Sustained response off-treatment in eltrombopag-treated adult patients with ITP who are refractory or relapsed after first-line steroids: Primary, final, and ad-hoc analyses of the Phase II TAPER trial.
Immune thrombocytopenia (ITP) is characterized by reduced platelet count due to increased destruction and is categorized according to the time following diagnosis (newly diagnosed, persistent, chronic). First-line corticosteroid therapy is associated with transient response, high relapse rates, and considerable toxicity. TAPER (NCT03524612) is a Phase II, prospective, single-arm trial investigating whether eltrombopag can induce a sustained response off-treatment (SRoT) in adult patients with ITP after first-line corticosteroid failure. This study defines SRoT as an off-treatment period wherein platelet count remains above 30 × 109 /L in the absence of bleeding or rescue therapy. The primary endpoint was the proportion of patients who achieved SRoT until Month 12, which was 30.5% (n = 32/105; p < .0001 testing hypothesis H1: proportion >15%) following eltrombopag tapering and discontinuation, and median SRoT duration was ~8 months until Month 12. Median platelet count increased within 1 month of treatment and remained elevated until Month 12. Quality of life improved within 3 months and was maintained. Headache (21%) was the most common adverse event. None of the 4 deaths reported were considered treatment-related. In summary, ~one-third of patients achieved SRoT until Month 12 following eltrombopag tapering and discontinuation. An ad-hoc early-use analysis, stratified by ITP duration at baseline, assessed initial hematologic responses and safety. Results suggest that eltrombopag has similar efficacy in newly diagnosed and later stages of ITP. In follow-up until Month 24, a median SRoT duration of ~22 months was observed (n = 20). The safety profile was comparable across analyses and ITP duration groups and aligned with its well-established safety profile.


[Effect of mexidol on efficacy of traditional therapy of sick sinus syndrome in adolescents].
ECG data obtained with a Holter monitor in a group of 90 adolescent patients with vegetovascular dystonia and sick sinus syndrome (SSS) showed that mexidol, intravenously instilled in a daily dose of 2-4 mg/kg over a period of 10 days in combination with a standard neurometabolic scheme results in the development of a therapeutic effect in 93-100% of patients with clinical-ECG variants I and II of the disorder. In most cases, both clinical state and ECG quality were improved and the functional capacity of myocardium was increased. Repeated courses of mexidol administration increased efficacy of the ambulatory SSS treatment on the average by 20%.


Chemical Complementarity of Tumor Resident, Adaptive Immune Receptor CDR3s and Previously Defined Hepatitis C Virus Epitopes Correlates with Improved Outcomes in Hepatocellular Carcinoma.
To better understand how adaptive immune receptors (IRs) in hepatocellular carcinoma (HCC) microenvironments are related to disease outcomes, we employed a chemical complementarity scoring algorithm to quantify electrostatic complementarity between HCC tumor TRB or IGH complementarity-determining region 3 (CDR3) amino acid (AA) sequences and previously characterized hepatitis C virus (HCV) epitopes. High electrostatic complementarity between HCC-resident CDR3s and 12 HCV epitopes was associated with greater survival probabilities, as indicated by two distinct HCC IR CDR3 datasets. Two of the HCV epitopes, HCV*71871 (TRB) and HCV*13458 (IGH), were also determined to represent significantly larger electrostatic CDR3-HCV epitope complementarity in HCV-positive HCC cases, compared with HCV-negative HCC cases, with the CDR3s representing yet a third, independent HCC dataset. Overall, the results indicated the utility of CDR3 AA sequences as biomarkers for HCC patient stratification and as potential guides for the development of therapeutic reagents.


Recasting Assessment in Continuing Professional Development as a Person-Focused Activity.
In this article, we examine assessment as conceptualized and enacted in continuing professional development (CPD). Assessment is pervasive throughout the life of an individual health professional, serving many different purposes compounded by varied and unique contexts, each with their own drivers and consequences, usually casting the person as the object of assessment. Assessment is often assumed as an included part in CPD development conceptualization. Research on assessment in CPD is often focused on systems, utility, and quality instead of intentionally examining the link between assessment and the person. We present an alternative view of assessment in CPD as person-centered, practice-informed, situated and bound by capability, and enacted in social and material contexts. With this lens of assessment as an inherently personal experience, we introduce the concept of subjectification, as described by educationalist Gert Biesta. We propose that subjectification may be a fruitful way of examining assessment in a CPD context. Although the CPD community, researchers, and educators consider this further, we offer some early implications of adopting a subjectification lens on the design and enactment of assessment in CPD.


Non-natural G-quadruplex in a non-natural environment.
The biocompatibility as well as the sustainability of a deep eutectic solvent makes it a good substitute for aqueous media in studying biomolecules. Understanding the structure and stability of natural and non-natural G-quadruplexes in aqueous and highly viscous media will be useful in biological and nanodevice applications. We report the synthesis and conformational analysis of a model G-rich oligonucleotide G3T3 and non-natural G-rich sequences Pyr1-Pyr3 in aqueous and highly viscous media. Progressive increases in the loop replacement with a non-natural pyrene linker leads to a systematic increase of the thermal denaturation temperature of the modified G-rich oligonucleotides Pyr1-Pyr3 in 10 mM cacodylate buffer (pH 7.2) containing 100 mM KCl, as monitored using UV-Vis spectroscopy. A circular dichroism signal clearly revealed the formation of a predominantly anti-parallel vs. parallel conformation in the natural G-rich oligonucleotide G3T3 as well as the non-natural G-rich oligonucleotides Pyr1-Pyr3 in 10 mM cacodylate buffer (pH 7.2) containing 100 mM KCl. On the other hand, we observed thermodynamic destabilization of G-rich oligonucleotides in a deep eutectic solvent (DES; 1 : 2 choline chloride-urea) containing 100 mm KCl with an increase in loop replacements. Interestingly, we observed an exclusively parallel G-quadruplex conformation in the case of G3T3 in DES containing 100 mm KCl. While pyrene containing G-rich oligonucleotides Pyr1-Pyr3 exhibited a predominantly parallel vs. anti-parallel G-quadruplex conformation in DES containing 100 mM KCl.


Isolation of bioactive peptides from tryptone that modulate lipase production in Yarrowia lipolytica.
In this work the effect of several organic nitrogen sources on lipase production in Yarrowia lipolytica LgX64.81 overproducing mutant was studied. Among them, tryptone and peptone showed the most prominent stimulatory effect. Interestingly, only tryptic and peptic casein digest were found to highly induce lipase biosynthesis while lipase production was very limited in the presence of casein digest from papain and pronase-catalysed hydrolysis and absent in case of chymotryptic digest. It was also demonstrated that the stimulatory peptides should be present in the culture medium at specific proportions and molecular size to match the physiological requirement of Yarrowia lipolytica strain for lipase biosynthesis. Herein, the lipase-production stimulatory peptides were isolated by ion exchange chromatography for the first time. These results had contributed to gain an insight on tryptone role in lipase production by Yarrowia lipolytica. Moreover the use of a chemically defined medium supplemented with the isolated peptides, will improve the efficiency of the process for lipase production in this yeast.


Quality of meta-analysis in nursing fields: An exploration based on the JBI guidelines.
Meta-analysis is often regarded as one of the best sources of evidence for clinical nurses due to its rigorous design and scientific reflection of the true results of nursing interventions. The quality of a meta-analysis is critical to the work of clinical decision-makers. Therefore, the objective of this study was to use the JBI guidelines to summarize the quality of RCT-based meta-analyses of reports published in domestic nursing professional journals, with a view to standardizing the research process and reporting methods. We performed a comprehensive literature search for RCT-based meta-analyses published in Chinese professional nursing journals, from their inception to December 31, 2015, using bibliographic databases (e.g. CNKI, WanFang Database). March 1, 2017, supplementary search 2016 literature. Candidate reviews were assessed for inclusion by two independent reviewers using pre-specified eligibility criteria. We evaluated the quality of reporting of the included meta-analyses using the systematic review literature reporting specification of JBI. Analyses were performed using Excel and STATA 12.0 software. Three hundred and twenty-two meta-analyses were included. According to the JBI guidelines, the overall quality of the meta-analysis report was poor. The quality of core journal reports and the implementation of retrieval were better than those of non-core journals. The nature of the authors and the availability of funding support had no significant impact on the quality of the meta-analyses. Multi-unit and multi-author collaboration can help improve the quality of meta-analyses with significant impact. The understanding and implementation of systematic evaluation and meta-analyses in domestic nursing professional journals is worthy of recognition, and there is more work that can be done to improve the quality of these reports. Systematic review / Meta-analysis (SR / MA) makers should include the findings of this study. Multi-institutional and multi-author collaborations appear to improve research capacity and provide more reliable evidence support for clinicians.


Acetylcholinesterase activity and neurodevelopment in boys and girls.
Organophosphate exposures can affect children's neurodevelopment, possibly due to neurotoxicity induced by acetylcholinesterase (AChE) inhibition, and may affect boys more than girls. We tested the hypothesis that lower AChE activity is associated with lower neurobehavioral development among children living in Ecuadorian floricultural communities. In 2008, we examined 307 children (age: 4-9 years; 52% male) and quantified AChE activity and neurodevelopment in 5 domains: attention/executive functioning, language, memory/learning, visuospatial processing, and sensorimotor (NEPSY-II test). Associations were adjusted for demographic and socioeconomic characteristics and height-for-age, flower worker cohabitation, and hemoglobin concentration. Mean ± standard deviation AChE activity was 3.14 ± 0.49 U/mL (similar for both genders). The range of scores among neurodevelopment subtests was 5.9 to 10.7 U (standard deviation: 2.6-4.9 U). Girls had a greater mean attention/executive functioning domain score than boys. In boys only, there were increased odds ratios of low (<9th percentile) neurodevelopment among those in the lowest tertile versus the highest tertile of AChE activity (odds ratios: total neurodevelopment: 5.14 [95% confidence interval (CI): 0.84 to 31.48]; attention/executive functioning domain: 4.55 [95% CI: 1.19 to 17.38], memory/learning domain: 6.03 [95% CI: 1.17 to 31.05]) after adjustment for socioeconomic and demographic factors, height-for-age, and hemoglobin. Within these domains, attention, inhibition and long-term memory subtests were most affected. Low AChE activity was associated with deficits in neurodevelopment, particularly in attention, inhibition, and memory in boys but not in girls. These critical cognitive skills affect learning and academic performance. Added precautions regarding secondary occupational pesticide exposure would be prudent.


Circulating MicroRNA-21 Correlates With Left Atrial Low-Voltage Areas and Is Associated With Procedure Outcome in Patients Undergoing Atrial Fibrillation Ablation.
Atrial fibrosis is a hallmark of arrhythmogenic structural remodeling in patients with persistent atrial fibrillation (AF) and is negatively correlated with procedure outcome in patients undergoing ablation. However, noninvasive methods to determine the extent of atrial fibrosis are limited. Here, we used microRNA (miRNA) expression analysis to detect markers of left atrial low-voltage areas (LVAs) in patients with persistent AF undergoing catheter ablation. We performed 3-dimensional voltage mapping in 102 patients (average age 62.1±13.1 years, CHA2DS2-VASc score of 2.3±1.6, LA size 41.5±5.7 mm) undergoing ablation for persistent AF and determined the extent of left atrial low-voltage. LVAs were defined if bipolar electrogram amplitudes were <0.5 mV during sinus rhythm. Before ablation, we obtained a blood sample, isolated miRNAs, and profiled them on a miRCURY LNA Universal RT microRNA PCR Human panel. Sixty-nine miRNAs were identified in all samples, with an average of 123 miRNAs detectable per sample. We found that the serum concentration of miR-21, a miRNA that has been previously linked to cardiac fibrosis development, was strongly associated with the extent of LVAs determined by voltage mapping. We could confirm that LVAs were negatively correlated with ablation success in a 1-year follow-up. In addition, miR-21 serum levels were associated with AF-free survival after catheter ablation. Circulating miR-21 correlates with left atrial LVAs and is associated with procedure outcome in patients with persistent AF undergoing ablation.


Deep Multimodal Feature Analysis for Action Recognition in RGB+D Videos.
Single modality action recognition on RGB or depth sequences has been extensively explored recently. It is generally accepted that each of these two modalities has different strengths and limitations for the task of action recognition. Therefore, analysis of the RGB+D videos can help us to better study the complementary properties of these two types of modalities and achieve higher levels of performance. In this paper, we propose a new deep autoencoder based shared-specific feature factorization network to separate input multimodal signals into a hierarchy of components. Further, based on the structure of the features, a structured sparsity learning machine is proposed which utilizes mixed norms to apply regularization within components and group selection between them for better classification performance. Our experimental results show the effectiveness of our cross-modality feature analysis framework by achieving state-of-the-art accuracy for action classification on five challenging benchmark datasets.


Plant enzymes but not Agrobacterium VirD2 mediate T-DNA ligation in vitro.
Agrobacterium tumefaciens, a gram-negative soil bacterium, transfers DNA to many plant species. In the plant cell, the transferred DNA (T-DNA) is integrated into the genome. An in vitro ligation-integration assay has been designed to investigate the mechanism of T-DNA ligation and the factors involved in this process. The VirD2 protein, which is produced in Agrobacterium and is covalently attached to T-DNA, did not, under our assay conditions, ligate T-DNA to a model target sequence in vitro. We tested whether plant extracts could ligate T-DNA to target oligonucleotides in our test system. The in vitro ligation-integration reaction did indeed take place in the presence of plant extracts. This reaction was inhibited by dTTP, indicating involvement of a plant DNA ligase. We found that prokaryotic DNA ligases could substitute for plant extracts in this reaction. Ligation of the VirD2-bound oligonucleotide to the target sequence mediated by T4 DNA ligase was less efficient than ligation of a free oligonucleotide to the target. T-DNA ligation mediated by a plant enzyme(s) or T4 DNA ligase requires ATP.


Genotypic diversity and serotype distribution of group B streptococcus isolated from women before and after delivery.
Most studies of the dynamics of maternal group B Streptococcus (GBS) colonization have relied on capsular serotyping to define GBS acquisition or loss. Newer molecular methods that distinguish GBS clones may expand our knowledge and influence vaccination strategies. We used multilocus sequence typing (MLST) and GBS capsular gene cluster (cps) genotyping to investigate the dynamics of perinatal GBS colonization. A total of 338 GBS isolates obtained from 212 colonized women who were enrolled in a prior prospective cohort study were serotyped and genotyped by MLST and cps typing before (visit 1) and 6 weeks after (visit 2) delivery. Of the 212 women, 126 were colonized at both visits, whereas 66 lost and 20 acquired GBS by visit 2. MLST of the 338 strains identified 29 sequence types marking distinct bacterial clones. A change in sequence type or cps and serotype occurred in 23 (18.3%) of the 126 women who were colonized at both visits. Specific sequence types were associated with GBS loss and persistence. Older maternal age and exclusive intrapartum antibiotic use were associated with persistent colonization. Although most GBS-positive pregnant women were stably colonized during the peripartum period, we detected changes in capsule expression and recolonization with antigenically distinct GBS clones over time by applying MLST. Combining the epidemiologic and molecular typing data revealed host factors and clones associated with persistent colonization, as well as a clone that was more readily lost. This knowledge is useful for the development of prevention and intervention strategies to reduce the likelihood of maternal GBS colonization.


Knowledge of laws regulating issues related to HIV and AIDS: development of the HIV/AIDS and the law scale.
42 middle-aged and older adults, ranging in age from 51 to 85 years, completed 10 items dealing with the assessment of knowledge regarding laws regulating issues related to HIV and AIDS. Participants also completed 40 items involving knowledge of risks for HIV infection. The Cronbach coefficient alpha and test-retest reliability coefficient on the HIV/AIDS and the Law Scale were .74 and .83, respectively. Over-all, the grand mean for correct answers was 46.9%, whereas the grand means for incorrect answers and "don't know" responses were 13.6% and 39.5%, suggesting substantial lack of knowledge of laws regulating issues related to HIV and AIDS. Women (50%) and younger participants (51 to 66 years old; 48.2%) showed more of this knowledge (50%) than men (43.0%) and older participants (46.2%). The sample reported a substantial amount of knowledge regarding HIV transmission assessed with factual (92.2% correct) and misconception (87.5% correct) items. The correlation between this knowledge and knowledge of laws regulating issues related to HIV and AIDS was .42 (p < .01). Research with this scale using adolescents and young adults as well as the utility of the scale in areas of clinical, legal, and policy development are discussed.


What next for preimplantation genetic screening (PGS)? A position statement from the ESHRE PGD Consortium Steering Committee.
Since 2004, there have been 11 randomized controlled trials (RCTs) mainly for advanced maternal age (AMA), which have shown no benefit of performing preimplantation genetic screening (PGS). Ten of the RCTs have been performed at the cleavage stage and one at the blastocyst stage. It is probable that the high levels of chromosomal mosaicism at cleavage stages, which may result in the tested cell not being representative of the embryo, and the inability to examine all of the chromosomes using fluorescence in situ hybridization, have contributed to the lack of positive outcome from the RCTs. We suggest that future RCTs should examine alternative biopsy timing (polar body and/or trophectoderm biopsy), and should apply technologies that allow more comprehensive testing to include all chromosomes (microarray-based testing) to determine if PGS shows an improvement in delivery rate. Currently there is no evidence that routine PGS is beneficial for patients with AMA and conclusive data (RCTs) on repeated miscarriage, implantation failure and severe male factor are missing. To evaluate benefits of PGS, an ESHRE trial has recently been started on patients with AMA using polar body biopsy and array-comparative genomic hybridization, which should bring more information on this patient group in the near future.


Microbiological changes after periodontal therapy in diabetic patients with inadequate metabolic control.
The present study investigated the effect of non-surgical periodontal treatment (SRP) on the composition of the subgingival microbiota of chronic periodontitis (CP) in individuals with type 2 diabetes (DM2) with inadequate metabolic control and in systemically healthy (SH) individuals. Forty individuals (20 DM2 and 20 SH) with CP underwent full-mouth periodontal examination. Subgingival plaque was sampled from 4 deep sites of each individual and tested for mean prevalence and counts of 45 bacterial taxa by the checkerboard method. Clinical and microbiological assessments were performed before and 3 months after SRP. At baseline, those in the DM2 group presented a significantly higher percentage of sites with visible plaque and bleeding on probing compared with those in the SH group (p<0.01). Those in the DM2 group presented significantly higher levels of C. rectus and P. gingivalis, and lower prevalence of P. micra and S. anginosus, compared with those in the SH group (p≤0.001). At the 3-month visit, both groups showed a significant improvement in all clinical parameters (p<0.01). Those in the DM2 group showed significantly higher prevalence and/or levels of A. gerencseriae, A. naeslundii I, A. oris, A. odontolyticus, C. sputigena, F. periodonticum, and G. morbillorum compared with those in the SH group (p≤0.001). However, those in the DM2 group showed a significant reduction in the levels of P. intermedia, P. gingivalis, T. forsythia, and T. denticola (p≤0.001) over time. Those in the SRP group showed improved periodontal status and reduced levels of putative periodontal pathogens at 3 months' evaluation compared with those in the DM2 group with inadequate metabolic control.


Predictors of severe neonatal compromise following caesarean section for clinically diagnosed foetal distress.
The potential harm to a mother and baby from caesarean delivery for clinically diagnosed foetal distress may not always be justified by the degree of neonatal depression at birth. To assess the accuracy of clinical diagnosis of foetal distress indicating caesarean section and identify antepartum and intrapartum characteristics that may predict severe neonatal compromise at birth. A chart analysis of 246 singleton caesarean births primarily indicated by clinically diagnosed foetal distress over a ten-year period at a Nigerian University Hospital. Gestational and intrapartum characteristics were compared for severely compromised neonates (Apgar score 0 to 3) and those with Apgar score of four-seven at one minute of birth. Multivariate logistic regression analysis was applied to determine independent predictors of severe neonatal compromise. Apgar score was less than 7 in 236 neonates: 120 (48.8%) were severely compromised, 116 (47.2%) had Apgar scores of four-seven and ten (4.1%) had normal Apgar scores. Eight (3.3%) neonates were stillborn. Multivariate logistic regression analyses indicate that meconium liquor (adjusted OR, 0.24 CI: 0.12 to 0.46) and long admission to diagnosis interval significantly reduce while combination of abnormal FHR and meconium liquor (adjusted OR: 3.84 CI: 1.89 to 7.76) significantly increased the odds of severe neonatal compromise at birth. Clinical diagnosis of foetal distress is valuable in identifying foetuses in need of expedited delivery in this setting. However, gestational and intrapartum characteristics have limited impact in predicting before delivery which foetus requires intensive resuscitative measures and neonatal support at birth.


DNA methylation profiles in bovine sperm are associated with daughter fertility.
The current decline in dairy cattle fertility has resulted in significant financial losses for dairy farmers. In the past, most efforts to improve dairy cattle fertility have been focused on either management or genetics, while epigenetics have received less attention. In this study, 12 bulls were selected from a provided 100 bull list and studied (High daughter fertility = 6, Low daughter fertility = 6) for Enzymatic methylation sequencing in the Illumina HiSeq platform according to the Canadian daughter fertility index (DFI), sires with high and low daughter fertility have average DFI of 92 and 112.6, respectively. And the bull list provided shows a mean DFI of 103.4. 252 CpGs with methylation differences greater than 20% (q < 0.01) were identified, as well as the top 10 promising DMRs with a 15% methylation difference (q < 1.1e-26). Interestingly, the DMCs and DMRs were found to be distributed more on the X chromosome than on the autosome, and they were covered by gene clusters linked to germ cell formation and development. In conclusion, these findings could enhance our ability to make informed decisions when deciding on superior bulls and advance our understanding of paternal epigenetic inheritance.


A dual-plate ITO-ITO generator-collector microtrench sensor: surface activation, spatial separation and suppression of irreversible oxygen and ascorbate interference.
Generator-collector electrode systems are based on two independent working electrodes with overlapping diffusion fields where chemically reversible redox processes (oxidation and reduction) are coupled to give amplified current signals. A generator-collector trench electrode system prepared from two tin-doped indium oxide (ITO) electrodes placed vis-à-vis with a 22 μm inter-electrode gap is employed here as a sensor in aqueous media. The reversible 2-electron anthraquinone-2-sulfonate redox system is demonstrated to give well-defined collector responses even in the presence of oxygen due to the irreversible nature of the oxygen reduction. For the oxidation of dopamine on ITO, novel "Piranha-activation" effects are observed and chemically reversible generator-collector feedback conditions are achieved at pH 7, by selecting a more negative collector potential, again eliminating possible oxygen interference. Finally, dopamine oxidation in the presence of ascorbate is demonstrated with the irreversible oxidation of ascorbate at the "mouth" of the trench electrode and chemically reversible oxidation of dopamine in the trench "interior". This spatial separation of chemically reversible and irreversible processes within and outside the trench is discussed as a potential in situ microscale sensing and separation tool.


Regulation of porcine brain alpha 2-adrenergic receptors by Na+,H+ and inhibitors of Na+/H+ exchange.
Previous reports from this laboratory have demonstrated that alpha 2-adrenergic receptors accelerate Na+/H+ exchange in NG108-15 neuroblastoma X glioma cells and evoke platelet secretion via a pathway involving Na+/H+ exchange. The present studies were designed to examine whether agents that interact with Na+/H+ antiporters also might influence alpha 2-adrenergic receptor-ligand interactions. We observed that Na+ decreases receptor affinity for the agonists epinephrine, norepinephrine, and UK14304 and slightly increases receptor affinity for the antagonists yohimbine and idazoxan in digitonin-solubilized preparations from porcine brain cortex. Increases in [H+] also decrease receptor affinity for agonists and cause either a slight increase or no change in receptor affinity for antagonists. Amiloride analogs accelerate the rate of [3H] yohimbine dissociation from digitonin-solubilized receptors with a relative effectiveness that parallels their ability to block Na+/H+ exchange in other systems. Interestingly, these modulatory effects of Na+,H+ and 5-amino-substituted analogs of amiloride are retained in homogeneous preparations of the alpha 2-adrenergic receptor, suggesting that the allosteric-binding sites for these agents are on the receptor-binding protein itself.


Ethics questions raised by the neuropsychiatric, neuropsychological, educational, developmental, and family characteristics of 18 juveniles awaiting execution in Texas.
Eighteen males condemned to death in Texas for homicides committed prior to the defendants' 18th birthdays received systematic psychiatric, neurologic, neuropsychological, and educational assessments, and all available medical, psychological, educational, social, and family data were reviewed. Six subjects began life with potentially compromised central nervous system (CNS) function (e.g., prematurity, respiratory distress syndrome). All but one experienced serious head traumas in childhood and adolescence. All subjects evaluated neurologically and neuropsychologically had signs of prefrontal cortical dysfunction. Neuropsychological testing was more sensitive to executive dysfunction than neurologic examination. Fifteen (83%) had signs, symptoms, and histories consistent with bipolar spectrum, schizoaffective spectrum, or hypomanic disorders. Two subjects were intellectually limited, and one suffered from parasomnias and dissociation. All but one came from extremely violent and/or abusive families in which mental illness was prevalent in multiple generations. Implications regarding the ethics involved in matters of culpability and mitigation are considered.


Genomic Insights Into Statin Therapy: Differential Expression Analysis of Key Genes.
In this study, we utilized microarray profiles, specifically GSE71220 and GSE11393 obtained from the GEO database, which provide gene expression data from blood samples. Through a comparison of differentially expressed genes in both datasets, we successfully identified 11 key genes that exhibited differential expression in groups A and B, respectively. To gain insights into their functional roles, we performed gene ontology (GO) enrichment analysis using the "BiNGO" plugin in Cytoscape. This analysis revealed that these genes are primarily associated with primary metabolic processes. Notably, 8 genes, namely EIF2S3, GZMK, PIK3R1, RORA, SART3, TGM2, WTAP, and ABCG1, were found to be involved in these processes. To further explore the interactions and relationships among these key genes, we conducted protein-protein interaction analysis using the STRING database and co-expression network analysis using the GeneMANIA plugin in Cytoscape. The PPI analysis highlighted RORA, NR1D2, PIK3R1, CKAP4, and GZMK as central players within the network. To validate our findings, we examined the expression profiles of the key genes using the GSE86216 dataset, which comprises blood samples from individuals using statins. The results from this validation set largely corroborated our previous findings, with the exception of 3 genes: LAMP3, NR1D2, and PIK3R1, which exhibited different expression patterns. In conclusion, our study utilized microarray datasets to identify key genes that are influenced by statin treatments. The differential expression and functional analysis of these genes provide valuable insights into the mechanisms underlying the effects of statins.


Does 'idiopathic pleuritis' exist? Natural history of non-specific pleuritis diagnosed after thoracoscopy.
Even after a complete work-up including thoracoscopic biopsies, a significant number of patients with pleural exudates are diagnosed with 'non-specific pleuritis', and no specific diagnosis can be made. The natural evolution of these patients is poorly understood. To study the natural evolution of patients with non-specific pleuritis diagnosed after thoracoscopy and to evaluate whether the histological diagnosis of non-specific pleuritis corresponds with the clinical diagnosis of 'idiopathic pleuritis'. We retrospectively studied the evolution of 75 patients between 1992 and 2002 (49 men and 26 women), mean (+/- SD) age 63.4 (+/- 13.3) years, who underwent diagnostic thoracoscopy because of an unexplained exudative pleural effusion, and in whom the histological diagnosis of non-specific pleuritis was made. Follow-up data were obtained through medical files and/or telephone contacts with general practitioners. Of these 75 patients, 8.3% eventually developed a malignancy during the follow-up period. In the remaining patients (91.7%), the clinical evolution followed a benign course. Ultimately, a probable cause was established on clinical grounds in 40 patients. True idiopathic pleuritis was finally observed in 25% of patients with the histological diagnosis of non-specific pleuritis. Recurrence of the effusion occurred in 10 out of 60 (16.7%) patients, after a mean period of 26.2 months. The majority of non-specific pleuritis patients (91.7%) followed a benign course, with a spontaneous resolution of the effusion in 81.8% of cases. In the majority of patients, a probable cause of the pleuritis was identified. True 'idiopathic benign pleuritis' hence occurs in only a minority (25%) of patients.


The intrinsically photosensitive retinal ganglion cell (ipRGC) mediated pupil response in young adult humans with refractive errors.
The intrinsically photosensitive retinal ganglion cells (ipRGCs) signal environmental light, with axons projected to the midbrain that control pupil size and circadian rhythms. Post-illumination pupil response (PIPR), a sustained pupil constriction after short-wavelength light stimulation, is an indirect measure of ipRGC activity. Here, we measured the PIPR in young adults with various refractive errors using a custom-made optical system. PIPR was measured on myopic (-3.50 ± 1.82 D, n = 20) and non-myopic (+0.28 ± 0.23 D, n = 19) participants (mean age, 23.36 ± 3.06 years). The right eye was dilated and presented with long-wavelength (red, 625 nm, 3.68 × 1014 photons/cm2/s) and short-wavelength (blue, 470 nm, 3.24 × 1014 photons/cm2/s) 1 s and 5 s pulses of light, and the consensual response was measured in the left eye for 60 s following light offset. The 6 s and 30 s PIPR and early and late area under the curve (AUC) for 1 and 5 s stimuli were calculated. For most subjects, the 6 s and 30 s PIPR were significantly lower (p < 0.001), and the early and late AUC were significantly larger for 1 s blue light compared to red light (p < 0.001), suggesting a strong ipRGC response. The 5 s blue stimulation induced a slightly stronger melanopsin response, compared to 1 s stimulation with the same wavelength. However, none of the PIPR metrics were different between myopes and non-myopes for either stimulus duration (p > 0.05). We confirm previous research that there is no effect of refractive error on the PIPR.


Systematic Evaluation of CRISPRa and CRISPRi Modalities Enables Development of a Multiplexed, Orthogonal Gene Activation and Repression System.
The ability to manipulate the expression of mammalian genes using synthetic transcription factors is highly desirable in both fields of basic research and industry for diverse applications, including stem cell reprogramming and differentiation, tissue engineering, and drug discovery. Orthogonal CRISPR systems can be used for simultaneous transcriptional upregulation of a subset of target genes while downregulating another subset, thus gaining control of gene regulatory networks, signaling pathways, and cellular processes whose activity depends on the expression of multiple genes. We have used a rapid and efficient modular cloning system to build and test in parallel diverse CRISPRa and CRISPRi systems and develop an efficient orthogonal gene regulation system for multiplexed and simultaneous up- and downregulation of endogenous target genes.


Women, healthcare leadership and societal culture: a qualitative study.
Women leaders encounter societal and cultural challenges that define and diminish their career potential. This occurs across several professions including healthcare. Scant attention has been drawn to the discursive dynamics among gender, healthcare leadership and societal culture. The aim of this study is to assess empirically gendered barriers to women's leadership in healthcare through the lens of sociocultural characteristics. The comparative study was conducted in Greece and Malta. The interest in these countries stems from their poor performance in the gender employment gap and the rapid sociocultural and economic changes occurring in the European-Mediterranean region. Thirty-six individual in-depth interviews were conducted with health-care leaders, including both women and men (18 women and 18 men). Directed content analysis was used to identify and analyze themes against the coding scheme of the Barriers Thematic Map to women's leadership. Summative content analysis was applied to quantify the usage of themes, while qualitative meta-summative method was used to interpret and contextualize the findings. Twenty and twenty-one barriers to women's leadership were identified within the Greek and Maltese healthcare settings, respectively. Prevailing barriers included work/life balance, lack of family (spousal) support, culture, stereotypes, gender bias and lack of social support. Inter-country similarities and differences in prevalence of the identified barriers were observed. The study appraised empirically the gendered barriers that women encounter in healthcare leadership through the lens of national sociocultural specificities. Findings unveiled underlying interactions among gender, leadership and countries' sociocultural contexts, which may elucidate the varying degrees of strength of norms and barriers embedded in a society's egalitarian practices. Cultural tightness has been found to be experienced by societal dividends as an alibi or barrier against sociocultural transformation. Findings informed a conceptual framework proposed to advance research in the area of women's leadership.


Incidence of infection following internal fixation of open and closed tibia fractures in India (INFINITI): a multi-centre observational cohort study.
Trauma is a major public health problem, particularly in India due to the country's rapid urbanization. Tibia fractures are a common and often complicated injury that is at risk of infection following surgical fixation. The primary objectives of this cohort study were to determine the incidence of infection within one year of surgery and to describe the distribution of infections by location and time of diagnosis for tibia fractures in India. We conducted a multi-center, prospective cohort study. Patients who presented with an open or closed tibia fracture treated with internal fixation to one of the participating hospitals in India were invited to participate in the study. Participants attended follow-up visits at 3, 6, and 12 months post-surgery, where they were assessed for infections, fracture healing, and health-related quality of life as measured by the EurQol-5 Dimensions (EQ-5D). Seven hundred eighty-seven participants were included in the study and 768 participants completed the 12 month follow-up. The overall incidence of infection was 2.9% (23 infections). The incidence of infection was 1.6% (10 infections) in closed and 8.0% (13 infections) in open fractures. There were 7 deep and 16 superficial infections, with 5 being early, 7 being delayed, and 11 being late infections. Intra-operative antibiotics were given to 92.1% of participants and post-operative antibiotics were given to 96.8% of participants. Antibiotics were prescribed for an average of 8.3 days for closed fractures and 9.1 days for open fractures. Infected fractures took significantly longer to heal, and participants who had an infection had significantly lower EQ-5D scores. The incidence of infection within this cohort is similar to those seen in developed countries. The duration of prophylactic antibiotic use was longer than standard practice in North America, raising concern for the potential development of antibiotic resistant microbes within Indian orthopaedic settings. Future research should aim to identify the best practice for antibiotic use in India to ensure that antibiotic usage patterns do not lead to unnecessary overuse, while maintaining a low incidence of infection. NCT01691599 , September 17, 2012.


The Influence of Shortening on Clinical Outcome in Healed Displaced Midshaft Clavicular Fractures After Nonoperative Treatment.
We aimed to evaluate the effect of clavicular shortening, measured with 3-dimensional computed tomography (3DCT), on functional outcomes and satisfaction in patients with healed displaced midshaft clavicular fractures up to 1 year following injury. The data used in this study were collected as part of a multicenter, prospective randomized controlled trial of open reduction and plate fixation compared with nonoperative treatment for acute, displaced midshaft clavicular factures. Patients who were randomized to nonoperative treatment and had healed by 1 year were included in the present study. Clavicular shortening relative to the uninjured, contralateral clavicle was measured on 3DCT. Outcome analysis was conducted at 6 weeks, 3 months, 6 months, and 1 year following injury and included the Disabilities of the Arm, Shoulder and Hand (DASH), Constant, and Short Form-12 (SF-12) scores and patient satisfaction. In the original trial, 105 patients were randomized to nonoperative treatment. Thirteen patients were lost to follow-up, leaving 92 patients, and an additional 16 (17%) developed nonunion and were excluded from the present study. Of the remaining 76 patients, 48 who had a 3DCT scan that included the whole length of both clavicles were included in the present study. The shortening of the injured clavicles, relative to the contralateral side, was a mean (and standard deviation) of 11.3 ± 7.6 mm, with a mean proportional shortening of 8%. Proportional shortening did not significantly correlate with the DASH (p ≥ 0.42), Constant (p ≥ 0.32), or SF-12 (p ≥ 0.08) scores at any point during follow-up. There was no significant difference in the mean DASH or Constant scores at any follow-up time point when the cutoff for shortening was defined as 1 cm (p ≥ 0.11) or as 2 cm (p ≥ 0.35). There was no significant difference in clavicular shortening between satisfied and unsatisfied patients (p ≥ 0.49). The present study demonstrated no association between shortening and functional outcome or satisfaction in patients with healed displaced midshaft clavicular fractures up to 1 year following injury. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Lead exposure induced lipid metabolism disorders by regulating the lipophagy process in microglia.
Environmental lead (Pb) pollution is a worldwide public health problem and causes various diseases, especially neurodegenerative diseases. It is increasingly recognized that microglia-mediated neuroinflammation plays a crucial role in lead neurotoxicity, but the underlying mechanisms remain to be further explored. Recent studies indicated that cell metabolism, especially lipid metabolism, regulates many microglial functions, including cytokine secretion and phagocytosis. Whether lipid metabolism is involved in Pb-induced neuroinflammation is still unknown. In the current studies, we investigated the effects of Pb on microglial lipid metabolism by utilizing lipidomics. Histochemistry staining and oxygen consumption rate (OCR) were used to validate lipidomics results. Fenofibrate (FEN), a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, was applied to investigate whether lipid metabolism regulation mitigated Pb's neuroinflammatory response. Microglial autophagic proteins were detected to investigate the role of lipophagy in Pb's effect on lipid metabolism. Our results showed that Pb exposure increased concentrations of various lipid metabolites and induced lipid metabolism disorders, especially in fatty acid metabolism. Pb caused lipid droplet (LD) accumulation and slightly enhanced fatty acid oxidation (FAO) in microglia. FEN pretreatment markedly inhibited Pb's effects on LDs and further mitigated Pb-induced inflammatory response by reducing pro-cytokines' expression and enhancing phagocytosis function. FEN intervention also inhibited Pb's neurotoxicity by improving cognition-related behaviors. Pb exposure induced an abnormal increase of autophagic proteins, but the FEN addition partially neutralized Pb's effects on autophagy. Our data indicate that the Pb-induced neuroinflammation is regulated by fatty acid metabolism via the lipophagy process. Therapies focusing on lipid metabolism regulation are powerful tactics in Pb toxicity prevention and treatment.


Population genetic structure and vocal dialects in an amazon parrot.
The relationship between cultural and genetic evolution was examined in the yellow-naped amazon Amazona auropalliata. This species has previously been shown to have regional dialects defined by large shifts in the acoustic structure of its learned contact call. Mitochondrial DNA sequence variation from a 680 base pair segment of the first domain of the control region was assayed in 41 samples collected from two neighbouring dialects in Costa Rica. The relationship of genetic variation to vocal variation was examined using haplotype analysis, genetic distance analysis, a maximum-likelihood estimator of migration rates and phylogenetic reconstructions. All analyses indicated a high degree of gene flow and, thus, individual dispersal across dialect boundaries. Calls sampled from sound libraries suggested that temporally stable contact call dialects occur throughout the range of the yellow-naped amazon, while the presence of similar dialects in the sister species Amazona ochrocephala suggests that the propensity to form dialects is ancestral in this clade. These results indicate that genes and culture are not closely associated in the yellow-naped amazon. Rather, they suggest that regional diversity in vocalizations is maintained by selective pressures that promote social learning and allow individual repertoires to conform to local call types.


A crab swarm at an ecological hotspot: patchiness and population density from AUV observations at a coastal, tropical seamount.
A research cruise to Hannibal Bank, a seamount and an ecological hotspot in the coastal eastern tropical Pacific Ocean off Panama, explored the zonation, biodiversity, and the ecological processes that contribute to the seamount's elevated biomass. Here we describe the spatial structure of a benthic anomuran red crab population, using submarine video and autonomous underwater vehicle (AUV) photographs. High density aggregations and a swarm of red crabs were associated with a dense turbid layer 4-10 m above the bottom. The high density aggregations were constrained to 355-385 m water depth over the Northwest flank of the seamount, although the crabs also occurred at lower densities in shallower waters (∼280 m) and in another location of the seamount. The crab aggregations occurred in hypoxic water, with oxygen levels of 0.04 ml/l. Barcoding of Hannibal red crabs, and pelagic red crabs sampled in a mass stranding event in 2015 at a beach in San Diego, California, USA, revealed that the Panamanian and the Californian crabs are likely the same species, Pleuroncodes planipes, and these findings represent an extension of the southern endrange of this species. Measurements along a 1.6 km transect revealed three high density aggregations, with the highest density up to 78 crabs/m(2), and that the crabs were patchily distributed. Crab density peaked in the middle of the patch, a density structure similar to that of swarming insects.


Correlation between Disease Severity and the Intestinal Microbiome in Mycobacterium tuberculosis-Infected Rhesus Macaques.
The factors that determine host susceptibility to tuberculosis (TB) are poorly defined. The microbiota has been identified as a key influence on the nutritional, metabolic, and immunological status of the host, although its role in the pathogenesis of TB is currently unclear. Here, we investigated the influence of Mycobacterium tuberculosis exposure on the microbiome and conversely the impact of the intestinal microbiome on the outcome of M. tuberculosis exposure in a rhesus macaque model of tuberculosis. Animals were infected with different strains and doses of M. tuberculosis in three independent experiments, resulting in a range of disease severities. The compositions of the microbiotas were then assessed using a combination of 16S rRNA and metagenomic sequencing in fecal samples collected pre- and postinfection. Clustering analyses of the microbiota compositions revealed that alterations in the microbiome after M. tuberculosis infection were of much lower magnitude than the variability seen between individual monkeys. However, the microbiomes of macaques that developed severe disease were noticeably distinct from those of the animals with less severe disease as well as from each other. In particular, the bacterial families Lachnospiraceae and Clostridiaceae were enriched in monkeys that were more susceptible to infection, while numbers of Streptococcaceae were decreased. These findings in infected nonhuman primates reveal that certain baseline microbiome communities may strongly associate with the development of severe tuberculosis following infection and can be more important disease correlates than alterations to the microbiota following M. tuberculosis infection itself.IMPORTANCE Why some but not all individuals infected with Mycobacterium tuberculosis develop disease is poorly understood. Previous studies have revealed an important influence of the microbiota on host resistance to infection with a number of different disease agents. Here, we investigated the possible role of the individual's microbiome in impacting the outcome of M. tuberculosis infection in rhesus monkeys experimentally exposed to this important human pathogen. Although M. tuberculosis infection itself caused only minor alterations in the composition of the gut microbiota in these animals, we observed a significant correlation between an individual monkey's microbiome and the severity of pulmonary disease. More importantly, this correlation between microbiota structure and disease outcome was evident even prior to infection. Taken together, our findings suggest that the composition of the microbiome may be a useful predictor of tuberculosis progression in infected individuals either directly because of the microbiome's direct influence on host resistance or indirectly because of its association with other host factors that have this influence. This calls for exploration of the potential of the microbiota composition as a predictive biomarker through carefully designed prospective studies.


Predictors of Escalation to Intensive Care Unit Level of Care Among Admissions for Alcohol Withdrawal.
According to the 2019 National Survey on Drug Use and Health, 14.5 million people ages 12 and older had alcohol abuse disorder. Alcohol withdrawal syndrome (AWS) can be defined as a collection of physical symptoms experienced due to abrupt cessation of alcohol after long-term dependence. In instances where regular inpatient management fails to control AWS symptoms, patients are shifted to intensive care units (ICUs) for closer monitoring and prevention of life-threatening complications like withdrawal seizures and delirium tremens (DTs), labeled as severe alcohol withdrawal syndrome (SAWS). Although this represents a significant healthcare burden, minimal studies have been conducted to determine objective predictors. In this study, we aim to determine the effect of patient demographics, socio-economic status, biochemical parameters, and clinical factors on the need for escalation to ICU level of care among admissions for AWS. Our study showed that factors such as a history of DTs or alcohol-related seizures, the initial protocol of management, degree of reported alcohol usage, activation of rapid response teams, mean corpuscular value, alcohol level on admission, highest Clinical Institute Withdrawal Assessment Alcohol Revised (CIWA-Ar) scored during the hospital stay, and the total amount of sedatives used were significantly associated with escalation to ICU level of care. Clinicians must use these objective parameters to identify high-risk patients and intervene early. We encourage further studies to establish a scoring algorithm incorporating biochemical parameters to tailor management algorithms that might better suit high-risk patients.


High-dose-rate brachytherapy in combination with stenting offers a rapid and statistically significant improvement in quality of life for patients with endobronchial recurrence.
Symptomatic endobronchial recurrence after treatment failure is common in advanced non-small cell lung cancer. Optimal palliation has yet to be defined. We examined the combination of near-simultaneous, high-dose-rate (HDR) brachytherapy with stenting in this cohort of patients. Informed consent for intervention was obtained for 10 patients experiencing severely symptomatic (hemoptysis and oxygen-dependent shortness of breath), biopsy-proven endobronchial recurrence. All patients (eight men, two women, aged 52-77 years) had failed to respond to chemoradiotherapy for stage IIIB non-small cell lung cancer. Intervention consisted of placement of a self-expanding metallic stent (Nitinol/Ultraflex stent, Boston Scientific Co., Natick, MA) into the obstructing region. During that same bronchoscopy, HDR catheters were introduced. A dose of 6 Gy at 0.5 cm from the catheter was then delivered via an HDR unit. Two additional HDR sessions followed at weekly intervals for a total dose of 18 Gy. Patients under went follow-up bronchoscopes 1 month after the last HDR and when clinically indicated. All patients completed the prescribed therapy. No morbidity was noted from bronchoscopy, HDR, or stenting. All patients had rapid relief of signs and symptoms. At 1 week after stenting/first HDR, a statistically significant improvement in Karnofsky status was noted. Pulmonary palliation was maintained for the duration of their survival. The radio-opaque stent also offered significant advantages for catheter placement and verification during the HDR procedure. Although this series is small, the beneficial outcome obtained deserves further evaluation.


A kinetic study of the ouabain-induced efflux of norepinephrine from the dog saphenous vein.
Dog saphenous vein strips were incubated with [3H]norepinephrine ([3H]NE), 1.4 microM, after inhibition of the NE-metabolizing enzymes and extraneuronal uptake, and superfused for up to 290 min. From the 70th min onwards the strips were exposed to 10 microM ouabain, some of them being subject to electrical stimulation from the 140th min onwards. Other strips were exposed to either 1, 10 or 100 microM ouabain from the 70th min onwards. The spontaneous efflux of [3H]NE had a long half-time (156 min), and over 90% of the [3H]NE accumulated did not participate in efflux ("bound fraction"). Ouabain, 10 microM, induced a pronounced increase of the rate of efflux of [3H]NE, which was delayed in its onset and reached a maximum at t = 135 min of superfusion. Increasing the concentration of ouabain decreased both the delay to the beginning of the overflow and the time to maximum efflux and increased the maximum rate of efflux. In Ca(++)-free medium (during the superfusion period), the maximum rate of efflux was lower than in Ca(++)-containing medium, but was attained earlier. The bound fraction amounted to 22% when the efflux was induced by 10 microM ouabain in Ca(++)-containing medium, a value unnaffected by electrical stimulation but reduced markedly by omitting calcium. The results support the view that the efflux of [3H]NE induced by ouabain is delayed and that it is both carrier-mediated and due to exocytosis.


Peri-Procedure Laser Scar Therapy Protocol: A Pilot Survey of Plastic Surgeons' Practices.
Scar management using laser phototherapy continues to evolve as it gains wide acceptance among patients and providers. Despite widespread use of laser therapy, there are no guidelines or consensus published regarding optimal pre- and post-procedure patient management. Our objective is to gain insight into the best laser practices; we decided to poll colleagues nationwide. An online survey was distributed to members of the American Society of Plastic Surgeons. The survey consisted of 34 questions regarding pre- and post-procedure protocols related to laser scar therapy. Forty plastic surgeons responded to the survey. The survey demonstrated that ten types of lasers are currently used to treat scars. The most commonly used lasers are fractional Er:YAG (44.7%), pulsed dye (42.1%), and fractional CO2 (36.8%). On a Likert 3-point scale, providers favored the use of pre-procedural sunblock (2.12), topical analgesics (1.91), and oral antivirals (1.83). They also preferred the use of topical moisturizer (2.45), oral analgesics (2.29), and oral antivirals (1.97) as a part of the post-laser treatment regimen. The study verified there is no consensus regarding peri-procedure laser scar therapy regimens. As laser scar management continues to grow in popularity, this lack of consensus suggests the need for experts in the field to come together and propose agreeable protocols to be used as guidelines. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Ribosomal RNAs are tolerant toward genetic insertions: evolutionary origin of the expansion segments.
Ribosomal RNAs (rRNAs), assisted by ribosomal proteins, form the basic structure of the ribosome, and play critical roles in protein synthesis. Compared to prokaryotic ribosomes, eukaryotic ribosomes contain elongated rRNAs with several expansion segments and larger numbers of ribosomal proteins. To investigate architectural evolution and functional capability of rRNAs, we employed a Tn5 transposon system to develop a systematic genetic insertion of an RNA segment 31 nt in length into Escherichia coli rRNAs. From the plasmid library harboring a single rRNA operon containing random insertions, we isolated surviving clones bearing rRNAs with functional insertions that enabled rescue of the E. coli strain (Delta7rrn) in which all chromosomal rRNA operons were depleted. We identified 51 sites with functional insertions, 16 sites in 16S rRNA and 35 sites in 23S rRNA, revealing the architecture of E. coli rRNAs to be substantially flexible. Most of the insertion sites show clear tendency to coincide with the regions of the expansion segments found in eukaryotic rRNAs, implying that eukaryotic rRNAs evolved from prokaryotic rRNAs suffering genetic insertions and selections.


The signature and predictive value of immune parameters in patients with secondary hemophagocytic lymphohistiocytosis.
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare but fatal clinical syndrome, characterized by severe immune dysfunction and overwhelming inflammatory response. However, the host immune signature and also its role in predicting the clinical outcome are not fully described. The present study aims to investigate the host immune status of sHLH patients in the early stage of the disease, including lymphocyte subsets, phenotypes and cytokines, and also to explore its clinical value in prognosis. Sixty-four patients with sHLH admitted to a tertiary hospital in central China between 2018 and 2022 were enrolled, of which 21 were deceased. The subsets and phenotypes of lymphocytes, and the levels of cytokines in serum were analyzed. In patients with sHLH, the percentages of total T cells, CD8+ T cells, HLA-DR+ T cells, HLA-DR+CD8+ T cells, CD45RO+CD4+ T cells, and the levels of IL-1β, IL-2R, IL-6, IL-8, IL-10 and TNF-α were significantly increased, while the percentages of CD4+ T cells, NK cells, CD45RA+CD4+ T cells, CD45RA+ regulatory T (Treg) cells, the counts of total T cells, total B cells, CD4+ T cells, CD8+ T cells, NK cells, and the ratio of CD4+ T/CD8+ T cells were significantly decreased, compared with healthy controls (HC). In addition, dysregulation of host immune response and high inflammatory status were more obvious in deceased patients than that of survivors. Kaplan-Meier survival analysis and multivariate logistic regression analysis demonstrated that lower levels of CD4+ T cells count and CD28+CD4+ T cells percentage, but higher levels of NK cells percentage and IL-1β were poor prognostic indicators of sHLH. The evaluation of immunological markers has critical value for selecting prognostic markers and potential treatment target among adults with sHLH.


District team problem solving as an approach to district health programme planning: a review, and survey of its status in selected districts in Indonesia.
District team problem solving (DTPS) was developed by WHO in the 1980s to explicitly engage local stakeholders in decentralized planning and, in later iterations, budgeting of health services. It became WHO's global flagship approach to district-level health priority-setting and planning. DTPS entails multisectoral stakeholders (the team) using local data to prioritize and fund services, and should enhance capacity in management of decentralized healthcare. From the late 1990s, DTPS evolved through several phases in Indonesia. Multiple donors supported its use for planning maternal and child health (MCH) services, with substantive national government input, despite no formal assessment of its sustained uptake or benefits. In the context of new interest to promote DTPS for MCH in Indonesia, we assessed its status there in 2013-14, focussing on its implementation status and on associated MCH data collection (PWS-KIA). We used mixed methods to capture local challenges to and opportunities for DTPS in seven sub-national locations in 6 of Indonesia's 31 provinces. DTPS remained active only in the two locations whose local government ever allocated funds to the process; in the others, it stopped once the initial non-government funding ceased. An official decree establishing DTPS and team membership was only issued in four locations, and it was not evident that the intended multisectoral representation was achieved in any site. Trained DTPS facilitators remained available in only four locations. In all districts, interviewees described PWS-KIA as potentially serving a revived DTPS, but insufficiently robust to underwrite local advocacy for investment in MCH. Although efforts to introduce DTPS as a uniform approach to district MCH planning in Indonesia have not been sustained, strong commitment to evidence-based planning remains. Decentralized health planning processes require quality data, local government buy-in and associated funding, and should link explicitly to broader administrative planning processes and budget cycles.


A study of maternal lymphoid organs and the progeny following treatment with immunomodulating agents during pregnancy.
Whether differences in foetoplacental weight and post-implantation mortality in rodents are secondary to heterosis and inbreeding depression or antigenic differences between mother and foetus has been a continuing controversy. To determine whether non-specific depression or stimulation of the maternal immune system affects the success of the foetoplacental allograft, groups of virgin Fischer (Ag-B1) females of similar age and weight mated with DA (Ag-B4) males were treated with daily intraperitoneal injections of: (a) saline, (b) methylprednisolone (MP), 1-0 mg/kg, (c) cyclophosphamide (CY), 3.0 mg/kg, or (d) azathioprine (AZ), 3.0 mg/kg; or they were injected intraperitoneally on the fifth day of gestation with: (a) B. pertussis, 1.0 ml, (b) C. parvum, 0.2 ml, or (c) BCG, 0.1 ml. None of the immunostimulating agents were detrimental to the progeny, but the immunosupprissive drugs caused an increased percentage of foetal deaths and foetoplacental growth retardation. The reduced foetal and placental size induced by CY or AZ could be partially blocked by simultaneous maternal treatment with BCG. Analysis of mean maternal weight gain, spleen weight assays, changes in the lymph nodes draining the uterus and comparison of data from non-pregnant animals and syngeneic pregnancies treated with these agents suggest that immunosuppressive drugs reduce foetal survival rates and produce foetoplacental growth retardation via a combination of immunological and cytotoxic mechanisms.


Proximal humeral nonunions treated with fixed-angle locked plating and an intramedullary strut allograft.
To determine if the use of a fixed-angle locked plate plus an intramedullary allograft in the treatment of proximal humeral nonunions resulted in improved union. Retrospective clinical analysis of patients' medical charts and radiographs. Clinical practice of senior authors. Eighteen patients who presented to the senior authors' clinic between 2001 and 2007 with clinical and radiographic evidence of symptomatic proximal humeral nonunions that were treated with the described method were included for analysis. Patients with severe humeral head bone loss, avascular necrosis, evidence of arthrosis, and less than 12-month clinical follow-up were excluded. All patients with a symptomatic viable nonunion of the proximal humerus were treated with a fixed-angle locked plate and an intramedullary cortical allograft. Patients were followed until radiographic union was achieved, with this being the principle determinant of a successful outcome. Radiographic union was achieved in 17 of 18 patients (94%). The average follow-up was 26.5 months (range 12-49 months). The average time from surgery to radiographic union was 5.4 months (range 2.5-8.8 months). There was 1 failure of fixation, and 2 patients developed transient neurologic sequelae. Range of motion measurements obtained from the most recent clinical follow-up were 115 degrees (range 20-180 degrees) active forward elevation, 37 degrees (range 0-70 degrees) passive external rotation, and active internal rotation was to the 10th thoracic vertebrae. American Shoulder and Elbow Surgeon scores improved from a level of 40 preoperatively to 81 postoperatively, and visual analog scale scores improved from 6.7 to 1.5. Intramedullary strut allograft insertion combined with fixed-angle plating is an effective technique for treating viable nonunions of the proximal humerus and was successful in achieving union in 94% of our patients.


Simultaneous tracking of 3D actin and microtubule strains in individual MLO-Y4 osteocytes under oscillatory flow.
Osteocytes in vivo experience complex fluid shear flow patterns to activate mechanotransduction pathways. The actin and microtubule (MT) cytoskeletons have been shown to play an important role in the osteocyte's biochemical response to fluid shear loading. The dynamic nature of physiologically relevant fluid flow profiles (i.e., 1Hz oscillatory flow) impedes the ability to image and study both actin and MT cytoskeletons simultaneously in the same cell with high spatiotemporal resolution. To overcome these limitations, a multi-channel quasi-3D microscopy technique was developed to track the actin and MT networks simultaneously under steady and oscillatory flow. Cells displayed high intercellular variability and intracellular cytoskeletal variability in strain profiles. Shear Exz was the predominant strain in both steady and oscillatory flows in the form of viscoelastic creep and elastic oscillations, respectively. Dramatic differences were seen in oscillatory flow, however. The actin strains displayed an oscillatory strain profile more often than the MT networks in all the strains tested and had a higher peak-to-trough strain magnitude. Taken together, the actin networks are the more responsive cytoskeletal networks in osteocytes under oscillatory flow and may play a bigger role in mechanotransduction pathway activation and regulation.


Correlated decision making across multiple phases of olfactory-guided search in Drosophila improves search efficiency.
Nearly all motile organisms must search for food, often requiring multiple phases of exploration across heterogeneous environments. The fruit fly, Drosophila, has emerged as an effective model system for studying this behavior; however, little is known about the extent to which experiences at one point in their search might influence decisions in another. To investigate whether prior experiences impact flies' search behavior after landing, I tracked individually labelled fruit flies as they explored three odor-emitting but food-barren objects. I found two features of their behavior that are correlated with the distance they travel on foot. First, flies walked larger distances when they approached the odor source, which they were almost twice as likely to do when landing on the patch farthest downwind. Computational fluid dynamics simulations suggest this patch may have had a stronger baseline odor, but only ∼15% higher than the other two patches. This small increase, together with flies' high olfactory sensitivity, suggests that their flight trajectory used to approach the patches plays a role. Second, flies also walked larger distances when the time elapsed since their last visit was longer. However, the correlation is subtle and subject to a large degree of variability. Using agent-based models, I show that this small correlation can increase search efficiency by 25-50% across many scenarios. Furthermore, my models provide mechanistic hypotheses explaining the variability through either a noisy or stochastic decision-making process. Surprisingly, these stochastic decision-making algorithms enhance search efficiency in challenging but realistic search scenarios compared with deterministic strategies.


The lactate issue revisited: novel feeding protocols to examine inhibition of cell proliferation and glucose metabolism in hematopoietic cell cultures.
It is well established that cell proliferation in batch (unfed) hematopoietic cell cultures is greatly inhibited relative to that in cultures with feeding. What is not known, however, is the nature of this inhibition. On the basis of our observations in hematopoietic cultures that cell proliferation ceases when the lactate concentration ([lactate]) exceeds 20 mM (accompanied by a decrease in culture pH), we investigated the effect of lactate accumulation on cell proliferation, metabolism, and differentiation. We differ in our approach from previous efforts in that we have tried to more accurately recreate the manner in which lactate accumulates in culture by employing a daily feeding protocol in which [lactate] and/or pH in the fresh medium was adjusted to match the conditions prior to feeding. We conclude that the decrease in pH associated with lactate accumulation significantly inhibits both cell proliferation and metabolism. Although inhibition in cultures with high [lactate] and low pH is similar to that in unfed cultures, pH control in unfed cultures does not alleviate the inhibition, indicating that other inhibitory factors are also present. Thus, pH control is necessary, but not sufficient, to eliminate inhibition of cell growth and metabolism in unfed hematopoietic cell cultures. We also conclude that high [lactate] and low pH have little effect on cell differentiation in fed cultures, although there is evidence to suggest that low pH may play a role in monocyte differentiation in unfed cultures.


Effects of olive oil and its minor constituents on serum lipids, oxidative stress, and energy metabolism in cardiac muscle.
Recent lines of evidence suggest that the beneficial effects of olive oil are not only related to its high content of oleic acid, but also to the antioxidant potential of its polyphenols. The aim of this work was determine the effects of olive oil and its components, oleic acid and the polyphenol dihydroxyphenylethanol (DPE), on serum lipids, oxidative stress, and energy metabolism on cardiac tissue. Twenty four male Wistar rats, 200 g, were divided into the following 4 groups (n = 6): control (C), OO group that received extra-virgin olive oil (7.5 mL/kg), OA group was treated with oleic acid (3.45 mL/kg), and the DPE group that received the polyphenol DPE (7.5 mg/kg). These components were administered by gavage over 30 days, twice a week. All animals were provided with food and water ad libitum. The results show that olive oil was more effective than its isolated components in improving lipid profile, elevating high-density lipoprotein, and diminishing low-density lipoprotein cholesterol concentrations. Olive oil induced decreased antioxidant Mn-superoxide dismutase activity and diminished protein carbonyl concentration, indicating that olive oil may exert direct antioxidant effect on myocardium. DPE, considered as potential antioxidant, induced elevated aerobic metabolism, triacylglycerols, and lipid hydroperoxides concentrations in cardiac muscle, indicating that long-term intake of this polyphenol may induce its undesirable pro-oxidant activity on myocardium.


Deep computational phenotyping of genomic variants impacting the SET domain of KMT2C reveal molecular mechanisms for their dysfunction.
Introduction: Kleefstra Syndrome type 2 (KLEFS-2) is a genetic, neurodevelopmental disorder characterized by intellectual disability, infantile hypotonia, severe expressive language delay, and characteristic facial appearance, with a spectrum of other distinct clinical manifestations. Pathogenic mutations in the epigenetic modifier type 2 lysine methyltransferase KMT2C have been identified to be causative in KLEFS-2 individuals. Methods: This work reports a translational genomic study that applies a multidimensional computational approach for deep variant phenotyping, combining conventional genomic analyses, advanced protein bioinformatics, computational biophysics, biochemistry, and biostatistics-based modeling. We use standard variant annotation, paralog annotation analyses, molecular mechanics, and molecular dynamics simulations to evaluate damaging scores and provide potential mechanisms underlying KMT2C variant dysfunction. Results: We integrated data derived from the structure and dynamics of KMT2C to classify variants into SV (Structural Variant), DV (Dynamic Variant), SDV (Structural and Dynamic Variant), and VUS (Variant of Uncertain Significance). When compared with controls, these variants show values reflecting alterations in molecular fitness in both structure and dynamics. Discussion: We demonstrate that our 3D models for KMT2C variants suggest distinct mechanisms that lead to their imbalance and are not predictable from sequence alone. Thus, the missense variants studied here cause destabilizing effects on KMT2C function by different biophysical and biochemical mechanisms which we adeptly describe. This new knowledge extends our understanding of how variations in the KMT2C gene cause the dysfunction of its methyltransferase enzyme product, thereby bearing significant biomedical relevance for carriers of KLEFS2-associated genomic mutations.


Improving Documentation and Communication Using Operative Note Proformas.
Accurate and detailed documentation of surgical procedures is part of good clinical practice, set out by the General Medical Council (GMC). Knee arthroscopy often involves large data sets which require accurate documentation for future assessment and management. This study assesses the quality of documentation of knee arthroscopy, followed by an evaluation of the implementation of a novel operative proforma. A review of 30 consecutive knee arthroscopy operation notes were analysed for missing information, set against a standardised 30 point criteria. An operation proforma was then introduced, and a further 30 consecutive knee arthroscopy operation notes were analysed. We evaluated allied health professional satisfaction with a Likert point scale survey of 21 allied healthcare professionals (recovery and ward nurses, and physiotherapists) following introduction of the proforma. The mean number of missing items on a 30 point scale was 8.8 (range 0 to 23). Examination under anaesthesia was missed in 43% of cases, tourniquet time in 37% of cases, and wear results in 17% of cases. Following introduction of the proforma, the mean number of missing items was 1.1 (range 0 to 24; p <0.001). This rose to 3.8 after one year (p <0.001) before improvement to 0.7 (p <0.01) with a new and improved proforma. Eighty percent strongly agreed the operation note was clearer, 90% strongly agreed it was more legible, 90% strongly agreed it was more understandable, 50% strongly agreed there was more information recorded, and 100% strongly agreed on the proforma having been improved. Knee arthroscopy is a common procedure with large data sets, which can often be missed or incomplete. A standardised proforma results in a statistically significant improvement in documentation and reduces the incidence of missing information. They are subjectively clearer, more legible, and generally better compared with handwritten notes. This study demonstrates the improvements in healthcare documentation, both clinically and legally, following introduction of a simple proforma. This concept should be applicable to different specialities and procedures in healthcare.


Does Instruction of Oral Health Behavior for Workers Improve Work Performance?-Quasi-Randomized Trial.
Oral disease can cause economic loss due to impaired work performance. Therefore, improvement of oral health status and prevention of oral disease is essential among workers. The purpose of this study was to investigate whether oral health-related behavioral modification intervention influences work performance or improves oral health behavior and oral health status among Japanese workers. We quasi-randomly separated participants into the intervention group or the control group at baseline. The intervention group received intensive oral health instruction at baseline and a self-assessment every three months. Both groups received oral examinations and answered the self-questionnaire at baseline and at one-year follow-up. At follow-up, the prevalence of subjects who use fluoride toothpastes and interdental brushes/dental floss were significantly higher in the intervention group than in the control group. Three variables (tooth brushing in workplace, using fluoride toothpaste, and experience of receiving tooth brushing instruction in a dental clinic) showed significant improvement only in the intervention group. On the other hand, work performance and oral status did not significantly change in either group. Our intensive oral health-related behavioral modification intervention improved oral health behavior, but neither work performance nor oral status, among Japanese workers.


Effects of weak bases on the degradation of endogenous and exogenous proteins by rat yolk sacs.
In rat yolk sacs incubated in vitro, the rates of degradation of endogenous [3H]leucine-labelled proteins and of pinocytically ingested 125I-labelled bovine serum albumin were both decreased in the presence of either ammonium, methylammonium or ethylammonium ions (0-20 mM) or much lower concentrations of chloroquine (0-500 microM). These effects were also accompanied by an inhibition of pinocytosis, as measured by the rate of uptake of 125I-labelled polyvinylpyrrolidone, and by a fall in the [ATP]/[ADP] ratio within the tissue. Re-incubation in inhibitor-free medium of yolk sacs previously exposed to a weak base restored pinocytic and proteolytic capacities, except for tissues exposed to chloroquine at concentrations above 0.1 mM (these appeared to be cytotoxic); an attendent rise in [ATP]/[ADP] ratios to near normal values was also observed. Weak bases, at concentrations that fully arrested the breakdown of 125I-labelled albumin, failed to inhibit by more than 45% the degradation of [3H]leucine-labelled endogenous proteins. Since 125I-labelled bovine serum albumin has been shown to be degraded entirely intralysosomally by yolk sacs, this suggests either that the hydrolysis of endogenous proteins is shared between lysosomes and some other site or that, unlike 125I-labelled albumin, some endogenous proteins can be degraded within lysosomes at abnormally high pH.


Isolation and characterization of sex-linked female-sterile mutants in Drosophila melanogaster.
The purpose of the experiments described was to identify X chromosome genes functioning mainly or exclusively during oogenesis. Two mutagenesis experiments were carried out with ethyl methane sulfonate. Following treatment inducing 60% lethals, 9% of the treated X chromosomes carried a female sterility mutation which did not otherwise seriously affect viability. Among--95 isolated mutants, 19 were heat-sensitive and 5 cold-sensitive. The mutants have been classified as follows: I (16 mutants; 12 complementation groups): the females laid few or no eggs; the defect concerned either ovulation or oogenesis. II (37 mutants; 18 complementation groups): the female laid morphologically abnormal eggs, often with increased membrane permeability. III A (13 mutants; at least 8 complementation groups): the homozygous females were sterile if mated to mutant males; their progeny (homo- and hemizygous) died at a late embryonic stage (11 mutants), at the larval stage (1 mutant) or at the pupal stage (1 mutant). However fertility was partly restored by breeding to wild-type males as shown by survival of some heterozygous descendants. III B (29 mutants; 22 complementation groups): the fertility of the females was not restored by breeding to a wild-type male. Most of the eggs of 13 of the mutants died at a late stage of embryogenesis. The eggs of the others ceased development earlier or, perhaps, remained unfertilized. The distribution of the number of mutants per complementation group led to an estimation of a total of about 150 X-linked genes involved in female fertility. The females of three mutants, heat-sensitive and totally sterile at 29 degrees, produced at a lower temperature descendants morphologically abnormal or deprived of germ cells. Three other mutants not described in detail showed a reduction in female fertility with many descendants lacking germ cells. A desirable mutant which was not recovered was one with normal fertile females producing descendants which, regardless of their genotype, bore specific morphological abnormalities. The value of the mutants isolated for analysis of the complex processes leading to egg formation and initiation of development is discussed.


Contextual body image and athletes' disordered eating: the contribution of athletic body image to disordered eating in high performance women athletes.
The present study investigated the contribution of a contextual body image perspective to understanding disordered eating in high performance women athletes. Because existing questionnaires were not suitable for measuring body image in the contexts of sport and daily life, we developed the 'Contextual Body Image Questionnaire for Athletes' (CBIQA) in which body image is divided into 'appearance', 'muscularity', 'thin-fat self-evaluations' and 'thin-fat perceived opinions of others', in both contexts. In Study 1, the internal validity and reliability of this questionnaire was established in a general, heterogeneous sample of female sport participants and exercisers. In Study 2, the external validity was determined in a sample of 52 high performance women athletes who mainly participated in aesthetic or endurance sports, 19 of which were classified with and 33 without disordered eating. The results of Study 2 showed that both 'thin-fat self' and 'thin-fat opinions of others' in sport made significant unique contributions to explaining eating disorder variance, indicating the important role of athletic body image. In conclusion, the contextual body image approach seems to be a promising framework for a better understanding of athletes' disordered eating.


On-chip electrocatalytic microdevice: an emerging platform for expanding the insight into electrochemical processes.
Electrochemical conversion is an important process in renewable energy conversion, and electrocatalysts play a vital role since they can improve the rate and efficiency of chemical transformations. Thus, the continuing interest in electrocatalysis is fueled both in terms of mechanism exploration and performance optimization, and this field is continuously being updated. However, conventional electrochemical methods still have room to be explored, such as in situ dynamic monitoring, external field regulation, and single-entity electrocatalytic detection. Noteworthily, inspired by the recent success in nanoelectronic semiconductor devices, the emerging field of on-chip electrocatalytic microdevices, focusing on the electrochemical behaviors at individual nanowire/nanosheet as the working electrode, has emerged as a powerful alternative platform to the traditional techniques. This unique device configuration enables several advantages, such as in situ electronic/electrochemical measurements and adjustable microstructure of individual catalysts, which is constantly expanded to directly probe electrochemical processes to obtain previously inaccessible information. Hence, herein, we first introduce the device configuration and its advantages as an emerging platform. Subsequently, the attempts to expand the insight into electrochemical processes through this type of microdevice are explicitly analyzed and summarized including dynamic monitoring, external field regulation, identification of active sites, and single structural factor regulation. Finally, some personal perspectives on the challenges and future research directions in this promising area are also presented. We believe that this review will provide new insight into electrochemical processes, ranging from dynamic exploration to performance optimization.


Characterization of ficolins as novel elastin-binding proteins and molecular cloning of human ficolin-1.
A novel elastin-binding protein, EBP-37, was recently identified and purified from human plasma. Its partial amino acid sequences showed significant homology to porcine ficolins, which were originally purified from porcine uterus membranes as multimeric proteins with fibrinogen- and collagen-like domains. Here we report the presence of ficolins in an elastin-binding fraction of porcine plasma and the direct binding of recombinant porcine ficolin-alpha to elastin. In addition, a cDNA encoding a human counterpart of porcine ficolins that is composed of 319 amino acids and is different from EBP-37 was cloned and named human ficolin-1. Northern blotting of various human tissues revealed that human ficolin-1 mRNA is highly expressed in peripheral blood leukocytes. These data suggested that there are at least two kinds of ficolin-related proteins in both pig and human, and they may function as plasma proteins with elastin-binding activities.


Local delivery of the cationic steroid antibiotic CSA-90 enables osseous union in a rat open fracture model of Staphylococcus aureus infection.
Treatment of infected open fractures remains a major clinical challenge. In this study, we investigated the novel broad-spectrum antibiotic CSA-90 (cationic steroid antibiotic-90) as an antimicrobial agent. CSA-90 was screened in an osteoblast cell culture model for effects on differentiation and mineralization. Local delivery of CSA-90 was then tested alone and in combination with recombinant human bone morphogenetic protein-2 (rhBMP-2) in a mouse ectopic bone formation model (n=40 mice) and in a rat open fracture model inoculated with pathogenic Staphylococcus aureus (n=84 rats). CSA-90 enhanced matrix mineralization in cultured osteoblasts and increased rhBMP-2-induced bone formation in vivo. All animals in which an open fracture had been inoculated with Staphylococcus aureus and not treated with local CSA-90, including those treated with rhBMP-2, had to be culled prior to the experimental end point (six weeks) because of localized osteolysis and deterioration of overall health, whereas CSA-90 prevented establishment of infection in all open fractures in which it was used (p≤0.012). Increased union rates were seen for the fractures treated with rhBMP-2 or with the combination of rhBMP-2 and CSA-90 compared with that observed for the fractures treated with CSA-90 alone (p=0.04). CSA-90 can promote osteogenesis and be used for prevention of Staphylococcus aureus infection in preclinical models. Local delivery of CSA-90 represents a novel strategy for prevention of infection and may have specific benefits in the context of orthopaedic injuries.


Quantified Binding Scale of Competing Ligands at the Surface of Gold Nanoparticles: The Role of Entropy and Intermolecular Forces.
A basic understanding of the driving forces for the formation of multiligand coronas or self-assembled monolayers over metal nanoparticles is mandatory to control and predict the properties of ligand-protected nanoparticles. Herein, 1 H nuclear magnetic resonance experiments and advanced density functional theory (DFT) modeling are combined to highlight the key parameters defining the efficiency of ligand exchange on dispersed gold nanoparticles. The compositions of the surface and of the liquid reaction medium are quantitatively correlated for bifunctional gold nanoparticles protected by a range of competing thiols, including an alkylthiol, arylthiols of varying chain length, thiols functionalized by ethyleneglycol units, and amide groups. These partitions are used to build scales that quantify the ability of a ligand to exchange dodecanethiol. Such scales can be used to target a specific surface composition by choosing the right exchange conditions (ligand ratio, concentrations, and particle size). In the specific case of arylthiols, the exchange ability scale is exploited with the help of DFT modeling to unveil the roles of intermolecular forces and entropic effects in driving ligand exchange. It is finally suggested that similar considerations may apply to other ligands and to direct biligand synthesis.


Initial signaling response to acute exercise bout is similar in hearts of rats bred for divergent exercise capacities.
Rats artificially selected as low capacity runners (LCR) exhibit features of the metabolic syndrome, and blunted exercise training-induced cardiac hypertrophy compared with high capacity runners (HCR). We tested the hypothesis that the divergent cardiac phenotypes may be due to diminished activation of signaling proteins in LCR vs HCR rats. LCR (n=18) and HCR (n=18) rats were randomly assigned to acute exercise or control groups. Ten minutes after a 10-min bout of high intensity treadmill exercise, rats were euthanized, and left ventricles (LV) were harvested. LV homogenates were immunoblotted for phosphorylated and total levels of extracellular regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), p38, Akt, S6, and the ribosomal S6 protein kinases S6K and p90RSK. Alterations in protein ubiquitination were examined as an index of protein turnover. In LCR and HCR rats, S6 was activated to a similar extent after exercise (5-fold vs control), as were JNK1/2, p38, and ERK1/2 (each 1.5-fold). Exercise significantly reduced ubiquitination of some proteins, suggesting diminished post-exercise protein degradation. That no significant LCR/HCR differences were observed 10-min post-exercise in the signaling pathways studied herein suggests that the source of the differing cardiac phenotypes in LCR/HCR rats may involve differing activation times and/or other signaling pathways.


Automated quantitation of cold-inducible human brown adipose tissue with FDG PET/CT with application to fibromyalgia.
Increasing recognition of the importance of brown adipose tissue (BAT) motivates the development of reproducible and quantitative methods for measuring it. Positron emission tomography (PET)/computerized tomography (CT) with 18F-fluorodeoxyglucose (FDG) has become the principal method to non-invasively detect brown adipose tissue (BAT) in humans. Improvements in quantitation and standardization will drive further clinical application. One disorder hypothesized to involve dysregulation in thermoregulation and the processing of pain involving BAT is fibromyalgia syndrome (FMS). This report describes an approach with additional technical standardization to measure cold-inducible, BAT activity (ci-BAT) semi-quantitatively and reliably with minimal operator intervention with the FDG PET/CT technique. Ci-BAT was measured to test whether FMS patients have decreased BAT activation compared to normal controls. Threshold parameters to optimally separate ci-BAT from non-ci-BAT were developed based on the distribution of the pixel-wise parametric data from each merged PET/CT scan for each study session occurring on different days. BAT activity was the same under warm conditions in both control and FMS subjects attesting to reproducibility and reliability. However, considerable variability arose between groups at cool temperatures consistent with other literature. Increases in ci-BAT activity were significantly less in FMS patients than in controls, as hypothesized. Ci-BAT recruitment can be quantified non-invasively using FDG PET/CT using semi-automated techniques in human subjects across different diagnostic groups or within groups undergoing manipulations of interest.


The Structure and Function of Acylglycerophosphate Acyltransferase 4/ Lysophosphatidic Acid Acyltransferase Delta (AGPAT4/LPAATδ).
Lipid-modifying enzymes serve crucial roles in cellular processes such as signal transduction (producing lipid-derived second messengers), intracellular membrane transport (facilitating membrane remodeling needed for membrane fusion/fission), and protein clustering (organizing lipid domains as anchoring platforms). The lipid products crucial in these processes can derive from different metabolic pathways, thus it is essential to know the localization, substrate specificity, deriving products (and their function) of all lipid-modifying enzymes. Here we discuss an emerging family of these enzymes, the lysophosphatidic acid acyltransferases (LPAATs), also known as acylglycerophosphate acyltransferases (AGPATs), that produce phosphatidic acid (PA) having as substrates lysophosphatidic acid (LPA) and acyl-CoA. Eleven LPAAT/AGPAT enzymes have been identified in mice and humans based on sequence homologies, and their localization, specific substrates and functions explored. We focus on one member of the family, LPAATδ, a protein expressed mainly in brain and in muscle (though to a lesser extent in other tissues); while at the cellular level it is localized at the trans-Golgi network membranes and at the mitochondrial outer membranes. LPAATδ is a physiologically essential enzyme since mice knocked-out for Lpaatδ show severe dysfunctions including cognitive impairment, impaired force contractility and altered white adipose tissue. The LPAATδ physiological roles are related to the formation of its product PA. PA is a multifunctional lipid involved in cell signaling as well as in membrane remodeling. In particular, the LPAATδ-catalyzed conversion of LPA (inverted-cone-shaped lipid) to PA (cone-shaped lipid) is considered a mechanism of deformation of the bilayer that favors membrane fission. Indeed, LPAATδ is an essential component of the fission-inducing machinery driven by the protein BARS. In this process, a protein-tripartite complex (BARS/14-3-3γ/phosphoinositide kinase PI4KIIIβ) is recruited at the trans-Golgi network, at the sites where membrane fission is to occur; there, LPAATδ directly interacts with BARS and is activated by BARS. The resulting formation of PA is essential for membrane fission occurring at those spots. Also in mitochondria PA formation has been related to fusion/fission events. Since PA is formed by various enzymatic pathways in different cell compartments, the BARS-LPAATδ interaction indicates the relevance of lipid-modifying enzymes acting exactly where their products are needed (i.e., PA at the Golgi membranes).


Eating disorders: Prevalence and associated factors among health occupation students in Monastir University (Tunisia).
Despite their high prevalence and severity among youth, national researches concerning eating disordered behavior among undergraduate students remains rare. Hence, it is imperative to determine the amplitude and to identify the risk factors of eating disorders (ED) to enable effective interventions. To assess prevalence and associated factors of (ED) among health occupation students in the university of Monastir during 2013. A cross sectional study using a self-administered questionnaire which was distributed by approaching directly students. The following items were collected: demographic, socioeconomic and educational characteristics; self-esteem; previous dieting; perceived stress score(Cohen's scale); depression (Beck Depression); sleep quality; sport practice; cyber addiction (Orman scale) and alcohol regular use (CRAFT-ADOPSA questionnaire). SCOFF questionnaire was used to identify students at risk of ED. A total of 974 students were included in the study. The mean age of students was 22.8 (Standard Deviation=2.2) with a sex ratio of 0.43. The prevalence of ED according to SCOFF questionnaire was 35%; 95% CI [32.0-38.5]. It was higher among female (39.8; 95% CI [35.8-43.7]) compared to male (24.3; 95% CI [18.8-29.7]) with a statistically significant difference (p<10-3). The risk factors associated independently with an eating disorder were "Previous dieting" (aOR=4.13; 95% CI [2.79-6.12]),"Sex" (aOR=1.77. 95% CI [1.13-2.77]) and "Repeat a year" (aOR=1.76; 95% CI [1.09-2.85]). The prevalence of health occupation students at risk of ED was high. These results emphasizes the need for diversified and adapted prevention and health education policies as well as a need for a systematic screening of ED among students in order to start an early treatment that can improve their prognosis.