the spinal needle with the stylet in place and lack of local anesthetic use are the most modifiable. Modification of these procedural factors may reduce the risk of traumatic or unsuccessful lumbar punctures in children.


Mean-field approximations of networks of spiking neurons with short-term synaptic plasticity.
Low-dimensional descriptions of spiking neural network dynamics are an effective tool for bridging different scales of organization of brain structure and function. Recent advances in deriving mean-field descriptions for networks of coupled oscillators have sparked the development of a new generation of neural mass models. Of notable interest are mean-field descriptions of all-to-all coupled quadratic integrate-and-fire (QIF) neurons, which have already seen numerous extensions and applications. These extensions include different forms of short-term adaptation considered to play an important role in generating and sustaining dynamic regimes of interest in the brain. It is an open question, however, whether the incorporation of presynaptic forms of synaptic plasticity driven by single neuron activity would still permit the derivation of mean-field equations using the same method. Here we discuss this problem using an established model of short-term synaptic plasticity at the single neuron level, for which we present two different approaches for the derivation of the mean-field equations. We compare these models with a recently proposed mean-field approximation that assumes stochastic spike timings. In general, the latter fails to accurately reproduce the macroscopic activity in networks of deterministic QIF neurons with distributed parameters. We show that the mean-field models we propose provide a more accurate description of the network dynamics, although they are mathematically more involved. Using bifurcation analysis, we find that QIF networks with presynaptic short-term plasticity can express regimes of periodic bursting activity as well as bistable regimes. Together, we provide novel insight into the macroscopic effects of short-term synaptic plasticity in spiking neural networks, as well as two different mean-field descriptions for future investigations of such networks.


Group cohesion and nurse satisfaction: examination of a team-building approach.
The purpose of this study was to determine the impact of a team-building intervention on group cohesion, nurse satisfaction, and turnover rates. Creating an environment that supports and retains nurses represents a formidable challenge for nursing leaders. Research related to strategies that positively impact the culture in which nurses practice, thus potentially improving nurse satisfaction and reducing turnover, is critically needed. Registered nurses (RNs) employed on inpatient units in a 247-bed, private acute care Magnet teaching hospital participated in this quasi experimental preintervention and postintervention design. The RN-RN interaction subscale from the National Database of Nursing Quality Indicators Adapted Index of Work Satisfaction, the National Database of Nursing Quality Indicators Adapted Index of Job Enjoyment, the Group Cohesion Scale, and a facilitator-developed measure were completed preimplementation and postimplementation of unit-tailored intervention strategies, which took place over a 12-month period. Turnover rates were collected 6 month preintervention and postintervention. Improvement in group cohesion, RN-RN interaction, job enjoyment, and turnover was demonstrated. Targeted, unit-based strategies can be an effective means of reducing turnover rates and improving group cohesion and nurse satisfaction.


Receptor activator of nuclear factor-kappaB ligand (RANKL) directly modulates the gene expression profile of RANK-positive Saos-2 human osteosarcoma cells.
Receptor activator of nuclear factor kappaB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) are the key regulators of bone metabolism. Recent findings demonstrated a crucial role of RANK in several bone-associated tumors. Indeed, we have recently demonstrated functional RANK expression both in a mouse and several human osteosarcoma cell lines. However, RANKL effects on osteosarcoma cells remain to be determined. In this study, we determined RANKL effects on RANK-positive Saos-2 human osteosarcoma cells. cDNA microarray and quantitative RT-PCR analyses clearly demonstrated that RANK-positive osteosarcoma cells were the target of RANKL as well as osteoclasts/osteoclast precursors. Thus, we present for the first time that RANKL can directly and significantly modulate gene expression of RANK-expressing Saos-2 cells. RANKL-modulated genes included genes that were implicated in protein metabolism, nucleic acid metabolism, intracellular transport, cytoskeleton organization and biogenesis, apoptosis and signaling cascade. Our results strengthen the involvement of the RANK/RANKL/OPG axis in osteosarcoma biology and capability to identify novel therapeutic approaches targeting RANK-positive osteosarcomas.


ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy.
Mounting evidence suggests that reactive oxygen species (ROS) are multifaceted signaling molecules implicated in a variety of cellular programs during physiological as well as pathological conditions. Recently, ROS produced endogenously, by deranged metabolism of cancer cells, or exogenously, by ROS-generating drugs, have been shown to promote macroautophagy, a lysosomal pathway of self-degradation with essential prosurvival functions. Several molecular aspects of the modulation of autophagy pathways by ROS have been revealed in the past years and it is now clear that these processes are mutually linked and play a crucial role in cancer progression and in response to cancer therapeutics. In this review we address the molecular mechanisms underlying the activation of autophagy pathways by ROS and focus on the role of autophagy in cancer cells responding to ROS-producing agents, which are utilized as a therapeutic modality to kill cancer cells.


A review of the metrics for One Health benefits.
One Health as a concept has been with us for many years, yet it is only recently that it is actively being discussed as a way of mitigating risks in society. Initiatives in the use of this concept require methods to monitor the benefits gained from an holistic approach to health, yet there is an absence of adequate frameworks to measure One Health benefits. This paper explores the problem with a review of the available literature and an examination of methods used. It concludes that most published work on One Health describes how this concept is valuable without trying to estimate the size of benefit or type of value. A framework for measuring the advantages of a One Health approach is needed and, through the process of an international workshop and the development of a One Health business case, the authors are working towards its development.


Profiling of ornithine lipids in bacterial extracts of Rhodobacter sphaeroides by reversed-phase liquid chromatography with electrospray ionization and multistage mass spectrometry (RPLC-ESI-MS(n)).
Ornithine lipids (OLs), a sub-group of the large (and of emerging interest) family of lipoamino acids of bacterial origin, contain a 3-hydroxy fatty acyl chain linked via an amide bond to the α-amino group of ornithine and via an ester bond to a second fatty acyl chain. OLs in extracts of Rhodobacter sphaeroides (R. sphaeroides) were investigated by high-performance reversed phase liquid chromatography (RPLC) with electrospray ionization mass spectrometry (ESI-MS) in negative ion mode using a linear ion trap (LIT). The presence of OLs bearing both saturated (i.e, 16:0, 17:0, 18:0, 19:0 and 20:0) and unsaturated chains (i.e., 18:1, 19:1, 19:2 and 20:1) was ascertained and their identification, even for isomeric, low abundance and partially co-eluting species, was achieved by low-energy collision induced dissociation (CID) multistage mass spectrometry (MS(n), n = 2-4). OLs signatures found in two R. sphaeroides strains, i.e., wild type 2.4.1 and mutant R26, were examined and up to 16 and 17 different OL species were successfully identified, respectively. OLs in both bacterial strains were characterized by several combinations of fatty chains on ester-linked and amide-linked 3-OH fatty acids. Multistage MS spectra of monoenoic amide-linked 3-OH acyl chains, allowed the identification of positional isomer of OL containing 18:1 (i.e. 9-octadecenoic) and 20:1 (i.e. 11-eicosenoic) fatty acids. The most abundant OL ([M-H](-) at m/z 717.5) in R. sphaeroides R26 was identified as OL 3-OH 20:1/19:1 (i.e., 3-OH-eicosenoic acid amide-linked to ornithine and esterified to a nonadecenoic chain containing a cyclopropane ring). An unusual OL (m/z 689.5 for the [M-H](-) ion), most likely containing a cyclopropene ester-linked acyl chain (i.e., OL 3-OH 18:0/19:2), was retrieved only in the carotenoidless mutant strain R26. Based on the biosynthetic pathways already known for cyclopropa(e)ne ring-including acyl chains, a plausible explanation was invoked for the enzymatic generation of this ester-linked chain in R. sphaeroides.


Synovial plicae syndrome.
The suprapatellar, medial patellar, and infrapatellar plicae are three embryonic remnants of synovial tissues that are often a cause of intermittent anterior knee pain. A primary blunt trauma or internal pathological derangement will result in the plicae becoming thickened and inelastic with an often inappropriate diagnosis of meniscal tear. The signs, symptoms and examination findings when combined with special testing enables the doctor to correctly establish a diagnosis and proceed with treatment. The chiropractic doctor may play a prime role in the conservative method of treatment and prevent further dysfunction leading to surgical excision as the treatment of choice. This paper will review and summarize the current knowledge of plicae anatomy, pathophysiology, diagnosis and therapeutics in an attempt to provide chiropractors with an increasing awareness of the synovial plicae syndrome.


Distribution of the leptospiral immunoglobulin-like (lig) genes in pathogenic Leptospira species and application of ligB to typing leptospiral isolates.
The family of leptospiral immunoglobulin-like (lig) genes comprises ligA, ligB and ligC. This study used PCR to demonstrate the presence of lig genes among serovars from a collection of leptospiral strains and clinical isolates. Whilst ligA and ligC appeared to be present in a limited number of pathogenic serovars, the ligB gene was distributed ubiquitously among all pathogenic strains. None of the lig genes were detected among intermediate or saprophytic Leptospira species. It was also shown that, similar to the previously characterized secY gene, a short specific PCR fragment of ligB could be used to correctly identify pathogenic Leptospira species. These findings demonstrate that ligB is widely present among pathogenic strains and may be useful for their reliable identification and classification.


In vitro and in vivo efficacy of carvacrol against Echinococcus granulosus.
Currently, benzimidazoles are used as chemotherapeutic agents and as a complement to surgery and PAIR in the treatment of cystic echinococcosis (CE). They are generally applied at high doses causing side effects and, 50% of cases do not respond favorably to such chemotherapy. The use of essential oils obtained by distillation from aromatic plants would be an effective alternative or complementary to the synthetic compounds, because would not bring the appearance of side effects. Carvacrol and his isomer thymol are the main phenolic components from essential oils of Origanum vulgare (oregano) and Thymus vulgaris (thyme). The aim of the present work was to evaluate the in vitro and in vivo efficacy of carvacrol against Echinococcus granulosus metacestodes. For the in vitro assay, protoscoleces and cysts of E. granulosus were incubated with carvacrol at the following final concentrations: 10, 5 and 1μg/ml of carvacrol. The maximum protoscolicidal effect was found with 10μg/ml of carvacrol. Results of viability tests were consistent with the structural and ultrastructural damage observed in protoscoleces. Ultrastructural studies revealed that the germinal layer of cysts treated with carvacrol lost the multicellular structure feature. In the clinical efficacy study, a reduction in cyst weight was observed after the administration of 40mg/kg of carvacrol during 20days in mice with cysts developed during 4 months, compared to that of those collected from control mice. Given that the in vivo effect of carvacrol was comparable with the treatment of reference with ABZ and the fact that is a safe compound, we postulated that carvacrol may be an alternative option for treatment of human CE.


Fluctuation-dissipation analysis of nonequilibrium thermal transport at the hydrate dissociation interface.
Herein, a nonequilibrium molecular-dynamics simulation in an NVE ensemble was performed to investigate the spontaneous dissociation of methane-hydrate when it came in contact with liquid water. The nonequilibrium in the interface region is linked to the dissociation process of the hydrate near the interface according to the Onsager's hypothesis. The simulated thickness of the interface was found to be close to the acoustic phonon mean path of methane hydrate and agreed with the reference value. The normalized heat flow autocorrelation function was introduced to study fluctuation-dissipation in terms of the thickness and moving velocity of the interface and the Stefan number. This helped to clearly identify three distinct hydrate-decomposition regimes dominated by sensible heat, latent heat and an intrinsically unstable lattice framework. It was found that the fluctuation-dissipation theory could express the nonequilibrium nature in the front two stages before the threshold was reached, and the dissociation rate increased in the latter stage; this was different from the case of thermal-driven dissociation. The Stefan number decreased rapidly with dissociation in the initial stage and then fluctuated in the intermediate stage; this was analogous to the fluctuation characteristics of the heat flow autocorrelation function. The Stefan number effect shows that thermal dissipation drives the hydrate dissociation and correlates fluctuation to the nonequilibrium nature. It was also found that a small Stefan number was enough to break up the residual hydrate soon after the threshold was achieved. The transient interfacial thermal resistance of the interfacial region was obtained as a typical value in the range of 10-7-10-9 m2 K W-1. This justifies that fluctuation-dissipation exists in the nonequilibrium process of hydrate dissociation either in terms of heat flux, as observed in this study, or the diffusion of guest molecules, as reported in other studies.


The protein phosphatases involved in cellular regulation. 6. Measurement of type-1 and type-2 protein phosphatases in extracts of mammalian tissues; an assessment of their physiological roles.
Methods were developed for quantifying protein phosphatases-1, 2A, 2B and 2C in cell extracts, and these procedures were exploited to determine their tissue and subcellular distributions. In addition, the contribution of each enzyme to the total protein phosphatase activity in skeletal muscle and liver extracts towards nine proteins involved in the control of glycogen metabolism, glycolysis/gluconeogenesis, fatty acid synthesis and cholesterol synthesis was assessed. Each protein phosphatase was present at significant concentrations in skeletal muscle, heart muscle, liver, brain and adipose tissue, although the relative amounts differed considerably. In skeletal muscle, protein phosphatase-1 was the major enzyme acting on phosphorylase, glycogen synthase and phosphorylase kinase (beta-subunit), and thus was the major protein phosphatase responsible for the inactivation of glycogenolysis and stimulation of glycogen synthesis. This idea was reinforced by the observation that 50% of the protein phosphatase-1 activity was associated with the protein-glycogen complex. In the liver, protein phosphatases-1, 2A and 2C each appear to play a role in the regulation of glycogen metabolism. Protein phosphatase-1 accounted for a significant fraction of the total potential activity towards phosphorylase and glycogen synthase, and was the major phosphorylase kinase (beta-subunit) phosphatase of this tissue. In addition, it was the only protein phosphatase present in the protein-glycogen complex. Protein phosphatase 2A was also a major phosphorylase phosphatase and glycogen synthase phosphatase in this tissue. Protein phosphatase 2C was a significant glycogen synthase phosphatase in the liver, but had negligible activity toward phosphorylase or phosphorylase kinase (beta-subunit). In the absence of Ca2+, protein phosphatase 2A was the major phosphorylase kinase (alpha-subunit) phosphatase and the only inhibitor-1 phosphatase, in skeletal muscle or liver. In the presence of Ca2+, protein phosphatase 2B accounted for most of the activity towards these substrates. Protein phosphatase 2A was the major enzyme acting on L-pyruvate kinase, ATP-citrate lyase and acetyl-CoA carboxylase in rat liver, suggesting an important role in the regulation of glycolysis/gluconeogenesis and fatty acid synthesis. Protein phosphatase 2C was the major enzyme acting on hydroxymethylglutaryl-CoA (HMG-CoA) reductase and HMG-CoA reductase kinase, suggesting an important role in the regulation of cholesterol synthesis. However, the observation that 20% of the protein phosphatase-1 in liver was associated with the microsomal fraction suggests that this enzyme may also be involved in regulating HMG-CoA reductase, which is tightly associated with microsomes. The activity of protein phosphatase-1 in dilute skeletal muscle and liver extracts was just as sensitive to inhibitor-1 and inhibitor-2 as the purified enzyme. In concentrated extracts, higher concentrations of the inhibitor proteins were required and the inhibition was time-dependent...


The critical role of histone H2A-deubiquitinase Mysm1 in hematopoiesis and lymphocyte differentiation.
Stem cell differentiation and lineage specification depend on coordinated programs of gene expression, but our knowledge of the chromatin-modifying factors regulating these events remains incomplete. Ubiquitination of histone H2A (H2A-K119u) is a common chromatin modification associated with gene silencing, and controlled by the ubiquitin-ligase polycomb repressor complex 1 (PRC1) and H2A-deubiquitinating enzymes (H2A-DUBs). The roles of H2A-DUBs in mammalian development, stem cells, and hematopoiesis have not been addressed. Here we characterized an H2A-DUB targeted mouse line Mysm1(tm1a/tm1a) and demonstrated defects in BM hematopoiesis, resulting in lymphopenia, anemia, and thrombocytosis. Development of lymphocytes was impaired from the earliest stages of their differentiation, and there was also a depletion of erythroid cells and a defect in erythroid progenitor function. These phenotypes resulted from a cell-intrinsic requirement for Mysm1 in the BM. Importantly, Mysm1(tm1a/tm1a) HSCs were functionally impaired, and this was associated with elevated levels of reactive oxygen species, γH2AX DNA damage marker, and p53 protein in the hematopoietic progenitors. Overall, these data establish a role for Mysm1 in the maintenance of BM stem cell function, in the control of oxidative stress and genetic stability in hematopoietic progenitors, and in the development of lymphoid and erythroid lineages.


Gene expression patterns in the human breast after pregnancy.
Epidemiologic studies have established that pregnancy has a bidirectional, time-dependent effect on breast cancer risk; a period of elevated risk is followed by a long-term period of protection. The purpose of the present study was to determine whether pregnancy and involution are associated with gene expression changes in the normal breast, and whether such changes are transient or persistent. We examined the expression of a customized gene set in normal breast tissue from nulliparous, recently pregnant (0-2 years since pregnancy), and distantly pregnant (5-10 years since pregnancy) age-matched premenopausal women. This gene set included breast cancer biomarkers and genes related to immune/inflammation, extracellular matrix remodeling, angiogenesis, and hormone signaling. Laser capture microdissection and RNA extraction were done from formalin-fixed paraffin-embedded reduction mammoplasty and benign biopsy specimens and analyzed using real-time PCR arrays containing 59 pathway-specific and 5 housekeeping genes. We report 14 of 64 (22%) of the selected gene set to be differentially regulated (at P < 0.05 level) in nulliparous versus parous breast tissues. Based on gene set analysis, inflammation-associated genes were significantly upregulated as a group in both parous groups compared with nulliparous women (P = 0.03). Moreover, parous subjects had significantly reduced expression of estrogen receptor alpha (ERalpha, ESR1), progesterone receptor (PGR), and ERBB2 (Her2/neu) and 2-fold higher estrogen receptor-beta (ESR2) expression compared with nulliparous subjects. These initial data, among the first on gene expression in samples of normal human breast, provide intriguing clues about the mechanisms behind the time-dependent effects of pregnancy on breast cancer risk.


Perceptions and Attitudes Toward Mobile Health in Development of an Exclusive Breastfeeding Tool: Focus Group Study With Caregivers and Health Promoters in the Dominican Republic.
Despite growing interest in the use of technology to improve health outcomes in low- and middle-income countries (LMICs), local attitudes toward mobile health (mHealth) use in these settings are minimally understood. This is especially true in the Dominican Republic, where mHealth interventions are starting to emerge. This information is critical for developing effective mHealth interventions to address public health issues, such as low exclusive breastfeeding (EBF) rates, which can lead to poor outcomes. With an EBF rate of 5% in the first 6 months of life, the Dominican Republic has one of the lowest EBF rates worldwide. This study aims to describe the current use of information and communication technology (ICT) and to analyze the attitudes and perceptions related to using mHealth interventions among caregivers of children aged ≤5 years and health promoters in the Dominican Republic. Findings can inform mHealth strategies aimed at improving EBF in this, and other, LMICs. Participants were recruited from 3 outpatient sites: the Niños Primeros en Salud program at Centro de Salud Divina Providencia in Consuelo (rural setting) and Clínica de Familia La Romana and its program Módulo de Adolescentes Materno Infantil in La Romana (urban setting). Focus groups were conducted with caregivers and community health promoters to identify the use, attitudes, perceptions, and acceptability of mHealth as well as barriers to EBF. Discussions were conducted in Spanish, guided by semistructured interview guides. All sessions were audio-recorded and later transcribed. Thematic content analysis was conducted in Spanish by two bilingual researchers and was structured around a hybrid behavioral theory framework to identify salient themes. All participants (N=35) reported having a mobile phone, and 29 (83%) participants had a smartphone. Sources for obtaining health information included the internet, physicians and clinic, family and friends, health promoters, and television. Barriers to mHealth use included the cost of internet service, privacy concerns, and perceived credibility of information sources. Participants indicated the desire for, and willingness to use, an mHealth intervention to support breastfeeding. The desired features of a possible mHealth intervention included offering diverse methods of information delivery such as images and video content, text messages, and person-to-person interaction as well as notifications for appointments, vaccines, and feeding schedules. Other important considerations were internet-free access and content that included maternal and child health self-management topics beyond breastfeeding. There is a high level of acceptance of ICT tools for breastfeeding promotion among caregivers in urban and rural areas of the Dominican Republic. As mHealth tools can contribute to increased breastfeeding self-efficacy, identifying desirable features of such a tool is necessary to create an effective intervention. Participants wanted to receive trusted and reliable information through various formats and were interested in information beyond breastfeeding.


Unveiling the Influence of Tumor Microenvironment and Spatial Heterogeneity on Temozolomide Resistance in Glioblastoma Using an Advanced Human In Vitro Model of the Blood-Brain Barrier and Glioblastoma.
Glioblastoma (GBM) is the most common primary malignant brain cancer in adults with a dismal prognosis. Temozolomide (TMZ) is the first-in-line chemotherapeutic; however, resistance is frequent and multifactorial. While many molecular and genetic factors have been linked to TMZ resistance, the role of the solid tumor morphology and the tumor microenvironment, particularly the blood-brain barrier (BBB), is unknown. Here, the authors investigate these using a complex in vitro model for GBM and its surrounding BBB. The model recapitulates important clinical features such as a dense tumor core with tumor cells that invade along the perivascular space; and a perfusable BBB with a physiological permeability and morphology that is altered in the presence of a tumor spheroid. It is demonstrated that TMZ sensitivity decreases with increasing cancer cell spatial organization, and that the BBB can contribute to TMZ resistance. Proteomic analysis with next-generation low volume sample workflows of these cultured microtissues revealed potential clinically relevant proteins involved in tumor aggressiveness and TMZ resistance, demonstrating the utility of complex in vitro models for interrogating the tumor microenvironment and therapy validation.


Function of Ltbp-4L and fibulin-4 in survival and elastogenesis in mice.
LTBP-4L and LTBP-4S are two isoforms of the extracellular matrix protein latent-transforming growth factor beta-binding protein 4 (LTBP-4). The mutational inactivation of both isoforms causes autosomal recessive cutis laxa type 1C (ARCL1C) in humans and an ARCL1C-like phenotype in Ltbp4-/- mice, both characterized by high postnatal mortality and severely affected elastogenesis. However, genetic data in mice suggest isoform-specific functions for Ltbp-4 because Ltbp4S-/- mice, solely expressing Ltbp-4L, survive to adulthood. This clearly suggests a requirement of Ltbp-4L for postnatal survival. A major difference between Ltbp4S-/- and Ltbp4-/- mice is the matrix incorporation of fibulin-4 (a key factor for elastogenesis; encoded by the Efemp2 gene), which is normal in Ltbp4S-/- mice, whereas it is defective in Ltbp4-/- mice, suggesting that the presence of Ltbp-4L might be required for this process. To investigate the existence of a functional interaction between Ltbp-4L and fibulin-4, we studied the consequences of fibulin-4 deficiency in mice only expressing Ltbp-4L. Resulting Ltbp4S-/-;Fibulin-4R/R mice showed a dramatically reduced lifespan compared to Ltbp4S-/- or Fibulin-4R/R mice, which survive to adulthood. This dramatic reduction in survival of Ltbp4S-/-;Fibulin-4R/R mice correlates with severely impaired elastogenesis resulting in defective alveolar septation and distal airspace enlargement in lung, and increased aortic wall thickness with severely fragmented elastic lamellae. Additionally, Ltbp4S-/-;Fibulin-4R/R mice suffer from aortic aneurysm formation combined with aortic tortuosity, in contrast to Ltbp4S-/- or Fibulin-4R/R mice. Together, in accordance with our previous biochemical findings of a physical interaction between Ltbp-4L and fibulin-4, these novel in vivo data clearly establish a functional link between Ltbp-4L and fibulin-4 as a crucial molecular requirement for survival and elastogenesis in mice.


The South Carolina Environmental Public Health Tracking Program's Role in Monitoring and Reducing Occupational Exposure to Lead: Public Health Actions in Collaboration with the South Carolina Occupational Safety and Health Administration.
Per South Carolina (SC) Law §44-29-10, all blood lead test records are reportable. The SC Environmental Public Health Tracking (SC EPHT) program is directly involved in blood lead surveillance in SC, as it maintains the blood lead record database. Although Adult Blood Lead Epidemiology and Surveillance funding from the Centers for Disease Control and Prevention was discontinued in 2013, SC EPHT has continued to monitor and record adult blood lead test records.In 2012, SC EPHT signed a memorandum of understanding with the SC Occupational Safety and Health Administration (SC OSHA). Per this agreement, quarterly reports of elevated adult blood lead concentrations (≥25 μg/dL) are supplied to SC OSHA, along with North American Industry Classification System codes of employers. This information is used for industrial inspections, mitigation, and abatement related to lead. The SC EPHT program's collaboration with SC OSHA has resulted in a number of public health actions that have improved the health and well-being of workers in SC. Of the 3 nationally accepted SC public health actions related to occupational lead exposure, 2 detail investigations and citations by SC OSHA. The other describes internal analyses conducted by the SC EPHT program regarding elevated blood lead levels in adults and associations with specific North American Industry Classification System codes.In this review, we outlined the role of SC EPHT related to adult blood lead surveillance in SC, including implementation of the memorandum of understanding with SC OSHA. We also examined demographics of adult blood lead records in SC for 2010-2015 and summarized public health actions related to occupational lead exposure in SC. Since federal funding for the SC EPHT program was initiated in 2009, the program has played an important part in lead surveillance in SC. The resulting health benefits to those with the potential for occupational exposure to lead are extremely important.


Association Between Toxoplasma gondii Exposure and Heart Disease: A Case-Control Study.
The parasite Toxoplasma gondii causes infections all around the world. Infections with T. gondii are systemic and the parasite can persist in the heart muscle. Very little is known about the impact of T. gondii on patients with heart disease. We determined the association between T. gondii exposure and patients suffering from heart diseases attending in a public hospital in Durango, Mexico; the association of T. gondii exposure with socio-demographic, behavioral, and clinical characteristics of these patients was also investigated. Through a case-control study, we examined the seroprevalence of anti-T. gondii IgG and IgM antibodies in 400 patients with heart diseases and 400 age- and gender-matched controls using enzyme-linked immunoassays. In addition, we analyzed the association of patient characteristics as determined by a standardized questionnaire with T. gondii exposure by bivariate and multivariate analyses. Fifty-five (13.8%) of 400 patients and 32 (8.0%) of 400 controls had anti-T. gondii IgG antibodies (odds ratio (OR) = 1.83; 95% confidence interval (CI): 1.15 - 2.90; P = 0.01). High anti-T. gondii IgG levels (> 150 IU/mL) were found in 28 (50.9%) of the 55 positive cases and in 14 (43.8%) of the 32 positive controls (P = 0.51). Anti-T. gondii IgM antibodies were found in 13 (23.6%) of the 55 anti-T. gondii IgG positive patients and in 19 (59.4%) of 32 anti-T. gondii IgG positive controls (OR = 0.21; 95% CI: 0.08 - 0.54; P = 0.0008). Multivariate analysis showed that T. gondii exposure was positively associated with being born out of Durango State (OR = 2.93; 95% CI: 1.40 - 6.13; P = 0.004), and with consumption of alcohol (OR = 2.04; 95% CI: 1.01 - 4.12; P = 0.04). Results obtained in this study indicate that T. gondii infection is associated with heart disease, and suggest that heart disease might be related with a chronic infection. This is the first report of an association of T. gondii exposure with alcohol consumption in this population. Results warrant for further research to determine the epidemiological impact of T. gondii exposure on patients with heart diseases. Risk factors associated with T. gondii exposure are critical to design future prevention strategies against T. gondii exposure.


Peripheral arterial response during haemodialysis - is two-dimensional speckle-tracking a useful arterial reactivity assessment tool?
Aim: 2D speckle tracking is a method used in myocardial strain assessment. However, several studies have confirmed the suitability of its application in the assessment of arterial strain (a marker of arterial stiffness). The aims of our study were to evaluate whether 2D speckle tracking can assess the changes in carotid and femoral strain caused by fluid loss during haemodialysis, and to determine the direction and amount of these changes. Material and methods: We examined the distal common carotid and proximal femoral arteries in 74 haemodialysed patients (28 women and 46 men) before and after their haemodialysis sessions. EchoPac software was used to analyse the recorded ultrasound examinations. Circumferential strain values were acquired for further analysis. Results: We found a decrease in carotid circumferential strain values after haemodialysis sessions (5.916 ± 2.632% before haemodialysis and 4.909 ± 2.409% after haemodialysis, p = 0.000022). The amount of fluid lost during haemodialysis sessions correlated (correlation coefficient of 0.434, p = 0.000222) with the decrease of carotid circumferential strain. The correlation coefficients were slightly higher (0.445, p = 0.000146) when a ratio of fluid loss volume to the BMI was used. No statistically significant changes were found in femoral circumferential strain. Conclusions: Our findings suggest that arterial response to body fluid loss may be assessed by 2D speckle tracking. This method enabled us to measure carotid circumferential strain changes caused by fluid volume contraction during haemodialysis sessions. We found an important decrease in the carotid circumferential strain values after the procedure. The amount of this decrease correlated significantly with the decrease in the volume of fluid lost during the haemodialysis session.


Exchange of oxygen across the epicardial surface distorts estimates of myocardial oxygen consumption.
The rate of oxygen consumption of isolated, Langendorff-circulated, saline-perfused hearts of guinea pigs, rats, and rabbits was measured using the classical Fick Principle method. The heart was suspended in a glass chamber the oxygen partial pressure, PO2, of which could be varied. The measured rate of oxygen consumption was found to vary inversely with the ambient (heart chamber) PO2. This result prevailed whether the chamber was filled with air, saline, or oil, and whether the pericardium was present or the heart was wrapped in Saran. The effect varied inversely with heart size both within and across species. It is concluded that the epicardial surface is permeable to oxygen which will diffuse either into or out of the heart as the PO2 gradient dictates. In either case the classically measured rate of oxygen consumption will be in error. The error can be large in studies of cardiac basal metabolism. A simple model is developed to describe the observed rate of oxygen consumption as classically measured. The measured rate is partitioned into two components: the true rate of oxygen consumption of the heart, and the rate of loss of oxygen by diffusive exchange across the epicardial surface. The latter component is proportional to the gradient of oxygen partial pressure from myocardium to environment and to the diffusive oxygen conductance of myocardial tissue. Application of the model allows the true rate of oxygen consumption of the heart to be recovered from measured values which may be considerably in error.


Heat Stress Causes Immune Abnormalities via Massive Damage to Effect Proliferation and Differentiation of Lymphocytes in Broiler Chickens.
Broiler chickens are highly sensitive to high ambient temperatures due to their feathers, lack of skin sweat glands, and high productivity. Heat stress (HS) is a major concern for the poultry industry because it negatively affects growth as well as immune functions, which increase the potential risk of infectious disease outbreaks. Therefore, it is vital to elucidate HS's effect on the avian immune system, especially considering the global rise in average surface temperature. Our study identified a series of immunological disorders in heat-stressed broiler chickens. We exposed 22-day-old broiler chickens to a continuous HS condition (34.5 ± 0.5°C) for 14 days and immunized them with a prototype bovine serum albumin (BSA) antigen. The plasma and lymphoid tissues (thymus, bursa of Fabricius, and spleen) were harvested at the end of the experiments to investigate the induction of BSA-specific immune responses. Our results revealed that plasma titers of immunoglobulin (Ig)Y, IgM, and IgA antibodies specific for BSA were lower than those of thermoneutral chickens immunized with BSA. Furthermore, the spleens of the heat-stressed broiler chickens displayed severe depression of Bu1+ B cells and CD3+ T cells, including CD4+ T cells and CD8+ T cells, and lacked a fully developed germinal center (GC), which is crucial for B cell proliferation. These immunological abnormalities might be associated with severe depression of CD4-CD8- or CD4+CD8+ cells, which are precursors of either helper or killer T cells in the thymus and Bu1+ B cells in the bursa of Fabricius. Importantly, HS severely damaged the morphology of the thymic cortex and bursal follicles, where functional maturation of T and B cells occur. These results indicate that HS causes multiple immune abnormalities in broiler chickens by impairing the developmental process and functional maturation of T and B cells in both primary and secondary lymphoid tissues.


Morphine and norepinephrine but not 5-hydroxytryptamine and gamma-aminobutyric acid inhibit the potassium-stimulated release of substance P from rat spinal cord slices.
We studied whether morphine, norepinephrine (NE), 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA) inhibit the potassium-stimulated release of substance P (SP) from rat spinal cord slices. Male Sprague-Dawley rats were decapitated and a 2-cm segment of lumbosacral spinal cord was removed, chopped into 0.5 X 0.5 mm pieces, weighed, placed in a perfusion chamber and perfused at 37 degrees C with a modified Krebs bicarbonate buffer. Perfusate was collected, lyophilized, then assayed for SP using radioimmunoassay. Exposure of spinal cord tissue to 50 mM KCl for 8 min produced a calcium-dependent increase in the release of SP from a basal level of approximately 0.1 pg/mg tissue/min to 0.3 pg/mg tissue/min. Morphine and NE at concentrations of 10(-4) and 10(-5) M did not alter basal release but caused a significant reduction in the potassium-stimulated release of SP. Naloxone (10(-5) M) and phentolamine (10(-5) M) did not affect SP release but attenuated the effects of morphine and NE, respectively. Naloxone did not antagonize the inhibition of release produced by NE nor did phentolamine block the effect of morphine, suggesting that the actions of the agonists are independent. In contrast, 5-HT and GABA at concentrations of 10(-4) M and 10(-5) M did not significantly alter the basal or potassium-stimulated release of SP. These results demonstrate a differential regulation of SP release in the spinal cord and support the hypothesis that morphine and NE may modify nociception, in part, by inhibiting the release of SP in the spinal cord.


Regulation of podocyte BK(Ca) channels by synaptopodin, Rho, and actin microfilaments.
Mechanosensitive large-conductance Ca(2+)-activated K(+) channels encoded by the Slo1 gene (BK(Ca) channels) are expressed in podocytes. Here we show that BK(Ca) channels reciprocally coimmunoprecipitate with synaptopodin (Synpo) in mouse glomeruli, in mouse podocytes, and in a heterologous expression system (HEK293T cells) in which these proteins are transiently expressed. Synpo and Slo1 colocalize along the surface of the glomerular basement membrane in mouse glomeruli. Synpo interacts with BK(Ca) channels at COOH-terminal domains that overlap with an actin-binding domain on the channel molecule that is necessary for trafficking of BK(Ca) channels to the cell surface. Moreover, addition of exogenous beta-actin to mouse podocyte lysates reduces BK(Ca)-Synpo interactions. Coexpression of Synpo increases steady-state surface expression of BK(Ca) channels in HEK293T cells. However, Synpo does not affect the stability of cell surface BK(Ca) channels, suggesting a primary effect on the rate of forward trafficking, and Synpo coexpression does not affect BK(Ca) gating. Conversely, stable knockdown of Synpo expression in mouse podocyte cell lines reduces steady-state surface expression of BK(Ca) channels but does not affect total expression of BK(Ca) channels or their gating. The effects of Synpo on surface expression of BK(Ca) are blocked by inhibition of Rho signaling in HEK293T cells and in podocytes. Functional cell surface BK(Ca) channels in podocytes are also reduced by sustained (2 h) but not acute (15 min) depolymerization of actin with cytochalasin D. Synpo may regulate BK(Ca) channels through its effects on actin dynamics and by modulating interactions between BK(Ca) channels and regulatory proteins of the podocyte slit diaphragm.


Copper(II) interactions with nonsteroidal antiinflammatory agents. II. Anthranilic acid as a potential. OH-inactivating ligand.
It has long been established that copper complexes of inactive substances exert antiinflammatory activity and that copper complexes of nonsteroidal antiinflammatory drugs (NSAIDs) are more active than these drugs by themselves. Based on these observations, it was proposed that copper complexes of NAIDs are their active metabolites. This hypothesis was not confirmed for salicylic acid, however, as computer-aided speciation studies have shown that no copper-salicylate complex can reach significant levels in blood plasma. In view of this result, it was of interest to test with the same technique the influence on copper metabolism of an inactive substance known to be activated by copper. Anthranilic acid was chosen for this test in the present work. First, copper(II)-anthranilate interactions have been investigated by glass electrode potentiometry under physiological conditions. Given the key role of histidine as copper(II) ligand in blood plasma, copper(II)-histidine-anthranilate ternary equilibra have also been determined. Computer simulations of copper distribution have then been run relative to the two main biofluids in respect of global metabolism, i.e., gastrointestinal (g.i.) fluid and blood plasma. Like salicylic acid, anthranilic acid is expected to favor copper g.i. absorption, but cannot either exert any significant influence on plasma copper distribution. Clearly, the fact that anthranilate becomes antiinflammatory when administered with copper cannot originate in any effect of anthranilate on copper global metabolism. Speciation investigations have then been extended to the synovial fluid. Whereas salicylate does not appear to be a better ligand of copper in this medium than in blood plasma at any pH between 7.4 and 5.5, anthranilate on the contrary can mobilize increasing fractions of copper as the pH decreases, i.e., the more inflammation, the more copper is bound to anthranilate. This is in line with the recent observation that salicylate inactivates copper-induced .OH radicals through its bulk scavenging properties whereas .OH inactivation by anthranilate under the same conditions is a direct function of the copper-anthranilate binding. Anthranilate thus seems to correspond to the recently defined notion of .OH-inactivating ligand (OIL). More generally, these results provide a beginning of rationale for the antiinflammatory properties of copper complexes with substances that are active or inactive against inflammation by themselves. The extra antiinflammatory activity induced by copper on NSAIDs appears to be independent of any Cu(II)-NSAID association in vivo. On the contrary, the binding of inactive substances with copper(II) at inflammatory sites seems to be essential to their activation by copper.


Cyclophosphamide followed by rituximab for aggressive multiple-relapsing antineutrophil cytoplasmic antibody-associated vasculitis.
To evaluate the long-term outcomes of patients with multi-relapsing antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), who received sequentially therapy with cyclophosphamide and rituximab, upon new onset of aggressive vasculitis. We retrospectively studied patients with multiple-relapsing AAV, who were treated with the standard regimen plus rituximab, given in sequence, upon a major relapse, compared to historical patients, who had been treated with the standard regimen alone in the same setting. The main outcomes of interest were relapse rates and frequency of adverse events. Of 147 patients with biopsy proven AAV, 35 (23.8%) experienced at least one major relapse, of whom, 14 (9.5%) received the sequential regimen and were compared to 21 (14.3%) historic patients, who had received the standard regimen alone for the same reason. Patients in both groups achieved remission in similar rates, but those treated with the sequential regimen experienced a significant decline in the relapse rate afterwards, compared to their corresponding rate prior to study entry [0.07 episodes of relapse per patient-year (95%CI: 0.03-0.2) vs. 0.38 (95%CI: 0.35-0.60) respectively, (p=0.004)]. The need for cyclophosphamide was significantly decreased in patients in whom cyclophosphamide was followed by rituximab [3.3(0-10.5) grams vs. 14.5 (4-177) grams, (p<0.0001)] but not in controls [17.2(0-108) grams vs. 14.5(0-63) grams, p=0.61]. Our data show that sequential therapy with cyclophosphamide and rituximab, upon a major relapse, in patients with frequently relapsing AAV, is associated with prolonged remission, allowing minimization of the ultimate exposure to cyclophosphamide.


Association between beverage consumption and risk of rheumatoid arthritis: a prospective study from the French E3N Cohort.
To assess the relationship between consumption of largely consumed beverages (coffee, tea, alcohol and soft drinks) and the risk of RA. The E3N Study (Étude Épidémiologique auprès des femmes de la Mutuelle Générale de l'Éducation Nationale) is a French prospective cohort including 98 995 women since 1990. Food and beverage consumption was assessed using a validated food-frequency questionnaire. Hazard ratios (HR) and their 95% CI for incident RA were estimated by Cox proportional hazards model. Among 62 631 women, 481 incident RA cases were identified. Consumptions of tea, alcohol and sugar-sweetened soft drinks were not associated with RA risk. We observed a linear association between coffee consumption and RA risk [≥4 cups/day vs ≤1cup/day, HR = 1.24; 95% CI (0.94, 1.64), Ptrend = 0.04], and a higher risk of RA with artificially sweetened soft drinks consumption [consumers vs not, HR = 1.66; 95% CI (1.12, 2.45)], particularly in never-smokers. Among ever-smokers, moderate liquor intake was associated with a reduced risk of RA [1-3 glasses/week vs non-consumers, HR = 0.63; 95% CI (0.43, 0.91)] and moderate wine consumption with a reduced risk of seropositive RA. In a large cohort of women, tea, alcohol and sugar-sweetened soft drinks consumption was not associated with RA risk, whereas consumption of coffee (especially caffeinated coffee), and artificially sweetened soft drinks was associated with higher RA risk, particularly among never-smokers. If further confirmed, these results could lead to novel mechanistic hypotheses and to simple prevention measures.


Rapid decadal convective precipitation increase over Eurasia during the last three decades of the 20th century.
Convective precipitation-localized, short-lived, intense, and sometimes violent-is at the root of challenges associated with observation, simulation, and prediction of precipitation. The understanding of long-term changes in convective precipitation characteristics and their role in precipitation extremes and intensity over extratropical regions are imperative to future water resource management; however, they have been studied very little. We show that annual convective precipitation total has been increasing astonishingly fast, at a rate of 18.4%/°C, of which 16% is attributable to an increase in convective precipitation occurrence, and 2.4% is attributable to increased daily intensity based on the 35 years of two (combined) historical data sets of 3-hourly synoptic observations and daily precipitation. We also reveal that annual daily precipitation extreme has been increasing at a rate of about 7.4%/°C in convective events only. Concurrently, the overall increase in mean daily precipitation intensity is mostly due to increased convective precipitation, possibly at the expanse of nonconvective precipitation. As a result, transitional seasons are becoming more summer-like as convective becomes the dominant precipitation type that has accompanied higher daily extremes and intensity since the late 1980s. The data also demonstrate that increasing convective precipitation and daily extremes appear to be directly linearly associated with higher atmospheric water vapor accompanying a warming climate over northern Eurasia.


Thyroid Function Screening in Children and Adolescents With Mood and Anxiety Disorders.
To determine the prevalence of abnormal thyroid-stimulating hormone (TSH) measures in youth with severe mood and anxiety disorders and to examine clinical and demographic predictors of abnormal TSH measures. We retrospectively examined screening TSH concentrations in psychiatrically hospitalized children and adolescents (3-19 years) with mood/anxiety disorders (DSM-IV and DSM-5 criteria) at a large, urban, pediatric hospital between September 2013 and April 2017. Symptoms were extracted from the medical record using adaptive natural language processing algorithms, and the utility of demographic, clinical, and treatment variables as predictors of abnormal TSH measures was evaluated using logistic regression. In this sample (N = 1,017, mean ± SD age = 14.7 ± 2.24 years), 62 patients had a TSH concentration > 3.74 μIU/mL (5.3% [n = 6] of patients < 12 years of age and 6.2% [n = 56] of patients ≥ 12 years of age), and 7 patients had a TSH concentration < 0.36 μIU/mL. Elevated TSH concentrations were associated with a recent weight gain (odds ratio [OR] = 3.60; 95% CI, 1.13-9.61; P = .017), a history of thyroid disease (OR = 6.88; 95% CI, 2.37-10.7; P ≤ .0001), abnormal menstrual bleeding/menometrorrhagia (OR = 2.03; CI, 1.04-3.63; P = .024), and benzodiazepine treatment (OR = 2.29; 95% CI, 1.07-4.52; P = .02). No association was observed for sex, age, or body mass index z score. Among patients with elevated TSH measures, 12.9% (n = 8, mean ± SD age = 16.5 ± 1.5 years, 87.5% female) had an abnormal free/total thyroxine (T₄) level or other biochemical findings consistent with thyroid disease. Patients with thyroid disease (compared to those patients with elevated TSH and normal active thyroid hormone concentrations) were older (16.5 ± 1.5 vs 14.6 ± 2.3 years, P = .020) but did not differ in sex distribution (87.5% vs 63.6% female, P = .444). TSH concentrations are abnormal in approximately 6% of psychiatrically hospitalized youth, although thyroid disease was present in < 1% of the total sample. Targeted screening should focus on patients with recent weight gain, those treated with benzodiazepines, and girls with a history of abnormal uterine bleeding/menometrorrhagia.


Eyelid tightening and improved eyelid aperture through nonablative fractional resurfacing.
The effects of fractional resurfacing on eyelid tightening and aperture are unknown. Our purpose was to retrospectively examine the potential for eyelid tightening and eye-aperture opening in patients treated with nonablative fractional resurfacing for facial photorejuvenation. Fractional laser treatments using a 1,550-nm erbium-doped fiber laser system on the upper and lower eyelids were given at a pulse energy of 17 to 20 mJ at 125 micro-thermal zones (MTZ)/cm(2) to a final density of 500 to 750 MTZ/cm(2). Each patient had 3 to 7 treatments. Standard pre- and post-treatment photographs were taken at each visit. Physicians who graded 31 preselected patient photographs using a 4-point scale evaluated eyelid tightening. Increase in eyelid aperture was also evaluated. All patients had some degree of eyelid tightening; 19% achieved 1% to 25% tightening, 26% achieved 25% to 50%, 26% achieved 50% to 75%, and 29% achieved 75% to 100%. Increase in eyelid aperture was seen in 55.9% of patients. Postoperative wounding, hypopigmentation, hyperpigmentation, persistent erythema, and scarring were not observed. All patients experienced mild or no edema for a few days after treatment. Fractional resurfacing tightens and increases eyelid aperture without wounding, downtime, or long-term complications.


An experimental study on the influence of water stagnation and temperature change on water quality in a full-scale domestic drinking water system.
The drinking water quality changes during the transport through distribution systems. Domestic drinking water systems (DDWSs), which include the plumbing between the water meter and consumer's taps, are the most critical points in which water quality may be affected. In distribution networks, the drinking water temperature and water residence time are regarded as indicators of the drinking water quality. This paper describes an experimental research on the influence of stagnation time and temperature change on drinking water quality in a full-scale DDWS. Two sets of stagnation experiments, during winter and summer months, with various stagnation intervals (up to 168 h of stagnation) were carried out. Water and biofilms were sampled at two different taps, a kitchen and a shower tap. Results from this study indicate that temperature and water stagnation affect both chemical and microbial quality in DDWSs, whereas microbial parameters in stagnant water appear to be driven by the temperature of fresh water. Biofilm formed in the shower pipe contained more total and intact cells than the kitchen pipe biofilm. Alphaproteobacteria were found to dominate in the shower biofilm (78% of all Proteobacteria), while in the kitchen tap biofilm Alphaproteobacteria, Betaproteobacteria and Gammaproteobacteria were evenly distributed.


[Mathematical model of the combined effects of ionizing radiation and hyperthermia on mammalian cells].
A previously proposed mathematical model for the depiction of the effects of combined ionizing radiation and hyperthermia on yeast cells of different species was applied to the description of experimental data on mammalian cells. The model suggests that the synergistic effect of combined ionizing radiation and hyperthermia is caused by additional lethal damages arising from the interaction of "sublesions" induced by both agents. These "sublesions" are not lethal after the action of these agents, each taken alone. It has been shown that the thermal enhancement ratios are strongly determined by the ratios of radiation and hyperthermia-induced lethal damages. The model predicts that the maximal synergistic effect after a separate action of these modalities will be achieved if the former agent induces a greater part of lethal damages as compared to the latter one. It has been shown that the model depicts quantitatively the synergism of the simultaneous action of the agents used for Chinese hamster cells and predicts the maximal value of the synergistic effect, conditions under which it can be achieved and the dependence of the synergistic effect on the do se rate.


[Jean-Baptiste de Lamarck (1744-1829). A dispute on the mechanism of evolution. On the bicentenary of the publication of Philosophie Zoologique (1809)].
The author of the paper has made an attempt to prove that a teleological interpretation of Lamarck's theory is false. It is unwarranted to attribute to Lamarck the idea that a living organism has an internal tendency to complicate its organization and to improve its mode of functioning; such a concept is not confirmed by existing textual evidence, and it is also in direct conflict with Lamarck's undisputed mechanicism. The proof presented in the paper begins with an outline of the history of this false interpretation, including the opinions of Charles Lyell and Charles Darwin. As the tendency is ascribed also to nature itself, the next phase of the proof has involved reconstructing the fully ateleological notion of nature to which Lamarck subscribed. Supposed evidence for the tendency is said to be provided by the existence of a series in which the organization of a living body grows from the simplest to the most complex. That is why the author of the current paper has analysed the concept of série animale used by Lamarck in some detail, in order to demonstrate that it is typological in character, and has nothing to do with the tendency that is allegedly inherent in the nature of an organism. Also presented in the paper, in connection with the construction of the series, is the problem of spontaneous generation, which was made complicated by Lamarck. Finally, the very notion of tendency is analysed and confronted with Lamarck's text; the latter in fact does not contain any explanations that would be teleological in the strict sense of the word. The analysis has enabled the author of the current paper to conduct an exegesis of the fragment of Lamarck's text which might give grounds to it being construed in terms of an explanation resorting to the notion of tendency, and possible interpretations of that fragment have been presented. The paper ends with a description of the mechanism which, according to Lamarck, is responsible for the rise in complexity of an organism that has the nature of a machine; such a mechanism leaves no place for any tendency to be in operation.


Diazoxide preconditioning alleviates caspase-dependent and caspase-independent apoptosis induced by anoxia-reoxygenation of PC12 cells.
Although there is increasing evidence that the ATP sensitive potassium channel (K(ATP)) opener exhibits neuroprotective effects against ischaemic neural damage, little is known about the mechanism. Mitochondria play a key role in apoptosis by releasing many important factors, including cytochrome c and apoptosis-inducing factor, which in turn initiate the caspase-dependent and -independent mitochondrial pathway, respectively. In the present study, we sought to determine the locus that K(ATP) opener uses to mediate this protection in PC12 cells. We found that pre-treatment of PC12 cells with diazoxide (DZX), a mitochondrial ATP sensitive potassium channel (mitoK(ATP)) opener, dose-dependently increased cell viability under conditions of oxygen glucose deprivation (OGD). The protective effect of this pre-conditioning was attenuated by 5-hydroxydecanoic acid, a selective mitoK(ATP) blocker. The results showed that DZX inhibits the release of cytochrome c, the activation of caspase-3 and the release of AIF evoked by OGD. Taken together, our results demonstrate for the first time that activation of the mitoK(ATP) channel elicits protective effects against OGD-induced cell apoptosis by caspase-dependent and -independent mitochondrial pathways.


Membrane electricity as a convertible energy currency for the cell.
The role of transmembrane electric potential difference (delta psi) in mitochondria, chloroplasts, and bacteria has been considered. Since the electric capacitance of membranes is much lower than the pH buffer capacitance of water phases, delta psi proves to be the primary form of energy produced by generators of electrochemical H+ potential difference (delta mu-H). There are 11 distinct types of delta mu-H-generating systems in coupling membranes, involved in respiratory and light-dependent electron and proton transfer, as well as in ATP and PP1 hydrolysis and synthesis. Bacteriorhodopsin is the simplest delta mu-H generator. However, even in this case, the molecular mechanism of delta psi production remains obscure. Many types of work can be supported by delta mu-H with no ATP involved so that delta mu-H proves to be not only a transient intermediate of oxidative and photosynthetic phosphorylation but also a convertible energy currency for the cell. Among the delta mu-H-supported activities, mechanical work was recently demonstrated. It can be exemplified by the motility systems of (i) flagellar bacteria and (ii) blud--green algae. As was found in multicellular cyanobacteria, delta mu-H can be used for a power transmission over distances as long as 1 mm. It seems to be probable that in large cells of eukaryotes (e.g., in muscle fibers) giant mitochondria may serve as power-transmitting structures. Na+--K+ gradients can be used to stabilize delta mu-H in bacteria. It is suggested that the primary function of unequal distribution of these cations between the microbial cell and the medium is delta mu-H buffering.


Regulation of intestinal ontogeny: effect of glucocorticoids and luminal microbes on galactosyltransferase and trehalase induction in mice.
Intestinal maturation can be influenced by intrinsic factors (glucocorticoid hormones) and by extrinsic factors (resident microflora); their relative roles in ontogeny of mouse intestinal trehalase expression, a marker of general gut development, and of beta1,4-galactosyltransferase (beta GT), a marker of glycosyltransferase development, were investigated. In conventional (CONV) mice, beta GT and trehalase gene expression rapidly increased to adult levels by the fourth postnatal week. In germ-free (GF) mice, beta GT expression remained at initial low levels and was rapidly induced on reintroduction of luminal microbes of the adult gut but not of microbes characteristic of the suckling gut. Similar developmental patterns were observed for colonic galactosyl beta1,4-linked glycoconjugates, products of beta GT activity. These results indicate an essential role for microbes in the ontogeny of beta GT. In both CONV and GF mice, cartisone acetate (CA) precociously accelerated the ontogeny of beta GT and trehalase until maturation of the gut occurred (day 22). In the mature gut of CONV mice, both beta GT and trehalase are elevated and insensitive to CA; in GF mature mice, the expression of beta GT remains low, whereas the expression of trehalase was at mature levels, regardless of CA treatment. These changes in enzyme activity were accompanied by parallel changes in mRNA, implying transcriptional regulation. Thus both microbes and cortisone regulate gut ontogeny, but only suckling gut responds to CA, an intrinsic factor, whereas adult gut beta GT expression remains sensitive to microflora, an extrinsic factor. However, induction of the adult pattern of glycosyltransferase expression in mature gut requires colonization by microflora typical of adult gut, suggesting an essential role for intestinal colonization in the ontogeny of normal intestinal mucosal cell surface glycoconjugate receptors.


Maternal Sick Leave Due to Psychiatric Disorders Following the Birth of a Child With Special Health Care Needs.
Child-related stress following the birth of a child with special health care needs (SHCN) can take a toll on parental health. This study examined how the risk of sick leave due to psychiatric disorders (PD) among mothers of children with SHCN compares with that of mothers of children without SHCN during early motherhood. Responses from 58,532 mothers participating in the Norwegian Mother and Child Cohort Study were linked to national registries and monitored for physician-certified sick leave from the month of their child's first birthday until the month of their child's fourth birthday. As compared with mothers of children without SHCN, mothers of children with mild and moderate/severe care needs were at substantial risk of a long-term sick leave due to PD in general and due to depression more specifically. Extensive childhood care needs are strongly associated with impaired mental health in maternal caregivers during early motherhood.


Evidence that tubulobulbar complexes in the seminiferous epithelium are involved with internalization of adhesion junctions.
Tubulobulbar complexes may be part of the mechanism by which intercellular adhesion junctions are internalized by Sertoli cells during sperm release. These complexes develop in regions where Sertoli cells are attached to adjacent cells by intercellular adhesion junctions termed ectoplasmic specializations. At sites where Sertoli cells are attached to spermatid heads, tubulobulbar complexes consist of fingerlike processes of the spermatid plasma membrane, corresponding invaginations of the Sertoli cell plasma membrane, and a surrounding cuff of modified Sertoli cell cytoplasm. At the terminal ends of the complexes occur clusters of vesicles. Here we show that tubulobulbar complexes develop in regions previously occupied by ectoplasmic specializations and that the structures share similar molecular components. In addition, the adhesion molecules nectin 2 and nectin 3, found in the Sertoli cell and spermatid plasma membranes, respectively, are concentrated at the distal ends of tubulobulbar complexes. We also demonstrate that double membrane bounded vesicles are associated with the ends of tubulobulbar complexes and nectin 3 is present on spermatids, but is absent from spermatozoa released from the epithelium. These results are consistent with the conclusion that Sertoli cell and spermatid membrane adhesion domains are internalized together by tubulobulbar complexes. PKCalpha, a kinase associated with endocytosis of adhesion domains in other systems, is concentrated at tubulobulbar complexes, and antibodies to endosomal and lysosomal (LAMP1, SGP1) markers label the cluster of vesicles associated with the ends of tubulobulbar complexes. Our results are consistent with the conclusion that tubulobulbar complexes are involved with the disassembly of ectoplasmic specializations and with the internalization of intercellular membrane adhesion domains during sperm release.


Cranial Nerve Involvement and Dysautonomia in Post-COVID-19 Guillain-Barré Syndrome.
The clinical characteristics of Guillain-Barré syndrome (GBS) after coronavirus disease 2019 (COVID-19) remain unclear due to the small number of cases. We herein report a case of a Japanese patient with post-COVID-19 GBS who presented with facial and limb muscle weakness, sensory deficits, and autonomic dysfunction. Nerve conduction studies revealed demyelination. Head magnetic resonance imaging showed contrast enhancement in the bilateral facial nerves. Systemic management, including intubation, intravenous immunoglobulin therapy, and rehabilitation, improved the patient's condition. This was the first Japanese case of acute inflammatory demyelinating polyneuropathy after COVID-19 and was characterized by autonomic dysfunction and facial nerve enhancement.


Systematic use of patient-rated depression severity monitoring: is it helpful and feasible in clinical psychiatry?
The gap between evidence-based treatments and routine care has been well established. Findings from the Sequenced Treatments Alternatives to Relieve Depression (STAR*D) emphasized the importance of measurement-based care for the treatment of depression as a key ingredient for achieving response and remission; yet measurement-based care approaches are not commonly used in clinical practice. The Nine-Item Patient Health Questionnaire (PHQ-9) for monitoring depression severity was introduced in 19 diverse psychiatric practices. During the one-year course of the project the helpfulness and feasibility of implementation of PHQ-9 in these psychiatric practices were studied. The project was modeled after the Institute for Healthcare Improvement Breakthrough Series. Two of the 19 practices dropped out during the course of the project. By the conclusion of the study, all remaining 17 practices had adopted PHQ-9 as a routine part of depression care in their practice. On the basis of responses from 17 psychiatrists from those practices, PHQ-9 scores influenced clinical decision making for 93% of 6,096 patient contacts. With the additional information gained from the PHQ-9 score, one or more treatment changes occurred during 40% of these clinical contacts. Changing the dosage of antidepressant medication and adding another medication were the most common treatment changes recorded by psychiatrists, followed by starting or increasing psychotherapy and by switching or initiating antidepressants. In 3% of the patient contacts, using the PHQ-9 led to additional suicide risk assessment. The study findings suggest that adopting measurement-based care, such as using the PHQ-9, is achievable, even in practices with limited resources.


Development of an intravascular impedance catheter for detection of fatty lesions in arteries.
Recent studies show that the presence of fatty lesions in the atherosclerotic vessel wall is a risk factor for acute occlusion of blood vessels. Although fat has a high electrical resistivity, existing impedance catheter systems cannot be used for detection of these lesions because artifacts owing to impedance variations in the extravascular surroundings have a major and irretraceable effect on the measurement. Standard algorithms used in attempt to compensate for these artifacts suffer from severe instability problems. We defined design guidelines to be met by a new impedance catheter system in order to make a robust reconstruction algorithm possible and have built an experimental in travascular impedance catheter (IIC) system according to these guidelines, using a normalized differential measurement procedure. With this IIC, we performed experiments on human iliac arteries from the section ward (fixed specimens), showing that plastic models of arterial fatty lesions (8 mm3) can be detected reliably.