Why Clinicians Choose Their Language Intervention Approach: An International Perspective on Intervention for Children with Developmental Language Disorder.
Considerable progress has been made in recent years in generating external evidence underpinning interventions for children with developmental language disorder (DLD), but less is known about the practitioner decision-making process underpinning such interventions and whether such decisions are context specific or are internationally generalizable. An online survey about clinical practice was developed by members of COST Action IS1406, an EU-funded research network, which included representation from 39 countries. The participants were 2,408 practitioners who answered questions in relation to their decision making for a specific child of their choosing with DLD. Analysis of open-ended questions was undertaken, and data were converted into codes for the purpose of quantitative analysis. Although a wide range of intervention approaches and rationales were reported, the majority of responses referenced a client-centred approach. Level of functioning was used as a rationale only if a child had severe DLD. Practitioners with university level education or above were less likely to report basing intervention on client-centred factors. A number of differently named interventions with variable theoretical and empirical underpinnings were used in different countries. Specific client and practitioner characteristics have an impact on the intervention approaches and rationales adopted across countries. A limited number of practitioners reported use of external scientific evidence, which suggests that there should be more initiatives in basic training of practitioners and continuing professional development to encourage the uptake of scientific evidence-based practice.


An exploration of the stroke co-ordinator role.
Although there is knowledge of the substantial benefits of collaborative approaches to stroke rehabilitation, information on alternative management strategies is sparse. This paper describes an exploratory survey, undertaken in the north-west of England, to highlight features of the stroke co-ordinator role. The role is explored in terms of rehabilitation management and service development. Some strategies to support practitioners in the role, and areas for role development, are suggested.


[Genomic distribution of AML1-ETO fusion protein binding sites].
This study was purposed to characterize the genomic distribution of the binding sites for AML1-ETO fusion protein on chromosome 2, 9 and 19, and to further gain insights into the characteristics of transcriptional regulation by AML1-ETO in acute myeloid leukemia so as to provide theoretical basis for the development of targeted therapy and optimization for treatment. Chromatin immunoprecipitation (ChIP) coupled with high density tiling arrays (chip), also known as ChIP-chip, was utilized in this study. ChIP-DNA enriched by an anti-ETO antibody and total genomic DNA of Kasumi cells were hybridized to tiling arrays, tiled through chromosome 2, 9 and 19. The ChIP enriched regions were identified using a model based analytical tool (MAT). Genomic distribution of the ChIP regions was analyzed using publicly available CEAS web server. The Gene Ontology (GO) enrichment analysis was performed to excavated the biological significance. The results indicated that a total of 588 enriched regions were identified on chromosome 2, 9 and 19 by the anti-ETO antibody. A number of the identified regions were located within enhancers (48.86%) or introns (37.35%), much smaller fractions were within proximal promoters (5.96%) or exons (5.49%). Functional enrichment analysis showed that cell proliferation and signal transduction biological pathways were enriched in potential genes of AML-ETO. It is concluded that half of the AML1-ETO binding sites are located within known transcriptional regulatory regions (promoter, 5' UTR and enhancer), while almost another half were within the sequences which were not previously reported as regulatory regions. The potential target molecular network of AML1-ETO is involved in several essential biological processes.


Preliminary investigation of a video-based stimulus preference assessment.
Video clips may be an effective format for presenting complex stimuli in preference assessments. In this preliminary study, we evaluated the correspondence between preference hierarchies generated from preference assessments that included either toys or videos of the toys. The top-ranked item corresponded in both assessments for 5 of the 6 participants, and the top- and bottom-ranked items corresponded for 4 participants. The implications of these results for future research on video preference assessments are discussed.


Diagnosis and classification of disorders specifically associated with stress: proposals for ICD-11.
The diagnostic concepts of post-traumatic stress disorder (PTSD) and other disorders specifically associated with stress have been intensively discussed among neuro- and social scientists, clinicians, epidemiologists, public health planners and humanitarian aid workers around the world. PTSD and adjustment disorder are among the most widely used diagnoses in mental health care worldwide. This paper describes proposals that aim to maximize clinical utility for the classification and grouping of disorders specifically associated with stress in the forthcoming 11th revision of the International Classification of Diseases (ICD-11). Proposals include a narrower concept for PTSD that does not allow the diagnosis to be made based entirely on non-specific symptoms; a new complex PTSD category that comprises three clusters of intra- and interpersonal symptoms in addition to core PTSD symptoms; a new diagnosis of prolonged grief disorder, used to describe patients that undergo an intensely painful, disabling, and abnormally persistent response to bereavement; a major revision of "adjustment disorder" involving increased specification of symptoms; and a conceptualization of "acute stress reaction" as a normal phenomenon that still may require clinical intervention. These proposals were developed with specific considerations given to clinical utility and global applicability in both low- and high-income countries.


Diversifying selection on flavanone 3-hydroxylase and isoflavone synthase genes in cultivated soybean and its wild progenitors.
Soybean isoflavone synthase (IFS) and flavanone 3-hydroxylase (F3H) are two key enzymes catalyzing the biosynthesis of isoflavonoids and flavonoids, both of which play diverse roles in stress responses. However, little is known about the evolutionary pattern of these genes in cultivated soybean and its wild progenitors. Herein, we investigated the nucleotide polymorphisms in Isoflavone synthase (IFS1, IFS2) and Flavanone 3-hydroxylase (F3H2) genes from 33 soybean accessions, including 17 cultivars (Glycine max) and 16 their wild progenitors (Glycine soja). Our data showed that the target genes shared the levels of nucleotide polymorphism with three reference genes involved in plant-microbe interactions, but possessed a much higher nucleotide polymorphism than other reference genes. Moreover, no significant genetic differentiation was found between cultivated soybean and its wild relatives in three target genes, despite of considering bottleneck and founder effect during domestication. These results indicate that IFS and F3H genes could have experienced gene introgressions or diversifying selection events during domestication process. Especially, F3H2 gene appears to evolve under positive selection and enjoy a faster evolutionary rate than IFS1 and IFS2 genes.


Fruit and vegetable intake and body mass index in a large sample of middle-aged Australian men and women.
Dietary guidelines around the world recommend increased intakes of fruits and non-starchy vegetables for the prevention of chronic diseases and possibly obesity. This study aimed to describe the association between body mass index (BMI) and habitual fruit and vegetable consumption in a large sample of 246,995 Australian adults aged 45 + year who had been recruited for the "45 and Up" cohort study. Fruit and vegetable intake was assessed using validated short questions, while weight and height were self-reported. Multinomial logistic regression was used, by sex, to assess the association between fruit and vegetable intake and BMI. Compared to the referent normal weight category (BMI 18.5 to 24.9), the odds ratio (OR) of being in the highest vegetable intake quartile was 1.09 (95% confidence interval (CI) 1.04-1.14) for overweight women (BMI 25.0-29.9) and 1.18 (95% CI 1.12-1.24) for obese women. The association was in the opposite direction for fruit for overweight (OR 0.85; 95% CI 0.80-0.90) and obese women (OR 0.75; 95% CI 0.69-0.80). Obese and overweight women had higher odds of being in the highest intake quartile for combined fruit and vegetable intake, and were more likely to meet the "2 and 5" target or to have five or more serves of fruit and vegetables per day. In contrast, overweight men were less likely to be in high intake quartiles and less likely to meet recommended target of 5 per day, but there was no consistent relationship between obesity and fruit and vegetable intake. Underweight women and underweight men were less likely to be in the highest intake quartiles or to meet the recommended targets. These data suggest that improving adherence to dietary targets for fruit and vegetables may be a dietary strategy to overcome overweight among men, but that overweight and obese women are already adhering to these targets. The association between fruit and vegetable intake and underweight in adults suggests that improving fruit and vegetables intakes are important for the overall dietary patterns of people in this group.


A systematic review of the use of health services by immigrants and native populations.
Changes in migration patterns that have occurred in recent decades, both quantitative, with an increase in the number of immigrants, and qualitative, due to different causes of migration (work, family reunification, asylum seekers and refugees) require constant u pdating of the analysis of how immigrants access health services. Understanding of the existence of changes in use patterns is necessary to adapt health services to the new socio-demographic reality. The aim of this study is to describe the scientific evidence that assess the differences in the use of health services between immigrant and native populations. A systematic review of the electronic database MEDLINE (PubMed) was conducted with a search of studies published between June 2013 and February 2016 that addressed the use of health services and compared immigrants with native populations. MeSH terms and key words comprised Health Services Needs and Demands/Accessibility/Disparities/Emigrants and Immigrants/Native/Ethnic Groups. The electronic search was supplemented by a manual search of grey literature. The following information was extracted from each publication: context of the study (place and year), characteristics of the included population (definition of immigrants and their sub-groups), methodological domains (design of the study, source of information, statistical analysis, variables of health care use assessed, measures of need, socio-economic indicators) and main results. Thirty-six publications were included, 28 from Europe and 8 from other countries. Twenty-four papers analysed the use of primary care, 17 the use of specialist services (including hospitalizations or emergency care), 18 considered several levels of care and 11 assessed mental health services. The characteristics of immigrants included country of origin, legal status, reasons for migration, length of stay, different generations and socio-demographic variables and need. In general, use of health services by the immigrants was less than or equal to the native population, although some differences between immigrants were also identified. This review has identified that immigrants show a general tendency towards a lower use of health services than native populations and that there are significant differences within immigrant sub-groups in terms of their patterns of utilization. Further studies should include information categorizing and evaluating the diversity within the immigrant population.


Can different types of anxiety states be differentiated electrodermally?
Increased electrodermal spontaneous fluctuation and decreased skin conductance OR recovery time were related to short duration increases in test anxiety. These electrodermal indices were unrelated to long-term worry associated with an impending stressful event. Amplitudes of responses were not related to short-term (or test) anxiety. Amplitude of the startle response was found to increase over a period of one week, as anxiety provoking events approached, where the subjects were in a position of helplessness. However, when an effective coping was subjectively perceived, 'startle response' appeared to be 'inhibited' to a significant degree. Amplitude of startle response may be a useful index for monitoring subjective 'worry' versus 'coping'.


Inhibition of notch1-dependent cardiomyogenesis leads to a dilated myopathy in the neonatal heart.
Physiological hypertrophy in the developing heart has been considered the product of an increase in volume of preexisting fetal cardiomyocytes in the absence of myocyte formation. In this study, we tested whether the mouse heart at birth has a pool of cardiac stem cells (CSCs) that differentiate into myocytes contributing to the postnatal expansion of the parenchymal cell compartment. We have found that the newborn heart contains a population of c-kit-positive CSCs that are lineage negative, self-renewing, and multipotent. CSCs express the Notch1 receptor and show the nuclear localization of its active fragment, N1ICD. In 60% of cases, N1ICD was coupled with the presence of Nkx2.5, indicating that the commitment of CSCs to the myocyte lineage is regulated by Notch1. Importantly, overexpression of N1ICD in neonatal CSCs significantly expanded the proportion of transit-amplifying myocytes. To establish whether these in vitro findings had a functional counterpart in vivo, the Notch pathway was blocked in newborn mice by administration of a gamma-secretase inhibitor. This intervention resulted in the development of a dilated myopathy and high mortality rates. Ventricular decompensation was characterized by a 62% reduction in amplifying myocytes, which resulted in a 54% decrease in myocyte number. After cessation of Notch blockade and recovery of myocyte regeneration, cardiac anatomy and function were largely restored. Notch1 signaling is a critical determinant of CSC growth and differentiation; when this cascade of events is altered, cardiomyogenesis is impaired, physiological cardiac hypertrophy is prevented, and a life-threatening myopathy supervenes.


Bay region distortions in cyclopenta[a]phenanthrenes.
Two newly synthesized cyclopenta[a]phenanthrenes, namely the 1-methyl (VIII) and 7,11-dimethyl (VII) derivatives of the parent ketone 15,16-dihydrocyclopenta[a]phenanthren-17-one (I), have been tested for their capacity to produce skin tumors in mice. The former (VIII) is essentially inactive, whereas the latter (VII) is very potent in both repeated application and two-stage tests. X-ray crystallographic structure analyses have been carried out on seven derivatives of (I), namely its 11-methyl (II), 11,12-dimethyl (III), 11-methoxy (V), 11-ethyl (VI) and 7,11-dimethyl (VII) analogues (carcinogens), the 1-methyl derivative (VIII), and 11,12,15,16-tetrahydro-11-methyl-17-oxocyclopenta[a]phenanthrene (IV) (both non-carcinogens). The detailed molecular structures resulting from these studies have shown the effects of steric interactions and substitutions on the bay-region geometry. The methyl group on C(11) causes distortions of the molecule in the bay region. Out-of-plane distortions in the bay regions of the 11-methyl derivatives (II, III, VII) are greater than for the 11-methoxy or the 11-ethyl derivatives (V, VI). Molecules (except for III and IV) are packed in the crystals with interactions that include C = O...H interactions; this packing is in layers that are nearly parallel to each other. A hydrogen atom of the 11-methyl group appears, from computer modeling, to interact sterically with the hydrogen atom of the bay-region expoxide group in the activated diol-epoxide; this steric interaction may force one conformer of the diol-epoxide to be the predominant form, thereby accounting for the importance of a bay-region methyl group. Further computer modeling has been used to analyze possible modes of interaction of the diol-epoxides of cyclopenta[a]phenanthrenes with DNA.


Relationship of serum novel adipokine chemerin levels with body composition, insulin resistance, dyslipidemia and diabesity in Saudi women.
Chemerin is believed to be a mediator for the adipose tissue inflammation that occurs in obesity. The present study compared chemerin levels between healthy and type 2 diabetic women matched for age and body composition. We also aimed to assess the relationship of serum chemerin levels with body composition, insulin resistance, dyslipidemia, and diabesity. This observational case-control study was conducted at the Departments of Physiology and Medicine, Saud University Riyadh, Saudi Arabia, from September 2013 to April 2014. A total of 100 subjects were recruited, including 51 adult diabetic females, and a control group consisting of 49 healthy females. Finally, 80 subjects were selected as per inclusion criteria. In the finally selected group, 45 of were type 2 diabetics and 35 were healthy subjects matched for age, body mass index (BMI) and body composition with age ranging between 30-65 years. Body composition analysis was estimated using bioelectrical impendence analyzer. Fasting venous blood samples were analyzed for glycemic markers, lipids, and chemerin. Insulin resistance and sensitivity indices were calculated by HOMA-IR and QUICKI using standard formulas. The two groups were matched for age, BMI, body fat percentage (BF%), basal metabolic rate (BMR), truncal fat and waist hip ratio (WHR). Serum chemerin levels were higher in diabetics than controls (p=0.001). Systolic blood pressure, weight, fat mass and visceral fat were found to be significantly higher in diabetics when compared to controls. Fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), low-density lipoprotein (LDL), triglycerides (TG), insulin and HOMA-IR were significantly higher in diabetics compared to controls. While QUICKI and HDL were significantly lower in diabetics compared to controls. Chemerin levels correlated positively with age (r=0.300, p=0.007), waist hip ratio (r=0.250, p=0.026), weight (r=0.270, p=0.016), BMI (r=0.334, p=0.003), BF% (r=0.325, p=0.003), fat mass (r=0.250, p=0.026), visceral fat (r=0.356, p=0.001), truncal fat mass (r=0.245, p=0.030), truncal fat % (r=0.249, p=0.027), serum basal insulin levels (r=0.354, p=0.001) and HOMA IR (0.275, p=0.015), while it correlated inversely with QUICKI (r=-0.283*, p=0.012). In multiple linear regression analysis age (r=0.236, p=0.023), BF% (r=0.265, p=0.014) and basal insulin levels (r=0.265, p=0.014) were independent predictors of chemerin. Serum chemerin levels are elevated in patients with type 2 DM compared to healthy control subjects and are positively correlated with adiposity and Insulin resistance in patients with type 2 DM.


Phenanthriplatin Acts As a Covalent Poison of Topoisomerase II Cleavage Complexes.
Drugs capable of trapping topoisomerase II (Top2), an essential enzyme that cleaves DNA to remove naturally occurring knots and tangles, can serve as potent anticancer agents. The monofunctional platinum agent phenanthriplatin, cis-[Pt(NH3)2(phenanthridine)Cl](NO3), is shown here to trap Top2 in addition to its known modes of inhibition of DNA and RNA polymerases. Its potency therefore combines diverse modes of action by which phenanthriplatin kills cancer cells. The observation that phenanthriplatin can act as a Top2 poison highlights opportunities to design nonclassical platinum anticancer agents with this novel mechanism of action. Such complexes have the potential to overcome current limitations with chemotherapy, such as resistance, and to provide treatment options for cancers that do not respond well to classical agents. Covalent DNA-platinum lesions implicated in Top2 poisoning are distinctive from those generated by known therapeutic topoisomerase poisons, which typically exert their action by reversible binding at the interface of Top2-DNA cleavage complexes.


Advancing the accuracy of SARS-CoV-2 phosphorylation site detection via meta-learning approach.
The worldwide appearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has generated significant concern and posed a considerable challenge to global health. Phosphorylation is a common post-translational modification that affects many vital cellular functions and is closely associated with SARS-CoV-2 infection. Precise identification of phosphorylation sites could provide more in-depth insight into the processes underlying SARS-CoV-2 infection and help alleviate the continuing COVID-19 crisis. Currently, available computational tools for predicting these sites lack accuracy and effectiveness. In this study, we designed an innovative meta-learning model, Meta-Learning for Serine/Threonine Phosphorylation (MeL-STPhos), to precisely identify protein phosphorylation sites. We initially performed a comprehensive assessment of 29 unique sequence-derived features, establishing prediction models for each using 14 renowned machine learning methods, ranging from traditional classifiers to advanced deep learning algorithms. We then selected the most effective model for each feature by integrating the predicted values. Rigorous feature selection strategies were employed to identify the optimal base models and classifier(s) for each cell-specific dataset. To the best of our knowledge, this is the first study to report two cell-specific models and a generic model for phosphorylation site prediction by utilizing an extensive range of sequence-derived features and machine learning algorithms. Extensive cross-validation and independent testing revealed that MeL-STPhos surpasses existing state-of-the-art tools for phosphorylation site prediction. We also developed a publicly accessible platform at https://balalab-skku.org/MeL-STPhos. We believe that MeL-STPhos will serve as a valuable tool for accelerating the discovery of serine/threonine phosphorylation sites and elucidating their role in post-translational regulation.


Multiple origins of human neocortical interneurons are supported by distinct expression of transcription factors.
Cortical γ-aminobutyric acid (GABA)ergic interneurons in rodents originate mainly in ventrally positioned ganglionic eminences (GEs), but their origin in primates is still debated. We studied human fetal forebrains during the first half of gestation (5-23 gestational weeks, gw) for the expression of ventral transcription factors, Nkx2.1, Dlx1,2, Lhx6, and Mash1, important for development of neocortical interneurons. In embryonic (5-8 gw) human forebrain, these factors were expressed in the GE but also dorsally in the neocortical ventricular/subventricular zones (VZ/SVZ). Furthermore, their expression was retained in cells of all fetal cortical layers up to midgestation (20 gw). Nkx2.1 continued to be expressed not only in the GE but also in a subpopulation of neocortical interneurons. Moreover, proliferation marker Ki67 revealed that calretinin(+), Mash1(+), and Nkx2.1(+) cells proliferate in the neocortical VZ/SVZ at midgestation. At least some of the Mash1(+) progenitors in the neocortical SVZ could be colabeled with GABA, whereas others were oligodendrocyte progenitors, indicating a link between the 2 lineages. Taken together, these results suggest the existence of several categories of dorsal interneuronal progenitors in the human neocortical VZ/SVZ, in addition to ventrally derived cortical interneurons described in rodents. These human-specific developmental events may underlie human brain's higher complexity and capacity to process information.


Knowledge about the probability of change affects change detection performance.
The visual system continually selects some information for processing while bypassing the processing of other information, and as a consequence, participants often fail to notice large changes to visual stimuli. In the present studies, the authors investigated whether knowledge about the probability of particular changes occurring over time increased the likelihood that changes that were likely to occur in the real world (probable changes) would be detected. The results of two experiments showed that participants were more likely to detect probable changes. This occurred whether or not they were processing the scene in a meaningful manner or actively searching the scene for changes. Furthermore, participants were unable to accurately predict change detection performance for probable and improbable changes.


Isoprene emission protects photosynthesis but reduces plant productivity during drought in transgenic tobacco (Nicotiana tabacum) plants.
Isoprene protects the photosynthetic apparatus of isoprene-emitting plants from oxidative stress. The role of isoprene in the response of plants to drought is less clear. Water was withheld from transgenic isoprene-emitting and non-emitting tobacco (Nicotiana tabacum) plants, to examine: the response of isoprene emission to plant water deficit; a possible relationship between concentrations of the drought-induced phytohormone abscisic acid (ABA) and isoprene; and whether isoprene affected foliar reactive oxygen species (ROS) and lipid peroxidation levels. Isoprene emission did not affect whole-plant water use, foliar ABA concentration or leaf water potential under water deficit. Compared with well-watered controls, droughted non-emitting plants significantly increased ROS content (31-46%) and lipid peroxidation (30-47%), concomitant with decreased operating and maximum efficiencies of photosystem II photochemistry and lower leaf and whole-plant water use efficiency (WUE). Droughted isoprene-emitting plants showed no increase in ROS content or lipid peroxidation relative to well-watered controls, despite isoprene emission decreasing before leaf wilting. Although isoprene emission protected the photosynthetic apparatus and enhanced leaf and whole-plant WUE, non-emitting plants had 8-24% more biomass under drought, implying that isoprene emission incurred a yield penalty.


Propargylamine Amino Acids as Constrained Nε-Substituted Lysine Mimetics.
Herein, alkylated propargylamines are reported as constrained lysine mimetics and constructed in a single step using a copper(I)-catalyzed A3-coupling reaction. Using multiple secondary amines, the reaction allowed the generation of a structurally diverse set of N-Fmoc protected amino acid derivatives. In addition, the A3-reaction was applied on solid phase via the assembly of short model tripeptides. Moreover, the internal alkyne moiety allowed further functionalization toward novel 1,4,5-trisubstituted 1,2,3-triazole-based amino acids.


In situ techniques in biomimetic mineralization studies of calcium carbonate.
The often astonishing material properties of crystalline biominerals are generally related to the hierarchical assembly of specifically interacting organic and inorganic components. To synthesize new materials with similar advanced properties applying nature's biomimeralization strategies we need to unravel the mechanisms of biologically and biomimetically controlled mineral formation. Since the literature is extensive this tutorial review is focussed on CaCO(3), the most abundant biomineral. We will first review the different approaches to biomimetic mineralization and describe the most recent advancements in the field. Subsequently the importance of in situ and time-resolved experiments, with their possibilities and limitations, is discussed with selected references.


A scientific review: the role of chromium in insulin resistance.
Chromium is an essential mineral that appears to have a beneficial role in the regulation of insulin action and its effects on carbohydrate, protein and lipid metabolism. Chromium is an important factor for enhancing insulin activity. Studies show that people with type 2 diabetes have lower blood levels of chromium than those without the disease. Insulin resistance is the common denominator in a cluster of cardiovascular disease risk factors. One out of every five Americans has metabolic syndrome. It affects 40% of people in their 60s and 70s. Insulin resistance, with or without the presence of metabolic syndrome, significantly increases the risk of cardiovascular disease. Insulin resistance is present in two serious health problems in women; polycystic ovarian syndrome (PCOS) and gestational diabetes. Several studies have now demonstrated that chromium supplements enhance the metabolic action of insulin and lower some of the risk factors for cardiovascular disease, particularly in overweight individuals. Chromium picolinate, specifically, has been shown to reduce insulin resistance and to help reduce the risk of cardiovascular disease and type 2 diabetes. Dietary chromium is poorly absorbed. Chromium levels decrease with age. Supplements containing 200-1,000 mcg chromium as chromium picolinate a day have been found to improve blood glucose control. Chromium picolinate is the most efficacious form of chromium supplementation. Numerous animal studies and human clinical trials have demonstrated that chromium picolinate supplements are safe.


Occupancy of Dopamine D3 and D2 Receptors by Buspirone: A [11C]-(+)-PHNO PET Study in Humans.
There is considerable interest in blocking the dopamine D3 receptor (DRD3) versus the D2 receptor (DRD2) to treat drug addiction. However, there are currently no selective DRD3 antagonists available in the clinic. The anxiolytic drug buspirone has been proposed as a potential strategy as findings suggest that this drug has high in vitro affinity for DRD3, binds to DRD3 in brain of living non-human primate, and also disrupts psychostimulant self-administration in preclinical models. No study has explored the occupancy of DRD3 by buspirone in humans. Here, we used positron emission tomography (PET) and the D3-preferring probe, [(11)C]-(+)-PHNO, to test the hypothesis that buspirone will occupy (decreases [(11)C]-(+)-PHNO binding) the DRD3 more readily than the DRD2. Eight healthy participants underwent [(11)C]-(+)-PHNO scans after single oral dose administration of placebo and 30, 60, and 120 mg of buspirone in a single-blind within-subjects design. [(11)C]-(+)-PHNO binding in DRD2- and DRD3-rich areas was decreased by the highest (60-120 mg), but not the lowest (30 mg), doses of buspirone. The maximal occupancy obtained was ~25% in both areas. Plasma levels of prolactin (a DRD2 marker) correlated with percentage occupancy after orally administered buspirone. Self-reported dizziness and drowsiness increased after buspirone but that did not correlate with receptor occupancy in any region. Overall, the modest occupancy of DRD2 and DRD3 even at high acute doses of buspirone, yielding high levels of metabolites, suggests that buspirone may not be a good drug to preferentially block DRD3 in humans.


Amniotic fluid glucose concentration as a marker for intra-amniotic infection.
This study evaluated the use of amniotic fluid (AF) glucose concentration as a rapid indicator of intra-amniotic infection. Amniotic fluid glucose concentrations were measured in 86 pregnancies and compared with AF cultures. There were 14 positive cultures with a mean AF glucose of 7.1 mg/dL (range 1-24) and 72 negative cultures with a mean AF glucose of 30.4 mg/dL (range 5-66), a significant difference (P less than .001). An AF glucose of less than or equal to 5 mg/dL had a positive predictive value of 90%; an AF glucose of greater than 20 mg/dL had a 98% negative predictive value. Amniotic fluid glucose can be obtained rapidly and inexpensively, and may be of use in the diagnosis of intra-amniotic infection.


Picture archiving and communication system design issues: the importance of modelling and simulation.
Picture archiving communication system (PACS) development turns out to be very complex. Due to both the vast amount of data and the complexity of hospital organizations, currently only small-scale systems have been realized. And although the experiences obtained with these systems are essential, there is a risk for underestimating the complexity and requirements inherent in hospital-wide PACS systems. In this paper, it is advocated that modelling and simulation be used as tools to obtain insight into the behavior and structure of future PACS systems. Modelling and simulation can also be used to actively support the design of PACS, especially its software. In order to capture the full complexity of PACS in a simulation model, and to take full advantage of simulation as a design tool, the development of a new modelling method has begun. This method is based on semantic data models and decision processes, and can be used for both system analysis and design. The first systems modelled with this method were imaging procedures in a hospital and a computer network. The resulting simulation models are a direct reflection of reality, and have a high degree of modularity. Consequently, in spite of the complexity of the systems, their models are easy to understand and maintain.


Non-allergic nature of docetaxel-induced acute hypersensitivity reactions.
Based on observations of a discrepancy between 'hypersensitivity' reactions to docetaxel (DT) and the clinical features of allergic reactions, we explored the hypothesis that DT-induced acute hypersensitivity reactions (AHRs) have a non-allergic origin. Forty cancer patients receiving DT and 16 patients receiving other potentially allergenic chemotherapeutic agents were included in the study. All DT patients received standard pre- and post-medication. Before, during and after administration of the drugs, clinical symptoms and signs were recorded, and serial blood sampling was performed for the first 2 cycles for all patients or in all subsequent cycles in case of AHRs. Plasma histamine and serum tryptase, two established drug allergy markers, were measured. Seventy-five chemotherapy sessions were evaluable. Nine patients on DT, two on paclitaxel (PT) and one on pegylated doxorubicin experienced an AHR during the first course of chemotherapy. In all cases, heart rate remained stable or increased, while arterial pressure was unchanged or raised; no hypotension or bradycardia was noted. All episodes resolved with discontinuation of drug and did not reappear during a re-challenge with the same agent 30 min later. Tryptase levels were normal in all pre- and post-exposure samples (post-exposure: 11.32+/-35.63 microg/l, normal values <13.5 microg/l). In all but one AHR-free PT, pre- and post-exposure histamine concentrations remained normal (post-exposure: 2.86+/-11.88 nM, normal values <10 nM). No eosinophilia or basophilia was observed. We conclude that 'hypersensitivity' reactions to DT seem not to be histamine or tryptase mediated; thus, their allergenic nature should be questioned. The underlying mechanism may be related to other biological processes such as the release of vasoactive molecules or non-histamine/tryptase-mediated allergy. If the former is demonstrated by further study, the safety of DT administration will be confirmed, and the pre- and post-medication practice might be revisited.


The influence of a central stimulus on visual field measurements in children from 3.5 to 30 months of age.
To provide normative data on the effect of a central competing stimulus on monocular visual field extent in 3.5- to 9-month-olds and adults, and binocular visual field extent in 11- to 30-month-olds. Visual field extent along diagonal meridia was measured in 180 infants and children (N = 30 at 3.5, 7, 9, 11, 17, and 30 months) and 20 adults, using static perimetry. Stimuli were 3-deg, 10-Hz flickering, yellow light-emitting diodes (LEDs). Each subject was tested with 12 trials in which the central stimulus remained on and 12 trials in which the central stimulus was turned off during presentation of the peripheral stimulus. A competing stimulus produced a decreased frequency of eye movements at 17 months and evidence suggestive of decreased measured field extent at 17 and 30 months. A continuously present central stimulus does not produce underestimation of visual field extent in 3.5- to 9-month-old infants with normal vision and adults tested monocularly and 11-month-old infants tested binocularly. However, visual field extent may be underestimated in 1- and 2-year-olds if a competing central stimulus is used.


Anti-inflammatory therapies for acute respiratory distress syndrome.
Treatments for the acute respiratory distress syndrome (ARDS) are mainly supportive, and ventilatory management represents a key approach in these patients. Despite progress in pharmacotherapy, anti-inflammatory strategies for the treatment of ARDS have shown controversial results. Positive outcomes with pharmacologic and nonpharmacologic treatments have been found in two different biological subphenotypes of ARDS, suggesting that, with a personalized medicine approach, pharmacotherapy for ARDS can be effective. This article reviews the literature concerning anti-inflammatory therapies for ARDS, focusing on pharmacological and stem-cell therapies, including extracellular vesicles. Despite advances, ARDS treatments remain primarily supportive. Ventilatory and fluid management are important strategies in these patients that have demonstrated significant impacts on outcome. Anti-inflammatory drugs have shown some benefits, primarily in preclinical research and in specific clinical scenarios, but no recommendations are available from guidelines to support their use in patients with ARDS, except in particular settings such as different subphenotypes, specific etiologies, or clinical trials. Personalized medicine seems promising insofar as it may identify specific subgroups of patients with ARDS who may benefit from anti-inflammatory treatment. However, additional efforts are needed to move subphenotype characterization from bench to bedside.


Monitoring of immunoglobulin levels identifies kidney transplant recipients at high risk of infection.
We aimed to analyze the incidence, risk factors and impact of hypogammaglobulinemia (HGG) in 226 kidney transplant (KT) recipients in which serum immunoglobulin (Ig) levels were prospectively assessed at baseline, month 1 (T(1) ), and month 6 (T(6) ). The prevalence of IgG HGG increased from 6.6% (baseline) to 52.0% (T(1) ) and subsequently decreased to 31.4% (T(6) ) (p < 0.001). The presence of IgG HGG at baseline (odds ratio [OR] 26.9; p = 0.012) and a positive anti-HCV status (OR 0.17; p = 0.023) emerged as risk factors for the occurrence of posttransplant IgG HGG. Patients with HGG of any class at T(1) had higher incidences of overall (p = 0.018) and bacterial infection (p = 0.004), bacteremia (p = 0.054) and acute pyelonephritis (p = 0.003) in the intermediate period (months 1-6). Patients with HGG at T(6) had higher incidences of overall (p = 0.004) and bacterial infection (p < 0.001) in the late period (>6 month). A complementary log-log model identified posttransplant HGG as an independent risk factor for overall (hazard ratio [HR] 2.03; p < 0.001) and bacterial infection (HR 2.68; p < 0.0001). Monitoring of humoral immunity identifies KT recipients at high risk of infection, offering the opportunity for preemptive immunoglobulin replacement therapy.


In the spine or in the brain? Recent advances in pain neuroscience applied in the intervention for low back pain.
Conservative, surgical and pharmacological strategies for chronic low back pain (CLBP) management offer at best modest effect sizes in reducing pain and related disability, indicating a need for improvement. Such improvement may be derived from applying contemporary pain neuroscience to the management of CLBP. Current interventions for people with CLBP are often based entirely on a "biomedical" or "psychological" model without consideration of information concerning underlying pain mechanisms and contemporary pain neuroscience. Here we update readers with our current understanding of pain in people with CLBP, showing that CLBP is not limited to spinal impairments, but is also characterised by brain changes, including functional connectivity reorganisation in several brain regions and increased activation in brain regions of the so-called 'pain matrix' (or 'pain connectome'). Indeed, in a subgroup of the CLBP population brain changes associated with the presence of central sensitisation are seen. Understanding the role of these brain changes in CLBP improves our understanding not only of pain symptoms, but also of prevalent CLBP associated comorbidities such as sleep disturbances and fear avoidance behaviour. Applying contemporary pain neuroscience to improve care for people with CLBP includes identifying relevant pain mechanisms to steer intervention, addressing sleep problems and optimising exercise and activity interventions. This approach includes cognitively preparing patients for exercise therapy using (therapeutic) pain neuroscience education, followed by cognition-targeted functional exercise therapy.


Raloxifene improves vascular reactivity in pressurized septal coronary arteries of ovariectomized hamsters fed cholesterol diet.
Although vascular effects of selective estrogen receptor modulators (SERMs) have been extensively examined in conduit arteries, whether SERMs could favorably modulate myogenic response in resistance arteries is unknown. The impact of raloxifene therapy and cholesterol diet on myogenic constriction during estrogen deficiency is unresolved. This study investigated changes in vascular reactivity and myogenic responses in female ovariectomized (Ovx) hamsters fed high-cholesterol diet (HCD) with and without chronic treatment of raloxifene. Functional studies were performed on hamster septal coronary arteries cannulated in a pressure myograph. Acetylcholine (ACh)-induced dilatation was reduced in arteries from cholesterol-fed Ovx hamsters, but not in those from cholesterol-fed hamsters, while pressure-induced myogenic constriction was unaffected. Chronic treatment with raloxifene restored ACh-induced dilatation in cholesterol-fed Ovx hamsters. U46619-induced constriction was increased in arteries from cholesterol-fed Ovx hamsters but not from cholesterol-fed control hamsters, which was normalized by chronic raloxifene treatment. The pressure-diameter relationship is presented as normalized diameter versus intraluminal pressure, while the effect of ACh or U46619 is expressed as percentage of tone at 80 mm Hg. Two-way analysis of variance (ANOVA) followed by Bonferroni post-tests were used for statistical evaluation among different treatment groups. P<0.05 was taken as statistically significant. The present results show that chronic treatment with raloxifene could benefit myogenically active coronary arteries by (i) restoring ACh-induced dilatation and (ii) reducing U46619-induced constriction without affecting pressure-induced myogenic responses in cholesterol-fed hamsters during estrogen deficiency. If such benefit can be observed in humans, raloxifene and other SERMs may be useful to preserve endothelial function and curtail vascular hypersensitivity in resistance coronary arteries in post-menopausal women with hypercholesterolemia or hyperlipidemia, a lipid condition implicated in the pathogenesis of myocardial infarction.


[Nature of riboflavin precursors in Pichia guilliermondi yeasts].
Thirty-nine riboflavin-deficient mutants have been isolated from three yeast strains of Pichia guilliermondii (ATSS 9058, VKM Y-1256, VKM Y-1257) and F5-121 mutant which is capable of production of large amounts of riboflavin in the presence of iron in the medium. All mutants were divided into five groups according to the nature of precursors accumulated in the medium and growth reaction in media with 6,7-dimethyl-8-ribityllumasine and diacetyl. The mutants of the first group did not accumulate specific precursors of riboflavin either in the cells or in the medium. The mutants of the second, third and fourth groups accumulated, after the incubation with diacetyl, 2-amino-4-hydroxy-6,7-dimethylpteridine, 2-amino-4-hydroxy-6,7-dimethyl-8-ribitylpteridine and 6,7-dimethyl-8-ribityllumasine; therefore, they synthesized the following precursors of riboflavin: 2,4,5-triamino-6-hydroxy-pyrimidine, 2,5-diamino-6-hydroxy-4-ribitylaminopyrimidine and 2,6-dihydroxy-5-amino-4-ribitylaminopyrimidine. The mutants of the fifth group accumulated 6,7-dimethyl-8-ribityllumasine in the medium and lacked riboflavin synthetase activity, as was confirmed by enzymatic studies.


Predicting the effectiveness of the online clinical clerkship curriculum: Development of a multivariate prediction model and validation study.
Given scientific and technological advancements, expectations of online medical education are increasing. However, there is no way to predict the effectiveness of online clinical clerkship curricula. To develop a prediction model, we conducted cross-sectional national surveys in Japan. Social media surveys were conducted among medical students in Japan during the periods May-June 2020 and February-March 2021. We used the former for the derivation dataset and the latter for the validation dataset. We asked students questions in three areas: 1) opportunities to learn from each educational approach (lectures, medical quizzes, assignments, oral presentations, observation of physicians' practice, clinical skills practice, participation in interprofessional meetings, and interactive discussions with physicians) in online clinical clerkships compared to face-to-face, 2) frequency of technical problems on online platforms, and 3) satisfaction and motivation as outcome measurements. We developed a scoring system based on a multivariate prediction model for satisfaction and motivation in a cross-sectional study of 1,671 medical students during the period May-June 2020. We externally validated this scoring with a cross-sectional study of 106 medical students during February-March 2021 and assessed its predictive performance. The final prediction models in the derivation dataset included eight variables (frequency of lectures, medical quizzes, oral presentations, observation of physicians' practice, clinical skills practice, participation in interprofessional meetings, interactive discussions with physicians, and technical problems). We applied the prediction models created using the derivation dataset to a validation dataset. The prediction performance values, based on the area under the receiver operating characteristic curve, were 0.69 for satisfaction (sensitivity, 0.50; specificity, 0.89) and 0.75 for motivation (sensitivity, 0.71; specificity, 0.85). We developed a prediction model for the effectiveness of the online clinical clerkship curriculum, based on students' satisfaction and motivation. Our model will accurately predict and improve the online clinical clerkship curriculum effectiveness.


Insights on the mechanisms of Ca(2+) regulation of connexin26 hemichannels revealed by human pathogenic mutations (D50N/Y).
Because of the large size and modest selectivity of the connexin hemichannel aqueous pore, hemichannel opening must be highly regulated to maintain cell viability. At normal resting potentials, this regulation is achieved predominantly by the physiological extracellular Ca(2+) concentration, which drastically reduces hemichannel activity. Here, we characterize the Ca(2+) regulation of channels formed by wild-type human connexin26 (hCx26) and its human mutations, D50N/Y, that cause aberrant hemichannel opening and result in deafness and skin disorders. We found that in hCx26 wild-type channels, deactivation kinetics are accelerated as a function of Ca(2+) concentration, indicating that Ca(2+) facilitates transition to, and stabilizes, the closed state of the hemichannels. The D50N/Y mutant hemichannels show lower apparent affinities for Ca(2+)-induced closing than wild-type channels and have more rapid deactivation kinetics, which are Ca(2+) insensitive. These results suggest that D50 plays a role in (a) stabilizing the open state in the absence of Ca(2+), and (b) facilitating closing and stabilization of the closed state in the presence of Ca(2+). To explore the role of a negatively charged residue at position 50 in regulation by Ca(2+), this position was substituted with a cysteine residue, which was then modified with a negatively charged methanethiosulfonate reagent, sodium (2-sulfanoethyl) methanethiosulfonate (MTSES)(-). D50C mutant hemichannels display properties similar to those of D50N/Y mutants. Recovery of the negative charge with chemical modification by MTSES(-) restores the wild-type Ca(2+) regulation of the channels. These results confirm the essential role of a negative charge at position 50 for Ca(2+) regulation. Additionally, charge-swapping mutagenesis studies suggest involvement of a salt bridge interaction between D50 and K61 in the adjacent connexin subunit in stabilizing the open state in low extracellular Ca(2+). Mutant cycle analysis supports a Ca(2+)-sensitive interaction between these two residues in the open state of the channel. We propose that disruption of this interaction by extracellular Ca(2+) destabilizes the open state and facilitates hemichannel closing. Our data provide a mechanistic understanding of how mutations at position 50 that cause human diseases are linked to dysfunction of hemichannel gating by external Ca(2+).


Lung recruitment maneuvers in acute respiratory distress syndrome and facilitating resolution.
To summarize the possible ways that acute respiratory distress syndrome (ARDS) lungs can be recruited and to present the experimental and clinical results of these maneuvers, along with the possible effects on patient outcome. Selected published medical literature from 1972 to 2002 and personal observations. In the experimental setting, repeated derecruitments accentuate lung injury during mechanical ventilation, whereas open lung concept strategies can attenuate lung injury. In the clinical setting, recruitment maneuvers that use a continuous positive airway pressure of 40 cm H(2)O for 40 secs improve oxygenation in patients with early ARDS who do not have an impairment in the chest wall. High intermittent positive end-expiratory pressure (PEEP), intermittent sighs, or high-pressure controlled ventilation improves short-term oxygenation in ARDS patients. Both conventional and electrical impedance thoracic tomography studies indicate that high airway pressures increase the lung volume and recruitment percentage of lung tissue in ARDS patients. To sustain the recruited ARDS lungs, it is important to maintain adequate PEEP levels. High PEEP/low tidal volume ventilation was seen to reduce inflammatory mediators in both bronchoalveolar lavage and plasma, compared with low PEEP/high tidal volume ventilation, after 36 hrs of mechanical ventilation in ARDS patients. Recruitment maneuvers that used continuous positive airway pressure levels of 35-40 cm H(2)O for 40 secs, with PEEP set at 2 cm H(2)O above the Pflex (the lowest inflection point on the pressure-volume curve), and tidal volume <6 mL/kg were associated with a 28-day intensive care unit survival rate of 62%. This contrasted with a survival rate of only 29% with conventional ventilation (defined as the lowest PEEP for acceptable oxygenation without hemodynamic impairment with a tidal volume of 12 mL/kg), without recruitment maneuvers (number needed to treat = 3; p <.001). High airway pressures can open collapsed ARDS lungs and partially open edematous ARDS lungs. High PEEP levels and low tidal volume ventilation decrease bronchoalveolar and plasma inflammatory mediators and improve survival compared with low PEEP/high tidal volume ventilation. In the near future, thoracic computed tomography associated with high-performance monitoring of regional ventilation (electrical impedance tomography) may be used at the bedside to determine the optimal mechanical ventilation of ARDS patients.


MiR-30c/PGC-1β protects against diabetic cardiomyopathy via PPARα.
Metabolic abnormalities have been implicated as a causal event in diabetic cardiomyopathy (DCM). However, the mechanisms underlying cardiac metabolic disorder in DCM were not fully understood. Db/db mice, palmitate treated H9c2 cells and primary neonatal rat cardiomyocytes were employed in the current study. Microarray data analysis revealed that PGC-1β may play an important role in DCM. Downregulation of PGC-1β relieved palmitate induced cardiac metabolism shift to fatty acids use and relevant lipotoxicity in vitro. Bioinformatics coupled with biochemical validation was used to confirm that PGC-1β was one of the direct targets of miR-30c. Remarkably, overexpression of miR-30c by rAAV system improved glucose utilization, reduced excessive reactive oxygen species production and myocardial lipid accumulation, and subsequently attenuated cardiomyocyte apoptosis and cardiac dysfunction in db/db mice. Similar effects were also observed in cultured cells. More importantly, miR-30c overexpression as well as PGC-1β knockdown reduced the transcriptional activity of PPARα, and the effects of miR-30c on PPARα was almost abated by PGC-1β knockdown. Our data demonstrated a protective role of miR-30c in cardiac metabolism in diabetes via targeting PGC-1β, and suggested that modulation of PGC-1β by miR-30c may provide a therapeutic approach for DCM.


2-[(Di-methyl-phenyl-phosphanyl-idene)aza-nium-yl]-5-methyl-benzene-sulfonate benzene monosolvate.
The title compound, C15H18NO3PS·C6H6, is a rare example of a crystallographically characterized exocyclic phosphiniminium-arene-sulfonate zwitterion, which crystallises as its benzene solvate. The crystal structure shows that the N atom is protonated and that the iminium H atom forms both intra- and inter-molecular hydrogen bonds to the single-bonded sulfonate O atom in an R 2 (2)(4) graph-set motif. The dihedral angle between the aromatic rings in the main molecule is 89.49 (8)°.


[Severe treatment-resistant tardive dystonia: is deep brain stimulation a treatment option].
Severe tardive dyskinesia or dystonia (TD) are side-effects of dopamine-blocking agents, most of which are antipsychotics. A small subgroup of patients develop a severe debilitating treatment-resistant form of TD. To assess the effects and side-effects of deep brain stimulation (DBS) in this subgroup of TD patients. We searched PubMed and Embase using the search terms 'tardive' and 'deep brain stimulation'. We found 19 articles containing data referring to 52 patients. Using the Burke Fahn Marsden Dystonia Rating Scale (BFMDRS), the Abnormal Involuntary Movement Scale (AIMS) and the Extrapyramidal Symptoms Rating Scale (ESRS) we calculated the average improvement in the patients' condition. On all the scales the improvement was statistically significant (p < 0.00001), the average improvement being 67% to 78%. In only 4% of the patients was there a deterioration in the psychiatric disorder. DBS seems to be an effective treatment for treatment-resistant TD and the side-effects seem to be limited. However, the evidence is limited because our conclusion is based on case-reports and on small-scale trials without randomisation or blinding.


Some modern aspects of the mode of action of non-steroidal anti-inflammatory drugs.
The modern concepts of the mode of action of non-steroidal anti-inflammatory drugs with reference to the mediators of inflammatory processes are reviewed. It seems likely that prostaglandins (E1 and E2) and the kinin system are closely associated inflammatory mediators which are responsible for maintenance of the signs and symptoms of chronic inflammatory joint disease. It is suggested that the analgesic action of aspirin-like drugs in rheumatoid arthritis is the result not only of blocking production of prostaglandins but also of limiting the increased availability of kinin precursor (kininogen).


Novel index for micromixing characterization and comparative analysis.
The most basic micromixer is a T- or Y-mixer, where two confluent streams mix due to transverse diffusion. To enhance micromixing, various modifications of T-mixers are reported such as heterogeneously charged walls, grooves on the channel base, geometric variations by introducing physical constrictions, etc. The performance of these reported designs is evaluated against the T-mixer in terms of the deviation from perfectly mixed state and mixing length (device length required to achieve perfect mixing). Although many studies have noticed the reduced flow rates for improved mixer designs, the residence time is not taken into consideration for micromixing performance evaluation. In this work, we propose a novel index, based on residence time, for micromixing characterization and comparative analysis. For any given mixer, the proposed index identifies the nondiffusive mixing enhancement with respect to the T-mixer. Various micromixers are evaluated using the proposed index to demonstrate the usefulness of the index. It is also shown that physical constriction mixer types are equivalent to T-mixers. The proposed index is found to be insightful and could be used as a benchmark for comparing different mixing strategies.


Enhancing health care worker ability to detect and care for patients with monkeypox in the Democratic Republic of the Congo.
Monkeypox (MPX) is an endemic disease of public health importance in the Democratic Republic of the Congo (DRC). In 2010, the DRC Ministry of Health joined with external partners to improve MPX surveillance in the Tshuapa Health District of DRC. A pivotal component of the program is training of health zone personnel in surveillance methods and patient care. In this report we evaluate outcomes of the training program. Health care worker knowledge of key concepts in the MPX training curriculum was assessed using an anonymous self-administered survey. Additionally, evaluators collected feedback about the capacity of participants to perform the surveillance tasks. Training impacts were determined by assessing various surveillance performance metrics. Correct trainee responses to questions about MPX symptoms and patient care increased significantly upon completion of training events. During the 12 months after the initial training, the proportion of suspected cases investigated increased significantly (from 6.7 to 37.3%), as compared to the 5 months prior. However, the proportion of reported cases that were ultimately confirmed remained unchanged, 20.1% (5/24) vs 23.3% (60/257). We have demonstrated that the MPX curriculum developed for this initiative was effective in transferring knowledge and was associated with improved detection of human MPX cases.


Whole genome sequencing reveals complex evolution patterns of multidrug-resistant Mycobacterium tuberculosis Beijing strains in patients.
Multidrug-resistant (MDR) Mycobacterium tuberculosis complex (MTBC) strains represent a major threat for tuberculosis (TB) control. Treatment of MDR-TB patients is long and less effective, resulting in a significant number of treatment failures. The development of further resistances leads to extensively drug-resistant (XDR) variants. However, data on the individual reasons for treatment failure, e.g. an induced mutational burst, and on the evolution of bacteria in the patient are only sparsely available. To address this question, we investigated the intra-patient evolution of serial MTBC isolates obtained from three MDR-TB patients undergoing longitudinal treatment, finally leading to XDR-TB. Sequential isolates displayed identical IS6110 fingerprint patterns, suggesting the absence of exogenous re-infection. We utilized whole genome sequencing (WGS) to screen for variations in three isolates from Patient A and four isolates from Patient B and C, respectively. Acquired polymorphisms were subsequently validated in up to 15 serial isolates by Sanger sequencing. We determined eight (Patient A) and nine (Patient B) polymorphisms, which occurred in a stepwise manner during the course of the therapy and were linked to resistance or a potential compensatory mechanism. For both patients, our analysis revealed the long-term co-existence of clonal subpopulations that displayed different drug resistance allele combinations. Out of these, the most resistant clone was fixed in the population. In contrast, baseline and follow-up isolates of Patient C were distinguished each by eleven unique polymorphisms, indicating an exogenous re-infection with an XDR strain not detected by IS6110 RFLP typing. Our study demonstrates that intra-patient microevolution of MDR-MTBC strains under longitudinal treatment is more complex than previously anticipated. However, a mutator phenotype was not detected. The presence of different subpopulations might confound phenotypic and molecular drug resistance tests. Furthermore, high resolution WGS analysis is necessary to accurately detect exogenous re-infection as classical genotyping lacks discriminatory power in high incidence settings.


The complexities of p97 function in health and disease.
p97 is a homohexameric, toroidal machine that harnesses the energy of ATP binding and hydrolysis to effect structural reorganization of a diverse and primarily uncharacterized set of substrate proteins. This action has been linked to endoplasmic reticulum associated degradation (ERAD), homotypic membrane fusion, transcription factor control, cell cycle progression, DNA repair, and post-mitotic spindle disassembly. Exactly how these diverse processes use p97 is not fully understood, but it is clear that binding sites, primarily on the N- and C-domains of p97, facilitate this diversity by coordinating a growing collection of cofactors. These cofactors act at the levels of mechanism, sub-cellular localization, and substrate modification. Another unifying theme is the use of ubiquitylation. Both p97 and many of the associated cofactors have demonstrable ubiquitin-binding competence. The present review will discuss some of the current mechanistic studies and controversies and how these relate to cofactors as well as discussing potential therapeutic targeting of p97.


Predictors of Long-term Major Adverse Cardiac Events Following Percutaneous Coronary Intervention in the Elderly.
We aimed to recognize the predictors of long-term major adverse cardiac events (MACE) in the elderly candidates for elective percutaneous coronary intervention (PCI) at our center. In this retrospective cohort study, we reviewed the data of the elderly (age ≥65 years) candidates for elective PCI who met our study criteria, at Tehran heart center between 2004 and 2013. Demographic, anthropometric, clinical, angiographic, procedural and follow-up data of the enrolled patients were retrieved from the angiography/PCI databank of our center. The study characteristics of the patients with or without MACE were compared in a univariable Cox-regression analysis. A multivariable Cox-regression model was applied using variables selected from the univariable model to determine the predictors of MACE. We reviewed the data of 2772 patients (mean age=70.8±4.7 years, male sex=1726 patients [62.3%]) from which 393 patients (14.4%) developed MACE. In the multivariable regression model, female sex was a protective factor for MACE (hazard ratio [HR]=0.701; P=0.001), while presence of diabetes mellitus (HR=1.333; P=0.007), family history of coronary artery disease (CAD) (HR=1.489; P=0.003) and plain balloon angioplasty (HR=1.810; P=0.010) were independent risk factors for MACE. PCI is a safe and effective method of revascularization in the elderly patients, and some clinical and procedural factors can predict MACE in this group of patients.


Concurrent pityriasis rosea and Bell's palsy.
Pityriasis rosea is a dermatological disease with a well-documented clinical appearance, but less is known about causes and treatment. Bell's palsy is a neurological condition leading to acute idiopathic hemifacial paralysis. Recent studies indicate that human herpesvirus (HHV) 6-7 reactivation may be a contributing factor to both conditions. We report a case of the 2 concurrent diagnoses that supports a common contributing factor and suggests further awareness and research into the role HHV 6-7 may play in the aetiology of both conditions.


Robotic or open radical prostatectomy after previous open surgery in the pelvic region.
We sought to evaluate the feasibility and safety of open or robotic radical prostatectomy (RP) after rectum, sigmoid, or colon surgery. Sixty-four patients with a median age of 65 years (range, 46-73 years) who underwent RP after previous pelvic surgery were included. Twenty-four patients (38%) underwent robotic RP and 40 patients (62%) underwent open RP. Bilateral lymph node dissection and nerve preservation were performed in 50 patients (78%) and 35 patients (55%), respectively. Variables evaluated included demographic characteristics, perioperative complications, and functional and oncological outcomes. The median hospitalization and follow-up periods were 2 days (range, 1-12 days) and 21 months (range, 1-108 months), respectively. No conversions from robotic to open surgery were performed and there were no intraoperative complications. Surgical margins were positive in 13 patients (20%), seminal vesicle involvement was detected in 6 patients (9%), and lymph node involvement was found in 2 patients (3%). Postoperative complications included lymphocele in 1 patient, urethral stricture in 1 patient, and bowel obstruction and persistent bladder leakage in 2 patients. Eighty-eight percent of the patients were continent at 7 months and 80% of patients were able to achieve erection with or without medical aid. Open or robotic RP can be done safely and effectively in patients who have previously undergone pelvic surgery. Although prior pelvic surgery of the large intestine was associated with increased morbidity, it should not be considered a contraindication for robotic or open RP.


Starving the brain: structural abnormalities and cognitive impairment in adolescents with anorexia nervosa.
Anorexia nervosa (AN) is one of the most common chronic illnesses afflicting adolescent girls and is associated severe medical complications. The structural abnormalities found in the brain of adolescents with AN are among the earliest and most striking physical consequences. In the past, it had been assumed that the brain abnormalities found in patients with AN reverse with weight-recovery. Recent evidence has shown that not all of these changes are completely reversible with weight recovery. To date, very little is known about the functional significance of these brain abnormalities. Several studies have shown that cognitive dysfunction is also a common feature of AN. Although current evidence suggests that there may be some degree of improvement in cognition with weight-recovery, it is unclear whether cognition recovers fully or equally across all neuropsychological domains. Furthermore, it remains unknown whether the reported functional consequences are associated with these structural brain changes. This article will review the current literature on structural brain abnormalities and cognitive dysfunction in adolescents with AN.


Perceived school safety is strongly associated with adolescent mental health problems.
School environment is an important determinant of psychosocial function and may also be related to mental health. We therefore investigated whether perceived school safety, a simple measure of this environment, is related to mental health problems. In a population-based sample of 11,130 secondary school students, we analysed the relationship of perceived school safety with mental health problems using multiple logistic regression analyses to adjust for potential confounders. Mental health problems were defined using the clinical cut-off of the self-reported Strengths and Difficulties Questionnaire. School safety showed an exposure-response relationship with mental health problems after adjustment for confounders. Odds ratios increased from 2.48 ("sometimes unsafe") to 8.05 ("very often unsafe"). The association was strongest in girls and young and middle-aged adolescents. Irrespective of the causal background of this association, school safety deserves attention either as a risk factor or as an indicator of mental health problems.


Are competing psychotherapists manageable?
Behavioral health care faces major overhauling. The twin objectives of improved access and greater efficiency require reorganization of the delivery system from a disjointed array of competitors to an integrated continuum of collaborators. Ironically, the motif for achieving such a change is that of competition. This article questions reform through market forces alone and suggests a guided five-step process: guaranteeing the right to necessary care, regionalizing resources under capped budgets, replacing fee-for-service reimbursement with prospective payment, aligning continuing education requirements with performance-defined gaps in knowledge, and funding professional retraining. Shared accountability is proposed as an alternative to the problematic ethic of competition.


A classification of circadian blood pressure profiles using a cumulative chi-square technique.
Non-invasive ambulatory blood pressure monitoring has been used to assess circadian rhythms in blood pressure in a qualitative fashion. However, there are no established methods for assessing circadian changes in blood pressure in a quantitative fashion. In this study, we developed a quantitative method to evaluate the circadian rhythm based on profile analysis and a cumulative chi-square technique. This method was used to analyse the circadian blood pressure variations in 100 normotensive volunteers and 127 hypertensive patients. Three blood pressure profiles were identified for the normotensive group, while four were identified for the hypertensive group. Furthermore, there was a relationship between the discriminate blood pressure profiles and the severity of hypertension. We conclude that profile analysis of 24-h ambulatory blood pressure monitoring may be used to stratify patients with regard to the risk of complications of hypertension.


Correcting in situ chlorophyll fluorescence time-series observations for nonphotochemical quenching and tidal variability reveals nonconservative phytoplankton variability in coastal waters.
Chlorophyll fluorometry is one of the most commonly implemented approaches for estimating phytoplankton biomass in situ, despite documented sources of natural variability and instrumental uncertainty in the relationship between in vivo fluorescence and chlorophyll concentration. A number of strategies are employed to minimize errors and quantify natural variability in this relationship in the open ocean. However, the assumptions underlying these approaches are unsupported in coastal waters due to the short temporal and small spatial scales of variability, as well as the optical complexity. The largest source of variability in the in situ chlorophyll fluorometric signal is nonphotochemical quenching (NPQ). Typically, unquenched nighttime observations are interpolated over the quenched daytime interval, but this assumes a spatial homogeneity not found in tidally impacted coastal waters. Here, we present a model that provides a tidally resolved correction for NPQ in moored chlorophyll fluorescence measurements. The output of the model is a time series of unquenched chlorophyll fluorescence in tidal endmembers (high and low tide extremes), and thus a time series of phytoplankton biomass growth and loss in these endmember populations. Comparison between modeled and measured unquenched time series yields quantification of nonconservative variations in phytoplankton biomass. Tidally modeled interpolation between these endmember time series yields a highly resolved time series of unquenched daytime chlorophyll fluorescence values at the location of the moored sensor. Such data sets provide a critical opportunity for validating the satellite remotely sensed ocean color chlorophyll concentration data product in coastal waters.


Electroclinical features of benign infantile seizures with mild gastroenteritis.
The purpose of this study was to analyze the electroclinical features of patients with benign infantile seizures with mild gastroenteritis and demonstrate the benign nature of this entity. From 30 patients who were included in the study, five were excluded (two with developmental delay, one with microcephaly and two lost during follow-up). Twenty-five patients who fulfilled the diagnostic criteria for benign infantile seizures with mild gastroenteritis were assessed and followed at the Pediatric Department, Armed Forces Hospital, Southern Region, Khamis Mushayt, Saudi Arabia, between January 2004 and January 2009. The median age at presentation was 10.4 months. Of the infants, 14 were females and 11 were males. Seizures were focal tonic or clonic in eight (32%) patients, focal with secondary generalisation in three (12%), generalised tonic-clonic in nine (36%) and consisted of staring only with no motor components in five (20%). Interictal electroencephalograms and brain imaging were normal for all patients. No patient required treatment with antiepileptic drugs. All the patients were found to have normal psychomotor development and neurological examination after a follow-up period of between 15 and 56 months. The limitations of this study are the relatively small sample size, relatively short study period and the fact that the study was conducted in a tertiary referral hospital. The prevalence of this entity may be more common at the level of primary health centres. Increasing the awareness of clinicians regarding the existence of this syndrome and its benign nature in children will limit unnecessary investigations. [Published with video sequences].


Magnetic Resonance Imaging of Idiopathic Intracranial Hypertension: Before and After Treatment.
This study aimed to identify the reversibility of MRI findings indicative of increased intracranial hypertension in idiopathic intracranial hypertension (IIH) patients after treatment. This retrospective, observational study included demographic and clinical data from 10 patients with IIH and 10 controls. Brain MRI findings in IIH patients were recorded twice: once when patients had papilledema and again after resolution of papilledema. Neuroradiologists graded MRI findings in both groups based on an imaging grading scale. After resolution of papilledema, all patients showed improvement in 2 or more of the MRI characteristics of IIH. This was especially the case for the height of the midsagittal pituitary gland and optic nerve sheath thickness (ONST), which were significantly different in all pairwise group comparisons. Sellar configuration, globe configuration, and horizontal orbital optic nerve tortuosity were different between the IIH pre-treatment group and controls, but not between controls and the IIH post-treatment group. We found no difference in optic nerve head hyperintensity or optic nerve thickness among the 3 groups. We demonstrated that several morphometric MRI characteristics in IIH are reversible to a certain extent after treatment. Enlarged subarachnoid spaces filled with cerebrospinal fluid seem to remain reduced, and the ONST and height of the pituitary gland are not fully normalized after treatment.


Comparison method for uranium determination in ore sample by inductively coupled plasma optical emission spectrometry (ICP-OES).
A comparison method for the determination (without sample pre-concentration) of uranium in ore by inductively coupled plasma optical emission spectrometry (ICP-OES) has been performed. The experiments were conducted using three procedures: matrix matching, plasma optimization, and internal standardization for three emission lines of uranium. Three wavelengths of Sm were tested as internal standard for the internal standardization method. The robust conditions were evaluated using applied radiofrequency power, nebulizer argon gas flow rate, and sample uptake flow rate by considering the intensity ratio of the Mg(II) 280.270 nm and Mg(I) 285.213 nm lines. Analytical characterization of method was assessed by limit of detection and relative standard deviation values. The certificated reference soil sample IAEA S-8 was analyzed, and the uranium determination at 367.007 nm with internal standardization using Sm at 359.260 nm has been shown to improve accuracy compared with other methods. The developed method was used for real uranium ore sample analysis.


Cross-border collaboration for neglected tropical disease efforts-Lessons learned from onchocerciasis control and elimination in the Mano River Union (West Africa).
Diseases don't respect borders, so efforts to control and eliminate diseases must also be flexible and adaptable enough to effectively reach the populations that live in the areas around national frontiers. Onchocerciasis, commonly known as river blindness is a tropical disease that has historically affected millions of people in 35 countries in Africa and Latin America. In Africa, programs and partnerships to address river blindness through mass drug administration have been active for more than 25 years. While in many cases the disease is found in isolated foci that fall entirely within national boundaries, the geographic scope of many affected areas crosses country borders. National river blindness programs are the responsibility of each nation's Ministry of Health, so in cross-border situations there is a need for effective country-country collaboration. Cross-border collaboration for onchocerciasis control efforts in the countries of the Mano River Basin illustrates the positive impact of a creative model, and offers lessons for expanded application for onchocerciasis elimination as well as other neglected tropical disease (NTD) control and elimination programs.


Fungal Bioreporters to Monitor Outcomes of Aspergillus: Host-Cell Interactions.
Fluorescence-based techniques enable researchers to monitor physiologic processes, specifically fungal cell viability and death, during cellular encounters with the mammalian immune system with single event resolution. By incorporating two independent fluorescent probes in fungal organisms either prior to, or ensuing experimental infection in mice or in cultured leukocytes, it is possible to distinguish and quantify live and killed fungal cells to interrogate genetic, pharmacologic, and cellular determinants that shape host-fungal cell outcomes. This chapter reviews the techniques and applications of fluorescent fungal reporters of viability, with emphasis on the filamentous mold Aspergillus fumigatus.


Attention to change: A multilevel theory on the process of emergent continuous organizational change.
Increasingly, continuous organizational change is viewed as the new reality for organizations and their members. However, this model of organizational change, which is usually characterized by ongoing, cumulative, and substantive change from the bottom up, remains underexplored in the literature. Taking a multilevel approach, the authors develop a theoretical model to explain the mechanisms behind the amplification and accumulation of valuable, ongoing work-unit level changes over time, which then become substantial changes at the organizational level. Drawing on the concept of emergence, they first focus on the cognitive search mechanisms of work-unit members and managers to illustrate how work-unit level routine changes may be amplified to the organization through 2 unique processes: composition and compilation emergence. The authors then discuss the managers' role in creating a sense of coherence and meaning for the accumulation of these emergent changes over time. They conclude this research by discussing the theoretical implications of their model for the existing literature of organizational change. (PsycINFO Database Record


New Klebsiella oxytoca beta-lactamase genes bla(OXY-3) and bla(OXY-4) and a third genetic group of K oxytoca based on bla(OXY-3).
The two genetic groups (oxy-1 and oxy-2) previously identified in the Klebsiella oxytoca taxon are recognizable by four independent molecular markers: (i). ERIC-1R profiles, (ii). 16S ribosomal DNA (rDNA) signature sequences, (iii). singular nucleotides in a defined fragment of the rpoB gene, and (iv) the type of the strain's bla(OXY) gene (i.e., bla(OXY-1) or bla(OXY-2)). K. oxytoca strains SG266 and SG271 could not be classified into these genetic groups based on their ERIC-1R profile and bla(OXY) gene sequence. With regard to the gene identity percentages between the bla(OXY-1) and bla(OXY-2) gene groups (86.8% +/- 0.4%) and within a bla(OXY) gene group (>99%), it was concluded that the bla(OXY) gene of strain SG271 was representative of a new bla(OXY) gene group (bla(OXY-3)), since the mean identity percentages between it and the two bla(OXY) gene groups were 85.5% +/- 0.2% and 84.4% +/- 0.4%, respectively. Since the corresponding percentages were 95.0% +/- 0.4% and 86.2% +/- 0.3% for strain SG266, it was impossible to classify its bla(OXY) gene, which was therefore named bla(OXY-4). The 16S rDNA signature sequences of the two strains could be determined only after cloning experiments. The SG266 clones displayed the same signature sequence as that of the genetic group oxy-1, whereas the SG271 clones displayed three different 16S rDNA signature sequences that also differed from those of the two genetic groups. Singular nucleotides were found within the rpoB sequence of the two strains, allowing for their distinction from the two genetic groups. All of these results, combined with those previously obtained by the ERIC-1R PCR method, indicate that strain SG271 is representative of a new K. oxytoca genetic group (oxy-3), whereas strain SG266 could not be classified.


Assessing Antimicrobial Resistance, Utilization, and Stewardship in Yemen: An Exploratory Mixed-Methods Study.
Antimicrobial resistance (AMR), largely driven by irrational use of antimicrobials, is a global, multifaceted problem calling for a complete understanding of all contributory factors for effective containment. In conflict settings, war-wounds and malnutrition can combine with existing social determinants to increase demand for antibiotics, compounding irrational use. In this study, we focus on Yemen, a low-income country with active conflict for the last 5 years, and analyze the current status of awareness and stewardship efforts regarding AMR. We performed a survey of prescribers/physicians and pharmacists to describe perceptions of AMR prevalence, antibiotic use practices, and stewardship in Yemen, supported by a nonsystematic scoping literature review and a key informant interview. Participants (96%, N = 54) reported a perceived high AMR prevalence rate. Prescribers (74%, 20/27) reported pressure to prescribe broad-spectrum antibiotics. In the majority of cases (81%, 22/27), antimicrobial sensitivity tests (AST) were not performed to inform antibiotic choice. The main barrier to AST was cost. Most pharmacists (67%, 18/27) sold antibiotics without prescriptions. Amoxicillin (including amoxicillin-clavulanate) was the most-commonly prescribed (63%, 17/27) or dispensed (81%, 22/27) antibiotic. AST was rated the least important solution to AMR in Yemen. While there was awareness of a high AMR rate, stewardship is poor in Yemen. We note that barriers to the use of AST could be addressed through the deployment of reliable, affordable, quality rapid diagnostics, and AST kits. Compulsory continuing education emphasizing the use of AST to guide prescribing and patients' awareness programs could help avoid irrational use.


Assessing the Prevalence and Potential Risks of Salmonella Infection Associated with Fresh Salad Vegetable Consumption in the United Arab Emirates.
This study aimed to investigate the occurrence and characteristics of Salmonella isolates in salad vegetables in the United Arab Emirates (UAE). Out of 400 samples tested from retail, only 1.25% (95% confidence interval, 0.41-2.89) were found to be positive for Salmonella, all of which were from conventional local produce, presented at ambient temperature, and featured as loose items. The five Salmonella-positive samples were arugula (n = 3), dill (n = 1), and spinach (n = 1). The Salmonella isolates from the five samples were found to be pan-susceptible to a panel of 12 antimicrobials tested using a disc diffusion assay. Based on whole-genome sequencing (WGS) analysis, only two antimicrobial resistance genes were detected-one conferring resistance to aminoglycosides (aac(6')-Iaa) and the other to fosfomycin (fosA7). WGS enabled the analysis of virulence determinants of the recovered Salmonella isolates from salad vegetables, revealing a range from 152 to 165 genes, collectively grouped under five categories, including secretion system, fimbrial adherence determinants, macrophage-inducible genes, magnesium uptake, and non-fimbrial adherence determinants. All isolates were found to possess genes associated with the type III secretion system (TTSS), encoded by Salmonella pathogenicity island-1 (SPI-1), but various genes associated with the second type III secretion system (TTSS-2), encoded by SPI-2, were absent in all isolates. Combining the mean prevalence of Salmonella with information regarding consumption in the UAE, an exposure of 0.0131 salmonellae consumed per person per day through transmission via salad vegetables was calculated. This exposure was used as an input in a beta-Poisson dose-response model, which estimated that there would be 10,584 cases of the Salmonella infection annually for the entire UAE population. In conclusion, salad vegetables sold in the UAE are generally safe for consumption regarding Salmonella occurrence, but occasional contamination is possible. The results of this study may be used for the future development of risk-based food safety surveillance systems in the UAE and to elaborate on the importance for producers, retailers, and consumers to follow good hygiene practices, particularly for raw food items such as leafy salad greens.


Recombinant Vaccinia Viruses Coding Transgenes of Apoptosis-Inducing Proteins Enhance Apoptosis But Not Immunogenicity of Infected Tumor Cells.
Genetic modifications of the oncolytic vaccinia virus (VV) improve selective tumor cell infection and death, as well as activation of antitumor immunity. We have engineered a double recombinant VV, coding human GM-CSF, and apoptosis-inducing protein apoptin (VV-GMCSF-Apo) for comparing with the earlier constructed double recombinant VV-GMCSF-Lact, coding another apoptosis-inducing protein, lactaptin, which activated different cell death pathways than apoptin. We showed that both these recombinant VVs more considerably activated a set of critical apoptosis markers in infected cells than the recombinant VV coding GM-CSF alone (VV-GMCSF-dGF): these were phosphatidylserine externalization, caspase-3 and caspase-7 activation, DNA fragmentation, and upregulation of proapoptotic protein BAX. However, only VV-GMCSF-Lact efficiently decreased the mitochondrial membrane potential of infected cancer cells. Investigating immunogenic cell death markers in cancer cells infected with recombinant VVs, we demonstrated that all tested recombinant VVs were efficient in calreticulin and HSP70 externalization, decrease of cellular HMGB1, and ATP secretion. The comparison of antitumor activity against advanced MDA-MB-231 tumor revealed that both recombinants VV-GMCSF-Lact and VV-GMCSF-Apo efficiently delay tumor growth. Our results demonstrate that the composition of GM-CSF and apoptosis-inducing proteins in the VV genome is very efficient tool for specific killing of cancer cells and for activation of antitumor immunity.


All-trans retinoic acid attenuates bleomycin-induced pulmonary fibrosis via downregulating EphA2-EphrinA1 signaling.
The role of all-trans retinoic acid (ATRA) in pulmonary fibrosis is relatively unknown, although this metabolite modulates cell differentiation, proliferation, and development. We aimed to evaluate the role of ATRA in bleomycin-induced pulmonary fibrosis, and whether the mechanism involves EphA2-EphrinA1 and PI3K-Akt signaling. We evaluated three groups of mice: a control group (intraperitoneal DMSO injection 3 times weekly after PBS instillation), bleomycin group (intraperitoneal DMSO injection 3 times weekly after bleomycin instillation), and bleomycin + ATRA group (intraperitoneal ATRA injection 3 times weekly after bleomycin instillation). The cell counts and protein concentration in the bronchoalveolar lavage fluid (BALF), changes in histopathology, Ashcroft score, hydroxyproline assay, expression of several signal pathway proteins including EphA2-EphrinA1, and PI3K-Akt, and cytokine levels were compared among the groups. We found that bleomycin significantly increased the protein concentration in the BALF, Ashcroft score in lung tissue, and hydroxyproline contents in lung lysates. Furthermore, bleomycin upregulated EphA2, EphrinA1, PI3K 110γ, Akt, IL-6 and TNF-α. However, administration of ATRA attenuated the upregulation of EphA2-EphrinA1 and PI3K-Akt after bleomycin instillation, and decreased pulmonary fibrosis. In addition, ATRA suppressed IL-6 and TNF-α production induced by bleomycin-induced injury. Collectively, these data suggest that ATRA attenuates bleomycin-induced pulmonary fibrosis by regulating EphA2-EphrinA1 and PI3K-Akt signaling.


Psychoneuroendocrine stress responses and mood as related to the menstrual cycle.
Psychoneuroendocrine stress responses were studied in normally ovulating women in the follicular, ovulatory, and luteal phases of two consecutive menstrual cycles. Psychologic stress was induced by having the subjects perform a battery of cognitive tasks under time pressure. Blood samples were drawn after each session for radioimmunoassay of 17 beta-estradiol, progesterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, prolactin, cortisol, and androstenedione. Urine samples were obtained for estimation of adrenaline, noradrenaline, and cortisol. The results showed that psychoneuroendocrine stress responses as estimated by urinary excretion of adrenaline and noradrenaline varied significantly across the menstrual cycle, the highest values being obtained in the luteal phase. Self-reported mood and somatic symptoms showed distinct phase-related changes, with more negative mood states predominating in the luteal and menstrual phases and increased positive mood states in the follicular and ovulatory phases.


Ventromedial Prefrontal Cortex Tracks Multiple Environmental Variables during Search.
To make efficient foraging decisions, we must combine information about the values of available options with nonvalue information. Some accounts of ventromedial PFC (vmPFC) suggest that it has a narrow role limited to evaluating immediately available options. We examined responses of neurons in area 14 (a putative macaque homolog of human vmPFC) as 2 male macaques performed a novel foraging search task. Although many neurons encoded the values of immediately available offers, they also independently encoded several other variables that influence choice, but that are conceptually distinct from offer value. These variables include average reward rate, number of offers viewed per trial, previous offer values, previous outcome sizes, and the locations of the currently attended offer. We conclude that, rather than serving as specialized economic value center, vmPFC plays a broad role in integrating relevant environmental information to drive foraging decisions.SIGNIFICANCE STATEMENT Decision makers must often choose whether to take an immediately available option or continue to search for a better one. We hypothesized that this process, which is integral to foraging theory, leaves neural signatures in the brain region ventromedial PFC. Subjects performed a novel foraging task in which they searched through differently valued options and attempted to balance their reward threshold with various time costs. We found that neurons not only encode the values of immediately available offers, but multiplexed these with environmental variables, including reward rate, number of offers viewed, previous offer values, and spatial information. We conclude that vmPFC plays a rich role in encoding and integrating multiple foraging-related variables during economic decisions.


Integrating proteomics and metabolomics to elucidate the molecular network regulating of inosine monophosphate-specific deposition in Jingyuan chicken.
Inosine monophosphate (IMP) plays a significant role in meat taste, yet the molecular mechanisms controlling IMP deposition in muscle tissues still require elucidation. The present study systematically and comprehensively explores the molecular network governing IMP deposition in different regions of Jingyuan chicken muscle. Two muscle groups, the breast and leg, were examined as test materials. Using nontargeted metabolomic sequencing, we screened and identified 20 metabolites that regulate IMP-specific deposition. We maintained regular author and institution formatting, used clear, objective, and value-neutral language, and avoided biased or emotional language. We followed a consistent footnote style and formatting features and used precise word choice with technical terms where appropriate. Out of these, 5 were identified as significant contributors to the regulation of IMP deposition. We explained technical term abbreviations when first used and ensured a logical flow of information with causal connections between statements. The results indicate that PGM1, a key enzyme involved in synthesis, is higher in the breast muscle compared to the leg muscle, which may provide an explanation for the increased deposition of IMP in the breast muscle. We aimed for a clear structure with logical progression, avoided filler words, and ensured grammatical correctness. The activity of key enzymes (PKM2, AK1, AMPD1) involved in this process was higher in the breast muscle than in the leg muscle. In the case of IMP degradation metabolism, the activity of its participating enzyme (PurH) was lower in the breast muscle than in the leg muscle. These findings suggest that the increased deposition of IMP in Jingyuan chickens' breast muscle may result from elevated metabolism and reduced catabolism of key metabolites. In summary, a metaomic strategy was utilized to assess the molecular network regulation mechanism of IMP-specific deposition in various segments of Jingyuan chicken. These findings provide insight into genetic improvement and molecular breeding of meat quality traits for top-notch broilers.


Granulocyte-macrophage colony-stimulating factor and B7-2 combination immunogene therapy in an allogeneic Hu-PBL-SCID/beige mouse-human glioblastoma multiforme model.
Glioblastoma multiforme is the most common primary central nervous system neoplasm. Its dismal prognosis has led to investigation of new treatment strategies such as immunogene therapy. We transduced the human glioblastoma cell line D54MG in vitro with genes encoding the proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), the T cell co-stimulatory molecule B7-2, or both (in a bicistronic vector) via retroviral vectors. Therapeutic gene expression by D54MG was high after transduction and selection (30 ng/10(6) cells/day for GM-CSF and > 2 orders of magnitude fluorescence shift on flow cytometry for B7-2). The effect of GM-CSF and/or B7-2 transduction on D54MG tumor growth in vivo was monitored in a novel allogeneic human peripheral blood lymphocyte-severe combined immunodeficiency mouse (Hu-PBL-SCID) model. GM-CSF- or B7-2-transduced tumors showed growth suppression in hu-PBL-reconstituted mice compared to untransduced and/or unreconstituted controls. Growth suppression was greatest for B7-2. Furthermore, vaccination with irradiated GM-CSF/B7-2-transduced tumor cells markedly inhibited growth of wild-type tumors at distant sites. Thus, this study illustrates a potential gene therapy strategy for glioblastoma multiforme patients using GM-CSF and/or B7-2 transduced tumor vaccines. Although extension of these allogeneic studies to an autologous system is critical, this is the first demonstration of in vivo efficacy of combination GM-CSF and B7-2 immunogene therapy for human glioblastoma multiforme.


Regulation of organ size: insights from the Drosophila Hippo signaling pathway.
Organ size control is a fundamental and core process of development of all multicellular organisms. One important facet of organ size control is the regulation of cell proliferation and cell death. Here we address the question, What are the developmental mechanisms that control intrinsic organ size? In several multicellular animals including humans and flies, organs develop according to an instructive model where proliferation is regulated by extracellular signals. However, the signals that regulate proliferation (and organ size) remain poorly understood. Recent data from flies have shed some light on the molecular mechanisms that regulate growth and size of organs. In this review, we will briefly discuss classic studies that revealed the mysteries of growth regulation. We will then focus on the recent findings from the Drosophila Hippo signaling pathway and its role in the regulation of organ size. Finally, we will discuss the mammalian Hippo pathway, and its implications in regulation of growth/proliferation during development and disease.