Resident Microglia Activate before Peripheral Monocyte Infiltration and p75NTR Blockade Reduces Microglial Activation and Early Brain Injury after Subarachnoid Hemorrhage.
Early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (SAH) contributes to high morbidity and mortality. Although it is well recognized that acute neuroinflammation reaction is one of the most important triggers of EBI, pharmacotherapy proved to be clinically effective against the initiating of neuroinflammation after SAH is lacking. The resident microglia and infiltrated peripheral monocyte are two main types of immune cells in central nervous system (CNS) and control the inflammation process in brain after SAH. But the time course and relative contributions of these two immune cell activations after SAH are unknown. The p75 neurotrophin receptor (p75NTR), member of TNF receptor superfamily, expresses on infiltrated peripheral monocytes and suppresses their proinflammatory action after brain insults. But the p75NTR expression on resident microglia in vivo is rarely explored and their function keeps elusive. Therefore, we designed this study to investigate the time course of resident microglia activation and peripheral monocyte infiltration, as well as the microglial expression of p75NTR by using CX3C-chemokine receptor 1 (Cx3cr1) and chemokine receptor 2 (Ccr2) double transgenic mice (Cx3cr1GFP/+Ccr2RFP/+) after SAH. The results showed activated microglia was observed in cortex as early as 24 h and further increased at 48 and 72 h post SAH, while the infiltrated monocyte was not found until 72h. In addition, activated microglia expressed p75NTR acutely and p75NTR specific antagonist TAT-Pep5 significantly reduced microglia activation, neuroinflammation and EBI from 24 to 72 h. Together, these data suggest that the early neuroinflammation reaction might be initiated and intensified mainly by resident microglia rather than infiltrated monocyte at least in the first 48 h after SAH and p75NTR blockading by TAT-Pep5P might alleviate EBI through mediating microglial activation.


Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies.
Mutations in alpha-synuclein (alpha S) and parkin cause heritable forms of Parkinson disease (PD). We hypothesized that neuronal parkin, a known E3 ubiquitin ligase, facilitates the formation of Lewy bodies (LBs), a pathological hallmark of PD. Here, we report that affinity-purified parkin antibodies labeled classical LBs in substantia nigra sections from four related human disorders: sporadic PD, inherited alphaS-linked PD, dementia with LBs (DLB), and LB-positive, parkin-linked PD. Anti-parkin antibodies also detected LBs in entorhinal and cingulate cortices from DLB brain and alphaS inclusions in sympathetic gangliocytes from sporadic PD. Double labeling with confocal microscopy of DLB midbrain sections revealed that approximately 90% of anti-alpha S-reactive LBs were also detected by a parkin antibody to amino acids 342 to 353. Accordingly, parkin proteins, including the 53-kd mature isoform, were present in affinity-isolated LBs from DLB cortex. Fluorescence resonance energy transfer and immunoelectron microscopy showed that alphaS and parkin co-localized within brainstem and cortical LBs. Biochemically, parkin appeared most enriched in cytosolic and postsynaptic fractions of adult rat brain, but also in purified, alpha S-rich presynaptic elements that additionally contained parkin's E2-binding partner, UbcH7. We conclude that parkin and UbcH7 are present with alphaS in subcellular compartments of normal brain and that parkin frequently co-localizes with alpha S aggregates in the characteristic LB inclusions of PD and DLB. These results suggest that functional parkin proteins may be required during LB formation.


Hydrodynamic synchronization of colloidal oscillators.
Two colloidal spheres are maintained in oscillation by switching the position of an optical trap when a sphere reaches a limit position, leading to oscillations that are bounded in amplitude but free in phase and period. The interaction between the oscillators is only through the hydrodynamic flow induced by their motion. We prove that in the absence of stochastic noise the antiphase dynamical state is stable, and we show how the period depends on coupling strength. Both features are observed experimentally. As the natural frequencies of the oscillators are made progressively different, the coordination is quickly lost. These results help one to understand the origin of hydrodynamic synchronization and how the dynamics can be tuned. Cilia and flagella are biological systems coupled hydrodynamically, exhibiting dramatic collective motions. We propose that weakly correlated phase fluctuations, with one of the oscillators typically processing the other, are characteristic of hydrodynamically coupled systems in the presence of thermal noise.


Chemoradiotherapy after gemcitabine plus erlotinib in patients with locally advanced pancreatic cancer.
To evaluate the outcomes of chemoradiotherapy (CRT) after neoadjuvant chemotherapy consisting of gemcitabine and erlotinib for unresectable locally advanced pancreatic cancer. Between 2010 and 2014, 24 patients with unresectable pancreatic cancer received neoadjuvant gemcitabine/erlotinib followed by CRT. There were 9 men and 15 women, and median age was 61 years (range 48-77). Radiotherapy (RT) was delivered to the tumor and regional lymph nodes with a median dose of 50.4 Gy (range 50.4-56). All patients received concurrent chemotherapy, with 5-fluorouracil (5-FU), capecitabine or gemcitabine and 17 patients received maintenance chemotherapy with gemcitabine plus erlotinib, 5-FU plus leukovorin or capecitabine plus oxaliplatin. The median follow-up period was 17 months (range 7-31). The median overall survival (OS) and post-RT OS (PROS) were 17.8 and 10.7 months, respectively. On multivariate analysis, RT dose (p=0.005) and maintenance chemotherapy (p=0.019) were significant prognostic factors for OS. In addition, RT dose ≥54Gy (p=0.021) and concurrent gemcitabine (p=0.012) were identified as favorable prognostic factors for PROS. Grade 3 hematologic and gastrointestinal toxicities occurred in 3 and 2 patients, respectively. Intensive treatment with gemcitabine-based CRT, high RT dose, and maintenance chemotherapy may improve survival outcomes in locally advanced pancreatic cancer patients receiving neoadjuvant gemcitabine/erlotinib.


In vivo dynamic cell tracking with long-wavelength excitable and near-infrared fluorescent polymer dots.
Development of cell-based therapeutic systems has attracted great interest in biomedicine. In vivo cell tracking by fluorescence provides indispensable information for further advancing cell therapy in clinical applications. However, it is still challenging in many cases because of the limited light penetration depth as well as the variations in fluorescent probes, cell lines, and labeling brightness. Here, we designed highly fluorescent polymer dots (Pdots) with far-red-light absorption and near-infrared (NIR) emission for cell tracking. The Pdots consisted of a donor-acceptor polymer blending system where intra-particle energy transfer yielded a narrow-band emission at 800 nm with a high quantum yield of ~0.22. We investigated biocompatibility and cell labeling brightness of the Pdots coated with cell penetrating peptides. Flow cytometry indicated that the cell-labeling brightness of both stem cells and cancer cells increased as much as ~4 orders of magnitude comparing the intensity measurements of labeled cells and controls. Yet, in vivo cell tracking results revealed distinctive fluorescence distribution for the same number of cells that were administered into mice through the tail vein. The stem cells initially accumulated in the lung and remained for seven days, whereas the cancer cells tended to be cleared by the liver in four days. The difference is likely due to the fact that cancer cells are easily attacked by the immune system, whereas stem cells have low immunogenicity. Results obtained herein confirm that NIR-fluorescent Pdots are promising platforms for in vivo cell tracking in small animals.


A role for control in an action-specific effect on perception.
According to the action-specific account of perception, people perceive the spatial layout of the environment in relation to their ability to act. Pioneering research by Bhalla and Proffitt (1999) demonstrated that hills were judged as steeper to perceivers with less physiological potential. Since this seminal work, much research has shown these action-specific effects generalize beyond hill slant perception and beyond physiological potential, but the underlying mechanisms are underspecified. The present experiments explore the potential mechanism that information about action is integrated with visual information about the target. According to an integration account, information from various sources are weighted, and the strength of these weights dictates the strength of that source of information on the resulting percept. One prediction is that it should be possible to vary the strength of the weights and thereby vary the size of a particular effect. To reduce the effect of action on perception, control over the action was taken away from participants. As predicted, losing control reduced the impact of action on spatial perception. This is the first reported instance of a partial action-specific effect, and is consistent with an integration-based mechanism. (PsycINFO Database Record


Second Wave, Late-Stage Neuroinflammation in Cleared Brains of Aged 5xFAD Alzheimer's Mice Detected by Macrolaser Light Sheet Microscopy Imaging.
This study leverages the innovative imaging capabilities of macrolaser light-sheet microscopy to elucidate the 3D spatial visualization of AD-associated neuropathologic networks in the transparent brains of 44-week-old 5xFAD mice. Brain samples from ten AD and seven control mice were prepared through a hydrophilic tissue-clearing pipeline and immunostained with thioflavin S (β-amyloid), anti-CD11b antibody (microglia), and anti-ACSA-2 antibody (astrocytes). The 5xFAD group exhibited significantly higher average total surface volumes of β-amyloid accumulation than the control group (AD, 898,634,368 µm3 [383,355,488-1,324,986,752]; control, 33,320,178 µm3 [11,156,785-65,390,988], p = 0.0006). Within the AD group, there was significant interindividual and interindividual variability concerning the number and surface volume of individual amyloid particles throughout the entire brain. In the context of neuroinflammation, the 5xFAD group showed significantly higher average total surface volumes of anti-ACSA-2-labeled astrocytes (AD, 59,064,360 µm3 [27,815,500-222,619,280]; control, 20,272,722 µm3 [9,317,288-27,223,352], p = 0.0047) and anti-CD11b labeled microglia (AD, 51,210,100 µm3 [15,309,118-135,532,144]; control, 23,461,593 µm3 [14,499,170-27,924,110], p = 0.0162) than the control group. Contrary to the long-standing finding that early-stage neuroinflammation precedes the subsequent later-stage of neurodegeneration, our data reveal that the second wave, late-stage active neuroinflammation persists in the aged AD brains, even as they continue to show signs of ongoing neurodegeneration and significant amyloid accumulation.


Unilateral Condylar Fracture with Review of Treatment Modalities in 30 Cases - An Evaluative Study.
The treatment of subcondylar mandible fractures is a topic of debate and can be variable even though these fractures are commonly seen. The present study aimed at evaluation of various treatment modalities for unilateral condylar fracture in adults. Thirty patients with unilateral condylar fractures between the age of 18 and 60 years were evaluated. Treatment protocol included closed reduction for 15 patients and open reduction for 15 patients. Assessment was done functionally for maximum interincisal mouth opening, deviation on maximum interincisal mouth opening, occlusion and facial nerve function, and radiologically for ramus height shortening. In general, there were no statistically significant differences between closed and open methods. Both the treatment options for condylar fractures of the mandible yielded acceptable results. Closed treatment appears to be a safe and appropriate modality for most unilateral condylar fractures. Although the open group, in general, showed similar outcomes, this treatment should be reserved for limited indications. The present study has confirmed that both treatment options can yield acceptable results. On clinical examination, there was no significant difference in mouth opening measures, the incidence of occlusal disturbances or in the degree of pain perception.


Men perspectives on attending antenatal care visits with their pregnant partners in Misungwi district, rural Tanzania: a qualitative study.
Mens'attendance with their pregnant partners at facility-based antenatal care (ANC) visits is important for maternal and child health and gender equality yet remains uncommon in parts of rural Tanzania. This study examined men's perspectives on attending ANC with their pregnant partners in Misungwi District, Tanzania. Twelve individual interviews and five focus group discussions were conducted using semi-structured questionnaires with fathers, expectant fathers, and in-depth interviews were done to health providers, volunteer community health workers, and village leaders. Interviews were recorded and transcribed in Swahili and later translated to English. The research team conducted thematic analysis to identify common themes among interviews. We identified two broad themes on the barriers to male attendance at facility-based ANC visits: (1) Perceived exclusion during ANC visits among men (2) Traditional gender norms resulting to low attendance among men. Attendance at health facility for ANC visits by men with their pregnant partners in the study areas were challenged by structural and local cultural norms. At the facility men were uncomfortable to sit with women due to lack of specific waiting area for men and that they perceived to be neglected. Local cultural norms demanded women to have secrecy in pregnancy while men perceived not to have a role of being with their partners during ANC visits.


Down-regulation and clinical significance of miR-7-2-3p in papillary thyroid carcinoma with multiple detecting methods.
Altered miRNA expression participates in the biological progress of thyroid carcinoma and functions as a diagnostic marker or therapeutic agent. However, the role of miR-7-2-3p is currently unclear. The authors' study was the first investigation of miR-7-2-3p expression level and diagnostic ability in several public databases. Potential target genes were obtained from DIANA Tools, and function enrichment analysis was then performed. Furthermore, the authors examined expression levels of potential targets in the Human Protein Atlas (HPA) and the Cancer Genome Atlas (TCGA). Finally, the potential transcription factors (TFs) were predicted by JASPAR. TCGA, GSE62054, GSE73182, GSE40807, and GSE55780 revealed that miR-7-2-3p expression in papillary thyroid carcinoma (PTC) tissues was notably lower compared with non-tumour tissues, while its expression in E-MATB-736 showed no remarkable difference. Function enrichment analysis showed that 698 genes were enriched in pathways, including pathways in cancer, and glioma. CCND1, GSK3B, and ITGAV of pathways in cancer were inverse correlations with miR-7-2-3p in both post-transcription and protein levels. According to the TF prediction, the prospective upstream TFs of miR-7-2-3p were ISX, SPI1, PRRX1, and BARX1. MiR-7-2-3p was significantly down-regulated and may act on PTC progression by crucial pathways. However, the mechanisms of miR-7-2-3p need further investigation.


Development of an internet-based intervention for parents of infants.
This paper reports on a study to describe the development of an internet-based intervention for parents with infants and to compare the participants and hospitals at baseline. There is a need for interventions to support parenting and for more research into the use of information technology as an intervention strategy. The design and development of healthcare interventions is a complex task, but these are rarely discussed in research reports. A quasi-experimental study was conducted. The data (N = 1300 families) were collected using a structured questionnaire at the hospital or no later than 1 week after discharge during the winter of 2006. The results were used to develop the intervention and to compare the participants at baseline. Statistically significant differences were determined by chi-squared or Fisher's exact tests for percentages and one-way anova for means. The internal consistency relialibility of the scales was analysed using Cronbach's alpha coefficients. Participants in the intervention (n = 469 mothers, n = 307 fathers) and control (n = 394 mothers, n = 218 fathers) hospitals were comparable in respect of parent and infant attributes. There were statistically significant differences between the hospitals in fathers' overnight stays and their access to social support from professionals on the maternity ward. Exclusive breastfeeding was more common in the intervention hospital. More support for infants' cues and behaviour, and day-rhythm and sleep were needed in the intervention hospital. More research is needed to gain a clearer understanding of the effect size of the differences for a reliable evaluation of the effectiveness of the proposed intervention.


White matter hyperintensity and stroke lesion segmentation and differentiation using convolutional neural networks.
White matter hyperintensities (WMH) are a feature of sporadic small vessel disease also frequently observed in magnetic resonance images (MRI) of healthy elderly subjects. The accurate assessment of WMH burden is of crucial importance for epidemiological studies to determine association between WMHs, cognitive and clinical data; their causes, and the effects of new treatments in randomized trials. The manual delineation of WMHs is a very tedious, costly and time consuming process, that needs to be carried out by an expert annotator (e.g. a trained image analyst or radiologist). The problem of WMH delineation is further complicated by the fact that other pathological features (i.e. stroke lesions) often also appear as hyperintense regions. Recently, several automated methods aiming to tackle the challenges of WMH segmentation have been proposed. Most of these methods have been specifically developed to segment WMH in MRI but cannot differentiate between WMHs and strokes. Other methods, capable of distinguishing between different pathologies in brain MRI, are not designed with simultaneous WMH and stroke segmentation in mind. Therefore, a task specific, reliable, fully automated method that can segment and differentiate between these two pathological manifestations on MRI has not yet been fully identified. In this work we propose to use a convolutional neural network (CNN) that is able to segment hyperintensities and differentiate between WMHs and stroke lesions. Specifically, we aim to distinguish between WMH pathologies from those caused by stroke lesions due to either cortical, large or small subcortical infarcts. The proposed fully convolutional CNN architecture, called uResNet, that comprised an analysis path, that gradually learns low and high level features, followed by a synthesis path, that gradually combines and up-samples the low and high level features into a class likelihood semantic segmentation. Quantitatively, the proposed CNN architecture is shown to outperform other well established and state-of-the-art algorithms in terms of overlap with manual expert annotations. Clinically, the extracted WMH volumes were found to correlate better with the Fazekas visual rating score than competing methods or the expert-annotated volumes. Additionally, a comparison of the associations found between clinical risk-factors and the WMH volumes generated by the proposed method, was found to be in line with the associations found with the expert-annotated volumes.


The role of apolipoprotein AIV on the control of food intake.
Apolipoprotein AIV (apo AIV) is a protein synthesized by the human intestine. The synthesis and secretion of apo AIV are stimulated by fat absorption. In 1992, Fujimoto et al. [1] first demonstrated that apo AIV is a satiety signal secreted by the small intestine following the ingestion of a lipid meal. This initial observation was followed by a number of studies supporting apo AIV's role as a satiety signal. This review article discusses the regulation of synthesis of apo AIV in the small intestine as well as the hypothalamus. In addition, the evidence that apo AIV is a satiety factor and its role of apo AIV in diet induced obesity will be discussed. We hope this review will serve as a catalyst to promote apo AIV research in the future. With most of the required reagents available, e.g., the apo AIV knockout and transgenic animals and apo AIV antibodies, the next few years should bring considerable new information on the function of apo AIV.


Bronchial carcinoid tumors: A rare malignant tumor.
Bronchial carcinoid tumors (BCTs) are an uncommon group of lung tumors. They commonly affect the young adults and the middle aged, the same age group affected by other more common chronic lung conditions such as pulmonary tuberculosis. Diagnosis is commonly missed or delayed due to a low index of suspicion. Surgery is the mainstay of treatment with an excellent outcome. There are many reports of this rare group of tumors in the Western and Asian regions. The only report around our sub-region is a post mortem report of an atypical variant. We wish to report a case of the typical variant and increase our index of suspicion. A 25-year-old male presented with a 4 years history of cough and haemoptysis. He was repeatedly treated for bronchial asthma and pulmonary tuberculosis with no improvement of symptoms. Chest X-ray and chest computed tomography scan revealed a left upper lobe tumor. Histology reported a typical variant of BCT which was confirmed by immunohistochemistry. He had a left upper lobectomy and has done excellently well thereafter. A high index of suspicion is needed to reduce the risk of missing or delaying the diagnosis.


The Effects of Sleep Continuity Disruption on Positive Mood and Sleep Architecture in Healthy Adults.
The purpose of this study was to test an experimental model of the effects of sleep continuity disturbance on sleep architecture and positive mood in order to better understand the mechanisms linking insomnia and depression. Participants were randomized to receive 3 consecutive nights of sleep continuity disruption via forced nocturnal awakenings (FA, n = 21), or one of two control conditions: restricted sleep opportunity (RSO, n = 17) or uninterrupted sleep (US, n = 24). The study was set in an inpatient clinical research suite. Healthy, good-sleeping men and women were included. Polysomnography was used to measure sleep architecture, and mood was assessed via self-report each day. Compared to restricted sleep opportunity controls, forced awakenings subjects had significantly less slow wave sleep (P < 0.05) after the first night of sleep deprivation, and significantly lower positive mood (P < 0.05) after the second night of sleep deprivation. The differential change in slow wave sleep statistically mediated the observed group differences in positive mood (P = 0.002). To our knowledge, this is the first human experimental study to demonstrate that, despite comparable reductions in total sleep time, partial sleep loss from sleep continuity disruption is more detrimental to positive mood than partial sleep loss from delaying bedtime, even when controlling for concomitant increases in negative mood. With these findings, we provide temporal evidence in support of a putative biologic mechanism (slow wave sleep deficit) that could help explain the strong comorbidity between insomnia and depression.


Ipilimumab in a real-world population: A prospective Phase IV trial with long-term follow-up.
Ipilimumab was the first treatment that improved survival in advanced melanoma. Efficacy and toxicity in a real-world setting may differ from clinical trials, due to more liberal eligibility criteria and less intensive monitoring. Moreover, high costs and lack of biomarkers have raised cost-benefit concerns about ipilimumab in national healthcare systems and limited its use. Here, we report the prospective, interventional study, Ipi4 (NCT02068196), which aimed to investigate the toxicity and efficacy of ipilimumab in a real-world population with advanced melanoma. This national, multicentre, phase IV trial included 151 patients. Patients received ipilimumab 3 mg/kg intravenously and were followed for at least 5 years or until death. Treatment interruption or cessation occurred in 38%, most frequently due to disease progression (19%). Treatment-associated grade 3 to 4 toxicity was observed in 28% of patients, and immune-related toxicity in 56%. The overall response rate was 9%. Median overall survival was 12.1 months (95% CI: 8.3-15.9); and progression-free survival 2.7 months (95% CI: 2.6-2.8). After 5 years, 20% of patients were alive. In a landmark analysis from 6 months, improved survival was associated with objective response (HR 0.16, P = .001) and stable disease (HR 0.49, P = .005) compared to progressive disease. Poor performance status, elevated lactate dehydrogenase and C-reactive protein were identified as biomarkers. This prospective trial represents the longest reported follow-up of a real-world melanoma population treated with ipilimumab. Results indicate safety and efficacy comparable to phase III trials and suggest that the use of ipilimumab can be based on current cost-benefit estimates.


Chemiluminescence of lung macrophages and blood leukocytes in sarcoidosis.
A luminol-enhanced chemiluminescence assay was used to measure light elaborated by peripheral blood polymorphonuclear leukocytes (PMNs) and by pulmonary alveolar macrophages (PAMs) from 14 healthy, normal subjects and 16 patients with sarcoidosis. Resting peripheral blood PMNs (incubated only in medium) from patients with sarcoidosis generated substantially more chemiluminescence than PMNs from normal control subjects (p = 0.002). With zymosan stimulation, greater chemiluminescence was produced by PMNs from untreated patients with sarcoidosis than from normal subjects (p less than 0.05), whereas no differences were noted with latex stimulation. Chemiluminescence for resting PAMs was not different between normal subjects and patients with sarcoidosis. However, PAMs from untreated patients with sarcoidosis had higher chemiluminescence with latex particle ingestion than PAMs from normal subjects (p less than 0.05), but no differences in PAM chemiluminescence were found when zymosan was the phagocytic particle. Increased chemiluminescence by PMNs and PAMs from patients with sarcoidosis may reflect phagocyte activation in the disease process.


Normative values for isometric muscle force measurements obtained with hand-held dynamometers.
The extent of a patient's impairment can be established by comparing measurements of that patient's performance with normative values obtained from apparently unimpaired individuals. Only a few studies have described normative values for muscle strength measured by hand-held dynamometry. The purpose of this study of older adults, therefore, was to obtain normative values of maximum voluntary isometric force using hand-held dynamometers. One hundred fifty-six asymptomatic adults (77 men, 70 women) participated in this study. The subjects' mean age was 64.4 years (SD=8.3, range=50-79). The male subjects' mean age was 64.5 years (SD=8.4, range=50-79), and the female subjects' mean age was 64.3 years (SD=8.2, range=50-79). Gender, age, dominant side, height, weight, and activity level were recorded. Eight upper-extremity movements (shoulder flexion, extension, abduction, and medial and lateral rotation; elbow flexion and extension; and wrist extension) and five lower-extremity movements (hip flexion and abduction, knee flexion and extension, and ankle dorsiflexion) were resisted by one of three experienced testers using a strain-gauge hand-held dynamometer. Gender, age, and weight were identified as independent predictors of force for all muscle actions on both the dominant and nondominant sides. These variables were used, therefore, to create regression equations and normative values for the force of each muscle action. The reference values provided may allow clinicians who follow the described testing protocol to estimate the severity of force-generating impairments in patients aged 50 to 79 years.


Accurate Decoding of Imagined and Heard Melodies.
Music perception requires the human brain to process a variety of acoustic and music-related properties. Recent research used encoding models to tease apart and study the various cortical contributors to music perception. To do so, such approaches study temporal response functions that summarise the neural activity over several minutes of data. Here we tested the possibility of assessing the neural processing of individual musical units (bars) with electroencephalography (EEG). We devised a decoding methodology based on a maximum correlation metric across EEG segments (maxCorr) and used it to decode melodies from EEG based on an experiment where professional musicians listened and imagined four Bach melodies multiple times. We demonstrate here that accurate decoding of melodies in single-subjects and at the level of individual musical units is possible, both from EEG signals recorded during listening and imagination. Furthermore, we find that greater decoding accuracies are measured for the maxCorr method than for an envelope reconstruction approach based on backward temporal response functions (bTRF env ). These results indicate that low-frequency neural signals encode information beyond note timing, especially with respect to low-frequency cortical signals below 1 Hz, which are shown to encode pitch-related information. Along with the theoretical implications of these results, we discuss the potential applications of this decoding methodology in the context of novel brain-computer interface solutions.


Axonal velocity distributions in neural field equations.
By modelling the average activity of large neuronal populations, continuum mean field models (MFMs) have become an increasingly important theoretical tool for understanding the emergent activity of cortical tissue. In order to be computationally tractable, long-range propagation of activity in MFMs is often approximated with partial differential equations (PDEs). However, PDE approximations in current use correspond to underlying axonal velocity distributions incompatible with experimental measurements. In order to rectify this deficiency, we here introduce novel propagation PDEs that give rise to smooth unimodal distributions of axonal conduction velocities. We also argue that velocities estimated from fibre diameters in slice and from latency measurements, respectively, relate quite differently to such distributions, a significant point for any phenomenological description. Our PDEs are then successfully fit to fibre diameter data from human corpus callosum and rat subcortical white matter. This allows for the first time to simulate long-range conduction in the mammalian brain with realistic, convenient PDEs. Furthermore, the obtained results suggest that the propagation of activity in rat and human differs significantly beyond mere scaling. The dynamical consequences of our new formulation are investigated in the context of a well known neural field model. On the basis of Turing instability analyses, we conclude that pattern formation is more easily initiated using our more realistic propagator. By increasing characteristic conduction velocities, a smooth transition can occur from self-sustaining bulk oscillations to travelling waves of various wavelengths, which may influence axonal growth during development. Our analytic results are also corroborated numerically using simulations on a large spatial grid. Thus we provide here a comprehensive analysis of empirically constrained activity propagation in the context of MFMs, which will allow more realistic studies of mammalian brain activity in the future.


Development and testing of a single frequency terahertz imaging system for breast cancer detection.
The ability to discern malignant from benign tissue in excised human breast specimens in Breast Conservation Surgery (BCS) was evaluated using single frequency terahertz radiation. Terahertz (THz) images of the specimens in reflection mode were obtained by employing a gas laser source and mechanical scanning. The images were correlated with optical histological micrographs of the same specimens, and a mean discrimination of 73% was found for five out of six samples using Receiver Operating Characteristic (ROC) analysis. The system design and characterization is discussed in detail. The initial results are encouraging but further development of the technology and clinical evaluation is needed to evaluate its feasibility in the clinical environment.


IRAP-dependent endosomal T cell receptor signalling is essential for T cell responses.
T cell receptor (TCR) activation is modulated by mechanisms such as TCR endocytosis, which is thought to terminate TCR signalling. Here we show that, upon internalization, TCR continues to signal from a set of specialized endosomes that are crucial for T cell functions. Mechanistically, TCR ligation leads to clathrin-mediated internalization of the TCR-CD3ζ complex, while maintaining CD3ζ signalling, in endosomal vesicles that contain the insulin responsive aminopeptidase (IRAP) and the SNARE protein Syntaxin 6. Destabilization of this compartment through IRAP deletion enhances plasma membrane expression of the TCR-CD3ζ complex, yet compromises overall CD3ζ signalling; moreover, the integrity of this compartment is also crucial for T cell activation and survival after suboptimal TCR activation, as mice engineered with a T cell-specific deletion of IRAP fail to develop efficient polyclonal anti-tumour responses. Our results thus reveal a previously unappreciated function of IRAP-dependent endosomal TCR signalling in T cell activation.


Ecological changes in subtidal macrobenthic communities of the Taean coast following the Hebei Spirit oil spill: A 10-year longitudinal study.
We examined long-term response (2008-2017) of the macrobenthos to the Hebei Spirit oil spill that occurred around the Taean coast, Korea, in December 2007. Oil concentrations were below the Korea/US environmental standards as of January 2008. Organic matter, chlorophyll-a, and zooplankton abundance dominated by Noctiluca scintillans were higher after the spill. Macrobenthic diversity recovered to pre-incident (2007) level in 2011. Biomass exceeded that level in 2011 and the increase prolonged for 5 years. Cross-correlation and regression analyses showed that chlorophyll-a at year t and zooplankton abundance at t-2 had a significant relationship with macrobenthic biomass at t (p < 0.05 for both), suggesting the transfer of increased organic matter (transformed from crude oil within the pelagic ecosystem) into the benthic ecosystem. Coastal wetlands around the incident area, vulnerable to oil pollution and slowly remobilizing accumulated oil, seemed to affect pelagic ecosystem processes and the unexpectedly increased and sustained biomass.


Effect of training and different measurement strategies on the reproducibility of brain MRI lesion load measurements in multiple sclerosis.
In this study, we evaluated the intra- and interobserver variabilities in measuring lesion load of brain MRI abnormalities present on proton-density scans from patients with MS, using using both manual outlining or a semiautomated local thresholding technique (LTT). We also evaluated how these variabilities were affected by the use of standard rules for lesion load measurements, training, and different measurement strategies. The intraobserver variabilities obtained after establishing rules for lesion load measurements and training were not significantly different from those obtained before any consensus among the observers, both for manual outlining and for the LTT. On the contrary, the interobserver variabilities obtained with manual outlining or the LTT were significantly reduced when rules for lesion load measurements were used. For manual outlining, the intraobserver variability did not significantly change when the measurements were performed after an experienced radiologist identified lesions or when using adjacent slices and the corresponding T2-weighted images as reference for lesion identification. On the contrary, for the LTT, the intraobserver variability was significantly reduced by the use of the radiologic marking. The interobserver variabilities for both manual outlining and the LTT were reduced compared with the free condition when these measurement strategies were used. Our findings demonstrate that both lesion identification and outlining are important sources of variation for MRI lesion load measurements in MS and that there are simple strategies to reduce such variation that might be useful when planning clinical trials.


Analgesic benefits of pre-operative versus postoperative transversus abdominis plane block for laparoscopic cholecystectomy: a frequentist network meta-analysis of randomized controlled trials.
Transversus abdominis plane (TAP) block has been utilized to alleviate pain following laparoscopic cholecystectomy (LC). However, the optimal timing of administration remains uncertain. This study aimed to compare the efficacy of pre-operative and postoperative TAP blocks as analgesic options after LC. A frequentist network meta-analysis of randomized controlled trials (RCTs) was conducted. We systematically searched PubMed (via the National Library of Medicine), EMBASE, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science up to March 2023. The study included RCTs that enrolled adult patients (≥ 18 years) who underwent LC and received either pre-operative or postoperative TAP blocks. The primary outcome assessed was 24-hour postoperative morphine consumption (mg). Additionally, pain rest scores within 3 hours, 12 hours, and 24 hours, as well as postoperative nausea and vomiting (PONV), were considered as pre-specified secondary outcomes. A total of 34 trials with 2317 patients were included in the analysis. Postoperative TAP block demonstrated superiority over the pre-operative TAP block in reducing opioid consumption (MD 2.02, 95% CI 0.87 to 3.18, I2 98.6%, p < 0.001). However, with regards to postoperative pain, neither pre-operative nor postoperative TAP blocks exhibited superiority over each other at any of the assessed time points. The postoperative TAP block consistently ranked as the best intervention using SUCRA analysis. Moreover, the postoperative TAP block led to the most significant reduction in PONV. The findings suggest that the postoperative TAP block may be slightly more effective in reducing 24-hour postoperative opioid consumption and PONV when compared to the pre-operative TAP block. PROSPERO, CRD42023396880 .


Expression of two distinct types of pili by a hospital-acquired Enterococcus faecium isolate.
Surface filamentous structures designated pili, and implicated in virulence, have been found on the surfaces of several Gram-positive pathogens. This work describes the conditional expression of two phenotypically distinct pilus-like structures, designated PilA and PilB, on the surface of a hospital-adapted Enterococcus faecium bloodstream isolate. E. faecium is an emerging Gram-positive opportunistic pathogen that can cause severe disease, particularly in immunocompromised patients. Expression of PilA- and PilB-type pili was analysed during different phases of growth in broth culture. During growth, PilA and PilB pilin subunits were expressed around the cross-wall in early-exponential-phase cells. Polymerization and migration of short PilB-type pili towards the poles occurred in cells from the exponential phase and long polymerized pili were expressed at the poles of cells grown to stationary phase. In contrast, PilA-type pili were not expressed in broth culture, but only when cells were grown on solid media. Furthermore, surface expression of the PilA- and PilB-type pili was regulated in a temperature-dependent manner, as polymerization of two distinct types of pili at the surface only occurred when cells were grown at 37 degrees C; no pili were observed on cells grown at 21 degrees C. Hospital-aquired E. faecium isolates were specifically enriched in pilin gene clusters, suggesting that conditional expression of pili may contribute to E. faecium pathogenesis.


Impact of Lipid Partitioning on the Design, Analysis, and Interpretation of Microsomal Time-Dependent Inactivation.
Nonspecific drug partitioning into microsomal membranes must be considered for in vitro-in vivo correlations. This work evaluated the effect of including lipid partitioning in the analysis of complex TDI kinetics with numerical methods. The covariance between lipid partitioning and multiple inhibitor binding was evaluated. Simulations were performed to test the impact of lipid partitioning on the interpretation of TDI kinetics, and experimental TDI datasets for paroxetine (PAR) and itraconazole (ITZ) were modeled. For most kinetic schemes, modeling lipid partitioning results in statistically better fits. For MM-IL simulations (KI,u = 0.1 µM, kinact = 0.1 minute-1), concurrent modeling of lipid partitioning for an fumic range (0.01, 0.1, and 0.5) resulted in better fits compared with post hoc correction (AICc: -526 vs. -496, -579 vs. -499, and -636 vs. -579, respectively). Similar results were obtained with EII-IL. Lipid partitioning may be misinterpreted as double binding, leading to incorrect parameter estimates. For the MM-IL datasets, when fumic = 0.02, MM-IL, and EII model fits were indistinguishable (δAICc = 3). For less partitioned datasets (fumic = 0.1 or 0.5), the inclusion of partitioning resulted in better models. The inclusion of lipid partitioning can lead to markedly different estimates of KI,u and kinact A reasonable alternate experimental design is nondilution TDI assays, with post hoc fumic incorporation. The best fit models for PAR (MIC-M-IL) and ITZ (MIC-EII-M-IL and MIC-EII-M-Seq-IL) were consistent with their reported mechanism and kinetics. Overall, experimental fumic values should be concurrently incorporated into TDI models with complex kinetics, when dilution protocols are used.


Cross-sectional study of sexual behaviour and knowledge about HIV among urban, rural, and minority residents in Viet Nam.
A cross-sectional survey was conducted in three districts of Quang Ninh province, Viet Nam, to find out what proportion of the people who lived there engaged in behaviour that put them at risk of becoming infected with HIV, and to measure their knowledge about HIV infection and AIDS. The survey was conducted in a rural district, Yen Hung; a mountainous district inhabited primarily by ethnic minority groups, Binh Lieu; and an urban district, Ha Long. Participants aged 15-45 years were randomly selected from the general population to be interviewed. A total of 630 people from 707 households were interviewed; 8% were not home despite repeated visits and 3% refused to participate. The prevalence of premarital intercourse ranged from 9% to 16% among married men and 4% to 7% among married women. Among single men the proportion who had ever had intercourse ranged from 6% to 16%. Fewer than 3% reported having ever had sex with a sex worker. The median number of extramarital sex partners was 1. Knowledge about HIV/AIDS was high in the urban and rural areas but low in the mountainous area. Being male and being 20-29 years old were associated with having multiple sex partners. The low prevalence of individuals reporting that they had had intercourse with sex workers and partners other than their spouse may explain the low rates of HIV infection among the heterosexual population; these rates are in contrast to the high rates of HIV infection found among injecting drug users. The association between having extramarital partners and being a younger man suggests that the tendency to have more sexual partners may increase in the future. If this happens, the potential for HIV to be spread through heterosexual sex will increase.


Human breast milk suppresses the transcriptional regulation of IL-1beta-induced NF-kappaB signaling in human intestinal cells.
Neonatal necrotizing enterocolitis (NEC), which is a disease with a poor prognosis, is considered to be caused by the coincidence of intestinal ischemia-reperfusion injury and systemic inflammation due to the colonization of pathogenic bacteria. Interleukin (IL)-8, a proinflammatory cytokine, plays an important role in the pathophysiology of NEC. It was recently reported that IL-1beta activates the IL-8 gene by regulating the transcriptional nuclear factor kappaB (NF-kappaB) signaling pathways in intestinal cells. The protective role of maternal milk in NEC pathogenesis has been reported in both human and animal studies. In this study, we show that human breast milk dramatically suppressed the IL-1beta-induced activation of the IL-8 gene promoter by inhibiting the activation pathway of NF-kappaB. Moreover, we also show that human breast milk induced the production of IkappaBalpha. These results suggest that human breast milk could be protective and therapeutic in neonates with NEC by inhibiting the activation pathway of NF-kappaB.


[Estimation of blood pressure in children using a regression equation].
Blood pressure was determined at the Instituto de Educação do Rio de Janeiro in apparently normal school children, aged 5 to 12 years. Among the 2045 school children, 12 were considered unfit for the study as they presented symptoms of illnesses which could affect the results. The total number was, then, reduced to 2033 children--689 boys and 1344 girls. The blood pressure was measured by auscultatory method of the right arm with children lying supine. A mercury manometer and cuffs of adequate sizes were used. A record of pulse rate, weight and height was also obtained. Normal maximum limits of blood pressure was established according to the 95th percentile. The correlations of weight, height and blood pressure were determined and a regression equation could be elaborated; thus, one can obtain an estimated blood pressure from a child's weight and height.


Pharyngeal collapsibility during sleep is elevated in insulin-resistant females with morbid obesity.
Insulin resistance is associated with sleep apnoea, leading us to hypothesise that it is also associated with elevations in pharyngeal collapsibility, even in the absence of sleep apnoea.90 bariatric patients were characterised for sleep apnoea, pharyngeal collapsibility and insulin resistance. Patients with a respiratory disturbance index (RDI) >10 events·h(-1), diabetes mellitus, tonsillar hypertrophy and pulmonary disease were excluded. The remaining 14 females underwent collapsibility measurements (passive critical pressure, Pcritp ) during non-rapid eye movement sleep. The homeostasis model assessment (HOMA) index, a measure of insulin resistance, was derived from measurements of fasting glucose and insulin levels, and compared to Pcritp Groups with high Pcritp compared to low Pcritp did not differ in age, body mass index or RDI. HOMA and insulin were elevated in the high Pcritp group compared to the low Pcritp group (p<0.02). Pcritp correlated with HOMA (Spearman's ρ=0.565, 95% CI 0.104-0.862; p=0.035) and insulin (Spearman's ρ=0.609 95% CI 0.196-0.835; p=0.021).Obese insulin-resistant subjects without frank diabetes or sleep apnoea demonstrate preclinical elevations in pharyngeal collapsibility, which may increase their susceptibility to sleep apnoea. Our findings suggest that insulin resistance could play a significant role in sleep apnoea pathogenesis by generating requisite elevations in pharyngeal collapsibility.


A Rapid, SuperSelective Method for Detection of Single Nucleotide Variants in Caenorhabditis elegans.
With the widespread use of single nucleotide variants generated through mutagenesis screens and genome editing technologies, there is pressing need for an efficient and low-cost strategy to genotype single nucleotide substitutions. We have developed a rapid and inexpensive method for detection of point mutants through optimization of SuperSelective (SS) primers for end-point PCR in Caenorhabditis elegans Each SS primer consists of a 5' "anchor" that hybridizes to the template, followed by a noncomplementary "bridge," and a "foot" corresponding to the target allele. The foot sequence is short, such that a single mismatch at the terminal 3' nucleotide destabilizes primer binding and prevents extension, enabling discrimination of different alleles. We explored how length and sequence composition of each SS primer segment affected selectivity and efficiency in various genetic contexts in order to develop simple rules for primer design that allow for differentiation between alleles over a broad range of annealing temperatures. Manipulating bridge length affected amplification efficiency, while modifying the foot sequence altered discriminatory power. Changing the anchor position enabled SS primers to be used for genotyping in regions with sequences that are challenging for standard primer design. After defining primer design parameters, we demonstrated the utility of SS primers for genotyping crude C. elegans lysates, suggesting that this approach could also be used for SNP mapping and screening of CRISPR mutants. Further, since SS primers reliably detect point mutations, this method has potential for broad application in all genetic systems.


Combined modality therapy for non-small cell lung carcinoma.
Combined modality therapy is frequently used to treat non-small cell lung carcinoma (NSCLC). Surgical resection is the mainstay of treatment for Stages I and II NSCLC. Little evidence supports the use of adjuvant therapy In patients with Stage I NSCLC. Adjuvant radiotherapy to the chest after resection for Stage II and IIIA NSCLC remains controversial but may be appropriate for many patients with resected Stage IIIA disease or inadequately pathologically staged II disease. For Stage IIIA NSCLC, surgery appears suboptimal, though no other single modality appears superior. Recent studies of neoadjuvant therapy for Stage IIIA NSCLC yielded promising results. The standard of care for Stage III unresectable NSCLC and strategies to improve local-regional control in Stage III NSCLC are discussed, as are the importance of toxicity protection with chemoradiation and the potential utility of prophylactic cranial irradiation for preventing brain relapse. Targeted therapies appear promising, and expedited evaluation in Stage III NSCLC is warranted.


Piperidine-4-methanthiol ester derivatives for a selective acetylcholinesterase assay.
The activity of acetylcholinesterase (AChE) is measured to obtain pathological information about the cholinergic system in various disease states and to assess the effect of AChE inhibitors. Using Ellman's method that is commonly used in such examinations, butyrylcholinesterase inhibitors must be added to measure AChE-specific activity because of low selectivity of AChE toward traditional substrates; however, such inhibitors also inhibit AChE. Therefore, it is desirable to obtain an AChE selective substrate that can be used with the Ellman's method. Here, we synthesized novel AChE substrates, 1-methyl-4-acetylthiomethylpiperidine and 1,1-dimethyl-4-acetylthiomethylpiperidine, and evaluated the hydrolysis rate and AChE selectivity by comparison with the results obtained when traditional substrates were used. The hydrolysis rate of the novel compounds by human AChE was one order of magnitude lower than that of the traditional substrates, acetylthiocholine and acetyl-beta-methylthiocholine, whereas the hydrolysis rate using human butyrylcholinesterase was two orders of magnitude lower than that of the traditional substrates. This indicated that AChE showed selectivity towards the novel substrates which was one order of magnitude higher than that of the traditional substrates. The hydrolysis of the novel compounds in a rat cerebral cortical homogenate and a monkey whole blood was completely inhibited by 1 muM of the specific AChE inhibitor, 1,5-bis(4-allyldimethylammoniumphenyl)pentan-3-one, indicating the high specificity of AChE towards the novel substrates in a crude tissue sample. From these results, we conclude that the novel compounds developed would be suitable AChE-selective substrates for Ellman's method.


Direct three-dimensional ultrasound-to-video registration using photoacoustic markers.
Modern surgical procedures often have a fusion of video and other imaging modalities to provide the surgeon with information support. This requires interventional guidance equipment and surgical navigation systems to register different tools and devices together, such as stereoscopic endoscopes and ultrasound (US) transducers. In this work, the focus is specifically on the registration between these two devices. Electromagnetic and optical trackers are typically used to acquire this registration, but they have various drawbacks typically leading to target registration errors (TRE) of approximately 3 mm. We introduce photoacoustic markers for direct three-dimensional (3-D) US-to-video registration. The feasibility of this method was demonstrated on synthetic and ex vivo porcine liver, kidney, and fat phantoms with an air-coupled laser and a motorized 3-D US probe. The resulting TRE for each experiment ranged from 380 to 850 μm with standard deviations ranging from 150 to 450 μm. We also discuss a roadmap to bring this system into the surgical setting and possible challenges along the way.


Sulfasalazine improves psoriasis. A double-blind analysis.
In an 8-week double-blind trial of sulfasalazine for the treatment of moderate-to-severe psoriasis, 23 and 27 patients received the active and placebo tablets, respectively. At the end of the double-blind phase, there were 17 assessable patients receiving sulfasalazine; 7 (41%) had marked improvement, 7 (41%) had moderate improvement, and 3 (18%) demonstrated minimal change. Only 1 patient receiving placebo demonstrated moderate improvement, whereas the rest had minimal improvement or worsening of psoriasis. When the randomization code was broken, patients receiving sulfasalazine were allowed to continue therapy for an additional 4 weeks in an open manner, while those using placebo left the study. Six of 23 patients discontinued sulfasalazine therapy during the double-blind phase because of side effects, 4 due to the development of a cutaneous eruption and 2 due to nausea. Fourteen of 17 patients, who were assessable at the end of the 8-week double-blind phase, completed the additional 4 weeks of sulfasalazine therapy. Of these 14 patients, marked improvement occurred in 8 (57%), moderate improvement in 2 (14%), and minimal improvement in 4 (29%), compared with pretherapy. The low incidence of severe side effects makes sulfasalazine a consideration for oral therapy in patients whose disease severity does not justify use of methotrexate, etretinate, or psoralen plus UV-A, but whose disease severity is too widespread for safe and practical use of topical corticosteroids.


The AFFORD clinical decision aid to identify emergency department patients with atrial fibrillation at low risk for 30-day adverse events.
There is wide variation in the management of patients with atrial fibrillation (AF) in the emergency department (ED). We aimed to derive and internally validate the first prospective, ED-based clinical decision aid to identify patients with AF at low risk for 30-day adverse events. We performed a prospective cohort study at a university-affiliated tertiary-care ED. Patients were enrolled from June 9, 2010, to February 28, 2013, and followed for 30 days. We enrolled a convenience sample of patients in ED presenting with symptomatic AF. Candidate predictors were based on ED data available in the first 2 hours. The decision aid was derived using model approximation (preconditioning) followed by strong bootstrap internal validation. We used an ordinal outcome hierarchy defined as the incidence of the most severe adverse event within 30 days of the ED evaluation. Of 497 patients enrolled, stroke and AF-related death occurred in 13 (3%) and 4 (<1%) patients, respectively. The decision aid included the following: age, triage vitals (systolic blood pressure, temperature, respiratory rate, oxygen saturation, supplemental oxygen requirement), medical history (heart failure, home sotalol use, previous percutaneous coronary intervention, electrical cardioversion, cardiac ablation, frequency of AF symptoms), and ED data (2 hours heart rate, chest radiograph results, hemoglobin, creatinine, and brain natriuretic peptide). The decision aid's c-statistic in predicting any 30-day adverse event was 0.7 (95% confidence interval 0.65, 0.76). In conclusion, in patients with AF in the ED, Atrial Fibrillation and Flutter Outcome Risk Determination provides the first evidence-based decision aid for identifying patients who are at low risk for 30-day adverse events and candidates for safe discharge.


Cobalt-catalyzed difluoroalkylation of tertiary aryl ketones for facile synthesis of quaternary alkyl difluorides.
The selective incorporation of gem-difluoroalkyl groups into biologically active molecules has long been used as an efficient strategy for drug design and discovery. However, the catalytic C(sp3)-CF2 bond-forming cross-coupling reaction for selective incorporation of difluoromethylene group into diverse alkyl chains, especially more sterically demanding secondary and tertiary functionalized alkanes, still remains as a major challenge. Herein, we describe a cobalt-catalyzed difluoroalkylation of tertiary aryl ketones for facile synthesis of quaternary alkyl difluorides, which exhibited high efficiency, broad scope and mild conditions. The synthetic utility of this method is demonstrated by late-stage difluoroalkylation of donepezil, a well-known acetylcholinesterase inhibitor used to treat the Alzheimer's disease. Preliminary mechanistic investigations indicate that a difluoroalkyl radical is involved in a Co(I)/Co(III) catalytic cycle. This cobalt-catalyzed fluoroalkylation thus offers insights into an efficient way for the synthesis of fluoroalkylated bioactive molecules for drug discovery.


Gene-lifestyle and gene-pharmacotherapy interactions in obesity and its cardiovascular consequences.
Obesity is a highly prevalent complex trait that raises the risk of other chronic diseases such as type 2 diabetes, certain cancers, sleep apnea, and cardiovascular disease, and shortens lifespan. Clinical intervention studies focused on weight loss and epidemiological studies of obesity indicate that genetic variation may modify the relationship between lifestyle behaviors and weight loss or weight gain. Similar observations have also emerged from pharmacogenetic studies. The literature includes several reports from these studies, but few examples of interactions have been adequately replicated. In this review we introduce the topics of population genetics and gene x environment interaction research. We also provide a systematic review of the published literature on gene x lifestyle (physical activity and dietary factors) and gene x drug interactions in relation to obesity. Finally, we overview the scope and findings from these studies and discuss some of their strengths and limitations.


Lack of correlation between amniotic fluid and maternal plasma contents of beta-endorphin, beta-lipotropin, and adrenocorticotropic hormone in normal and pathologic pregnancies.
Reported are the concentrations of beta-endorphin, beta-lipotropin, and adrenocorticotropic hormone (ACTH) in the amniotic fluid and plasma of 40 healthy pregnant women at different stages of gestation. Moreover, the amniotic fluid levels of the three peptides were evaluated in 20 other pregnant women affected by different pathologic conditions (Cooley's disease, gestosis, diabetes, placental insufficiency, etc.). A silicic acid extraction procedure was performed on the samples. Each extract was subjected to Sephadex G-75 column chromatography, and the two fractions corresponding to beta-lipotropin and beta-endorphin were collected, freeze-dried, and assayed by two specific radioimmunoassays. Levels of ACTH were measured by radioimmunoassay directly on the extracts. Levels of beta-endorphin in amniotic fluid showed the highest values in the first trimester (173 +/- 30 fmol/ml, mean +/- SEM) but were significantly decreased in the second (75.2 +/- 14) and third trimesters (14.3 +/- 1.8). An inverse trend characterized plasma levels of beta-endorphin, which showed a progressive increase from the first trimester to term (10.4 +/- 11.1). Amniotic fluid levels of beta-lipotropin remained stable during the first (48.6 +/- 6.3) and second (54.6 +/- 11.1) trimesters, but decreased significantly in the third trimester (17.9 +/- 2.3). The plasma concentrations of beta-lipotropin showed the highest levels in the first trimester (10.9 +/- 0.9), and decreased significantly at term (8.9 +/- 1.3). Last, amniotic fluid levels of ACTH decreased from 55.3 +/- 4.75 fmol/ml in the first trimester to 12.5 +/- 1.16 in the second trimester, and rose again in the third trimester to 34.4 +/- 6.6 fmol/ml. Plasma levels of ACTH were characterized in the first two trimesters by values twice those recorded for nonpregnant women, and decreased at term to 8.9 +/- 1.4 fmol/ml. In the pregnant patients with fetuses affected by Cooley's disease (second trimester) and in those with edema-proteinuria-hypertension (EPH) gestosis (third trimester), amniotic fluid levels of beta-endorphin, beta-lipotropin, and ACTH were in the same range as those in healthy pregnant women.


An introduction to recurrent nucleotide interactions in RNA.
RNA secondary structure diagrams familiar to molecular biologists summarize at a glance the folding of RNA chains to form Watson–Crick paired double helices. However, they can be misleading: First of all, they imply that the nucleotides in loops and linker segments, which can amount to 35% to 50% of a structured RNA, do not significantly interact with other nucleotides. Secondly, they give the impression that RNA molecules are loosely organized in three-dimensional (3D) space. In fact, structured RNAs are compactly folded as a result of numerous long-range, sequence-specific interactions, many of which involve loop or linker nucleotides. Here, we provide an introduction for students and researchers of RNA on the types, prevalence, and sequence variations of inter-nucleotide interactions that structure and stabilize RNA 3D motifs and architectures, using Escherichia coli (E. coli) 16S ribosomal RNA as a concrete example. The picture that emerges is that almost all nucleotides in structured RNA molecules, including those in nominally single-stranded loop or linker regions, form specific interactions that stabilize functional structures or mediate interactions with other molecules. The small number of noninteracting, 'looped-out' nucleotides make it possible for the RNA chain to form sharp turns. Base-pairing is the most specific interaction in RNA as it involves edge-to-edge hydrogen bonding (H-bonding) of the bases. Non-Watson–Crick base pairs are a significant fraction (30% or more) of base pairs in structured RNAs.


Anticipated violence, arousal, and enjoyment of movies: viewers' reactions to violent previews based on arousal-seeking tendency.
The authors investigated the effects of violent portrayals in movie previews on viewers' arousal and anticipated enjoyment of movies based on their arousal-seeking tendencies. A total of 159 college students watched 6 movie previews, each in a violent or nonviolent version, and reported their expectations of enjoying watching the movies. The results show that high arousal seekers reported a higher level of anticipated enjoyment after watching the violent previews than the nonviolent previews. In contrast, low arousal seekers did not expect much difference in their enjoyment between the two versions. In line with the theory of optimal stimulation level, the results indicate that viewers' anticipated enjoyment of movies after watching violent images in previews is moderated by individuals' arousal-seeking tendencies.


Haemorrhagic versus non haemorrhagic ascites in cirrhosis: Their relationship and impact on prognosis of liver cirrhosis.
To evaluate the impact of haemorrhagic ascites on prognosis of patients with advance cirrhosis, this study was further aimed to assess the relationship between haemorrhagic ascites and advance cirrhosis and its effect on prognosis. Eight hundred and thirty-eight patients having liver cirrhosis with ascites were analyzed retrospectively (over three years) while segregated into two groups haemorrhagic and non haemorrhagic ascites. Patient outcome variables were identified among both groups and independent predictors for survival were analyzed. Kaplan-Meier survival estimates determined survival rate comparison between groups. Haemorrhagic ascites was detected in (26.6%) patients. Spontaneous haemorrhagic ascites(79%) was the main cause of haemorrhagic ascites followed by hepatocellular carcinoma (14%) and iatrogenic (7.6%). Spontaneous bacterial peritonitis and acute kidney injury were statistically significant (p= 0.0001, 0.0001) among groups. Overall mortality at year three was higher (83%) in haemorrhagic ascites group. Survival among both groups (haemorrhagic versus non haemorrhagic) at one month, one year and three year was found to be significant (p= 0.000, 0.000 and 0.000). Haemorrhagic ascites impact overall survival with more mortality in comparison to non haemorrhagic ascites. Haemorrhagic ascites was an independent predictor of survival. Haemorrhagic ascites is possibly considered another predictor of survival among advance cirrhosis.


The receptor super-antagonist Sant7.
Interleukin-6 (IL-6) plays a central role in the pathogenesis of multiple myeloma, acting both as a growth and a survival factor for myeloma cells. IL-6 has been recently shown to possess three topologically distinct receptor binding sites: site 1 for binding to the subunit specific chain IL-6R alpha and sites 2 and 3 for the interaction with two separate subunits of the signalling chain gp130. We have generated a set of IL-6 receptor antagonists carrying substitutions that abolish interaction with gp130 at either site 2 alone (site 2 antagonist) or at both sites 2 and 3 (site 2+3 antagonist). In addition, substitutions were introduced at site 1 that increased affinity for IL-6R alpha. When tested as growth inhibitors on a representative set of IL-6-dependent human myeloma cell lines (XG-1, XG-2, XG-4 and XG-6), although site 2 antagonists were effective on 3 out of 4 of the cell lines, only the site 2+3 antagonist Sant7 showed full antagonism on the entire spectrum of cells tested. Moreover, IL-6 receptor antagonists were also pro-apoptotic factors for myeloma cells. Their capacity to induce cell death was directly related to the impairment of binding to gp130 and to their ability to fully block intracellular signalling. In fact, the most potent inducer of apoptosis was again Sant7, which also counteracted the protective autocrine effect excercised by the endogenously produced IL-6. On the basis of these results we propose the super-antagonist Sant7 as a possible candidate for the immunotherapy of multiple myeloma.


Understanding the relationship between couple dynamics and engagement with HIV care services: insights from a qualitative study in Eastern and Southern Africa.
To explore the interplay between couple dynamics and the engagement of people living with HIV (PLHIV) with HIV care and treatment services in three health and demographic surveillance sites in Tanzania, Malawi and South Africa. A qualitative study was conducted involving 107 in-depth interviews with PLHIV with a range of HIV care and treatment histories, including current users of HIV clinics, and people not enrolled in HIV care. Interviews explored experiences of living with HIV and how and why they chose to engage or not with HIV services. Thematic analysis was conducted with the aid of NVivo 10. We found an interplay between couple dynamics and HIV care and treatment-seeking behaviour in Tanzania, Malawi and South Africa. Being in a relationship impacted on the level and type of engagement with HIV services in multiple ways. In some instances, couples living with HIV supported each other which improved their engagement with care and strengthened their relationships. The desire to fulfil societal expectations and attract a new partner, or have a baby with a new partner, or to receive emotional or financial support, strengthened on-going engagement with HIV care and treatment. However, fear of blame, abandonment or abuse resulted in unwillingness to disclose and often led to disputes or discord between couples. There was little evidence of intracouple understanding of each other's lived experiences with HIV, and we found that couples rarely interacted with the formal health system together. Couple dynamics influenced engagement with HIV testing, care and treatment for both partners through a myriad of pathways. Couple-friendly approaches to HIV care and treatment are needed that move beyond individualised care and which recognise partner roles in HIV care engagement.


Biological aspects of tooth fragment reattachment in immature incisors.
Tooth fragment reattachment is a relatively new technique and there are many aspects which still need to be explored. Reported here is a case of enamel and dentin fracture of 11 and 21. There was a very thin layer of dentin clinically over the pulp chamber and the root apices were immature. The reattachment procedure was modified slightly. The initial joint was made with protective calcium hydroxide and glass ionomer cement on the approximating surfaces. The further reattachment was accomplished using composites and acid etch technique. This was done for pulpal protection. After six months, reattachment was intact and successful with no staining, sensitivity or pain. The radiographs revealed root completion of the immature incisors. The reattachment procedure proved to be biologically superior in addition to its esthetic value and psychological advantage.


Self-assembled octanuclear [Ni5Ln3] (Ln = Dy, Tb and Ho) complexes: synthesis, coordination induced ligand hydrolysis, structure and magnetism.
The variable coordination behavior of 2-{[(2-hydroxy-3-methoxybenzyl)imino]methyl}-6-methoxyphenol (H2L) and its hydrolyzed congener towards NiCl2·6H2O and LnIII nitrate salts provides a family of coordination aggregates containing an [Ni5Ln3] octanuclear core structure. Room temperature reactions in MeOH-CHCl3 medium and in the presence of NEt3 yielded isostructural [Ni5Ln3(L)4(μ-OH)2(μ3-OH)6(o-val)2(H2O)6]NO3·7H2O (Ln = Dy3+ (1), Tb3+ (2), and Ho3+ (3); o-val = o-vanillin) heterometallic complexes. All the three complexes hold an octanuclear fused partial hexacubane topology from the utilization of phenolate-based ligand anions, clipping five 3d and three 4f ions. Direct current magnetic susceptibility measurements showed an upsurge at low temperature for complexes 1 and 2, indicative of ferromagnetic interactions, while antiferromagnetic exchange interaction predominates for complex 3. AC magnetic susceptibility measurements were not able to show any slow relaxation property to the magnetization. CASSCF calculations for complex 1 indicate that all three Dy3+ centres have anisotropic axes but the relative orientation of the magnetic axes reduces the probability of this molecule to behave like an SMM which is further established by the POLY_ANISO calculations.


Microbial toxicity of ethanolamines--multiwalled carbon nanotubes.
In the present study, antimicrobial activities of multiwalled carbon nanotubes (MWCNTs) functionalized with ethanolamine (EA) groups were investigated. Therefore, MWCNT were first functionalized with mono-, di-, and triethanolamine (MEA, DEA, and TEA) under microwave technique. Development of functional groups on the MWCNT surface was confirmed by Fourier transform infrared and thermogravimetric analysis. Morphological variation was investigated by transmission electron microscopy. Then, antimicrobial activities of pristine and functionalized MWCNT (MWCNT-MEA, -DEA, and -TEA) were tested against different bacteria species. The studies have been done on four Gram-negative bacteria (Escherichia coli, Klebsiella pneumonia, Pseudomonas aeroginosa, and Salmonella typhimurium) as well as four Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus, Bacillus cereus, and Streptococcus pneumonia). The results based on minimal inhibitory concentration and radial diffusion assay were shown that the antimicrobial activity of MWCNT-TEA > MWCNT-DEA > MWCNT-MEA > pristine MWCNT. Based on the results, it seems that EA groups could play an important role in antimicrobial activity of MWCNT.


A biopsychosocial model of social anxiety and substance use.
Emerging prospective work suggests that individuals with social anxiety disorder (SAD) may be at particular risk for developing substance use disorders (SUD). Yet, little is known about why this may be so. Most research has utilized existing theories of substance use (e.g. tension reduction-based theories) to understand SAD-SUD relations. However, these theories do not address why individuals with social anxiety, in particular, experience such high rates of substance-related problems. A possible explanation may lie in the nature of social anxiety itself, which is characterized not only by chronically elevated negative affective states, but by low positive affect, fear of scrutiny, and social avoidance. These aspects of social anxiety may work in concert to place these especially vulnerable individuals at risk for SUD. The current paper presents a biopsychosocial model of SAD-SUD comorbidity that focuses on several specific facets of social anxiety that may be especially related to SUD risk. The utility of this model is evaluated via a review of the literature on the relations between SAD and substance-related behaviors.


The Lateral Habenula and Its Input to the Rostromedial Tegmental Nucleus Mediates Outcome-Specific Conditioned Inhibition.
Animals can readily learn that stimuli predict the absence of specific appetitive outcomes; however, the neural substrates underlying such outcome-specific conditioned inhibition remain largely unexplored. Here, using female and male rats as subjects, we examined the involvement of the lateral habenula (LHb) and of its inputs onto the rostromedial tegmental nucleus (RMTg) in inhibitory learning. In these experiments, we used backward conditioning and contingency reversal to establish outcome-specific conditioned inhibitors for two distinct appetitive outcomes. Then, using the Pavlovian-instrumental transfer paradigm, we assessed the effects of manipulations of the LHb and the LHb-RMTg pathway on that inhibitory encoding. In control animals, we found that an outcome-specific conditioned inhibitor biased choice away from actions delivering that outcome and toward actions earning other outcomes. Importantly, this bias was abolished by both electrolytic lesions of the LHb and selective ablation of LHb neurons using Cre-dependent Caspase3 expression in Cre-expressing neurons projecting to the RMTg. This deficit was specific to conditioned inhibition; an excitatory predictor of a specific outcome-biased choice toward actions delivering the same outcome to a similar degree whether the LHb or the LHb-RMTg network was intact or not. LHb lesions also disrupted the ability of animals to inhibit previously encoded stimulus-outcome contingencies after their reversal, pointing to a critical role of the LHb and of its inputs onto the RMTg in outcome-specific conditioned inhibition in appetitive settings. These findings are consistent with the developing view that the LHb promotes a negative reward prediction error in Pavlovian conditioning.SIGNIFICANCE STATEMENT Stimuli that positively or negatively predict rewarding outcomes influence choice between actions that deliver those outcomes. Previous studies have found that a positive predictor of a specific outcome biases choice toward actions delivering that outcome. In contrast, a negative predictor of an outcome biases choice away from actions earning that outcome and toward other actions. Here we reveal that the lateral habenula is critical for negative predictors, but not positive predictors, to affect choice. Furthermore, these effects were found to require activation of lateral habenula inputs to the rostromedial tegmental nucleus. These results are consistent with the view that the lateral habenula establishes inhibitory relationships between stimuli and food outcomes and computes a negative prediction error in Pavlovian conditioning.


Environmental heterogeneity, dispersal mode, and co-occurrence in stream macroinvertebrates.
Both environmental heterogeneity and mode of dispersal may affect species co-occurrence in metacommunities. Aquatic invertebrates were sampled in 20-30 streams in each of three drainage basins, differing considerably in environmental heterogeneity. Each drainage basin was further divided into two equally sized sets of sites, again differing profoundly in environmental heterogeneity. Benthic invertebrate data were divided into three groups of taxa based on overland dispersal modes: passive dispersers with aquatic adults, passive dispersers with terrestrial winged adults, and active dispersers with terrestrial winged adults. The co-occurrence of taxa in each dispersal mode group, drainage basin, and heterogeneity site subset was measured using the C-score and its standardized effect size. The probability of finding high levels of species segregation tended to increase with environmental heterogeneity across the drainage basins. These patterns were, however, contingent on both dispersal mode and drainage basin. It thus appears that environmental heterogeneity and dispersal mode interact in affecting co-occurrence in metacommunities, with passive dispersers with aquatic adults showing random patterns irrespective of environmental heterogeneity, and active dispersers with terrestrial winged adults showing increasing segregation with increasing environmental heterogeneity.


Leukemia inhibitory factor/human interleukin for DA cells: a growth factor that stimulates the in vitro development of multipotential human hematopoietic progenitors.
We investigated the in vitro hematopoietic stimulatory activity of leukemia inhibitory factor/human interleukin for DA cells (LIF/HILDA) on bone marrow progenitor populations in 17 normal individuals. In serum-free cultures LIF/HILDA did not induce colony growth. In serum containing media, LIF/HILDA stimulated the growth of colony forming unit (CFU)-MIX and CFU-EO in a dose-dependent fashion and resulted in an increased CFU-MIX and burst forming unit-erythrocytes (BFU-E) colony size. Similar stimulatory effects were seen on a highly purified hematopoietic progenitor population obtained after immunomagnetic depletion of mature myeloid precursors and lymphoid cells. Addition of LIF/HILDA to cultures containing maximally stimulatory concentrations of recombinant human interleukin-3 (rhuIL3), rhuIL3 + rhuIL6, or rhu granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) in serum containing media significantly increased the number of CFU-MIX and eosinophil colonies and increased size and cluster number of CFU-MIX and BFU-E. Depletion of accessory T lymphocytes or monocytes from bone marrow progenitors did not alter the response of hematopoietic precursors to LIF/HILDA. A similar increased colony growth was seen when LIF/HILDA was added to cultures of positively selected CD34/HLA-DR+ or CD34+/HLA-DR- bone marrow hematopoietic progenitor cells stimulated with maximally stimulatory concentrations of rhuIL3 + rhuIL6. LIF/HILDA is a novel cytokine capable of stimulating growth and proliferation of multi-lineage, erythroid, and eosinophil colonies in the presence of serum. LIF/HILDA exerts its activity by direct interaction with highly purified immature bone marrow progenitor cells, has an additive effect when used with other cytokines known to stimulate primitive hematopoietic precursors, and does not require accessory cells.


Program adaptation by health departments.
The dissemination of evidence-based interventions (i.e., programs, practices, and policies) is a core function of US state health departments (SHDs). However, interventions are originally designed and tested with a specific population and context. Hence, adapting the intervention to meet the real-world circumstances and population's needs can increase the likelihood of achieving the expected health outcomes for the target population from the implemented intervention. This study identified how SHD employees decide to adapt public health programs and what influences decisions on how to adapt them. SHD employees (n = 45) were interviewed using a qualitative semi-structured interview guide. Telephone interviews were audio-recorded and transcribed verbatim. The transcripts were consensus-coded and themes were identified using thematic analysis. Several themes aligned with the Model for Adaptation Design and Impact. Data, outcomes, and health department evaluations influenced decisions to adapt a program (pre-adaptation), and reasons to adapt a program included organizational and sociopolitical contextual factors. SHD middle-level managers, program managers and staff, and local agencies were involved in the decisions to adapt the programs. Finally, the goals for adapting a program included enhancing effectiveness/outcomes, reach and satisfaction with the program; funding; and partner engagement. After SHD employees decided to adapt a program, data and evidence guided the changes. Program staff and evaluators were engaged in the adaptation process. Program managers consulted partners to gather ideas on how best to adapt a program based on partners' experiences implementing the program and obtaining community input. Lastly, program managers also received input on adapting content and context from coalition meetings and periodic technical assistance calls. The findings related to decisions to adapt public health programs provide practitioners with considerations for adapting them. Findings reaffirm the importance of promoting public health competencies in program evaluation and adaptation, as well as systematically documenting and evaluating the adaptation processes. In addition, the themes could be studied in future research as mechanisms, mediators, and moderators to implementation outcomes.


Kinetic correlates of methotrexate transport and therapeutic responsiveness in murine tumors.
Net accumulation of methotrexate by carrier-mediated transport in different murine tumor cells in vitro exhibits a positive correlation with the relative drug pharmacokinetics and therapeutic responsiveness in these tumors in vivo. The transport of methotrexate by Sarcoma 180, Ehrlich carcinoma, P388, P288, and L1210 leukemia cells is qualitatively similar. Influx of drug exhibits saturation kinetics and is highly temperature dependent (Q10, 6.1 to 9.4). Efflux of exchangeable methotrexate from all of the different tumor cells exhibited first-order kinetics and the same high temperature dependence seen for influx (Q10, 6.1 to 8.0). The major kinetic determinant of responsiveness is the Km for influx. Values vary from 3.1 to 11.2 X 10(-6) M and are highest in cells from a nonresponsive Sarcoma 180 tumor, somewhat lower in the poorly responsive Ehrlich tumor, lower in moderately responsive P388 and P288 leukemias, and lowest in the highly responsive L1210 leukemia. Values for the influx Vmax differ to some extent, but in a manner not correlatable with responsiveness. The level of responsiveness of the P388 leukemia in vivo can also be partially attributed to an efflux rate that is lower than that measured for the other tumor cells. Steady-state levels of drug accumulation in vitro reflected influx and efflux rates and were consistently correlatable with therapeutic responsiveness. There was no significant difference in the extent to which folate and reduced 5-substituted folate derivatives compete with methotrexate for uptake in cells from all five tumors. The average value for Ki measured with folate for each tumor cell type was 50- and 80-fold higher than for 5-formyltetrahydrofolate and 5-methyltetrahydrofolate.


Resting Pd/Pa and haemodynamic relevance of coronary stenosis as evaluated by fractional flow reserve.
Fractional flow reserve (FFR) currently represents the gold standard in the evaluation of the haemodynamic relevance of coronary stenoses. However, both intracoronary and intravenous adenosine may be tolerated poorly by some patients. Therefore, considerable interest had been focused in the last few years on new adenosine-free indexes to define the haemodynamic relevance of coronary stenoses. So far, few data have been reported on resting Pd/Pa and its correlation with FFR as evaluated with high-dose intracoronary adenosine administration, which is the aim of the current study. FFR was assessed in 120 patients with 137 intermediate lesions during cardiac catheterization by a pressure-recording guidewire (PrimeWire). FFR was calculated as the ratio of the distal coronary pressure to the aortic pressure at hyperaemia. Intracoronary doses of adenosine were administered up to 720 μg as intracoronary boli. Exclusion criteria were as follows: (a) allergy to adenosine; (b) baseline bradycardia (heart rate <50 bpm); (c) hypotension (blood pressure <90 mmHg); and (d) refusal to provide signed informed consent. High doses of intracoronary adenosine were well tolerated, with no major side effects. Increasing doses up to 720 μg progressively decreased FFR values and increased the percentage of patients showing an FFR less than 0.80. Resting Pd/Pa showed good accuracy in the identification of patients with significant FFR values (<0.80) [area under the curve=0.9 (0.84-0.96), P<0.0001]. Using receiver-operating characteristic curves, we identified a threshold less than 0.93 as the best accurate cut-off value in the prediction of a positive FFR value. A value up to 0.88 was associated with a 100% positive predictive value, whereas a value of at least 0.95 was associated with a 95% negative predictive value. This study showed that in intermediate lesions, resting Pd/Pa was related linearly to FFR. We identified 0.93 as the best cut-off value in the prediction of haemodynamically significant coronary stenosis as evaluated by FFR. However, cut-off values of 0.88 and 0.95 could provide the maximal predictive positive and negative values, suggesting the additional use of FFR only in patients with resting values within this range.


Classification of human chronic inflammatory skin disease based on single-cell immune profiling.
Inflammatory conditions represent the largest class of chronic skin disease, but the molecular dysregulation underlying many individual cases remains unclear. Single-cell RNA sequencing (scRNA-seq) has increased precision in dissecting the complex mixture of immune and stromal cell perturbations in inflammatory skin disease states. We single-cell-profiled CD45+ immune cell transcriptomes from skin samples of 31 patients (7 atopic dermatitis, 8 psoriasis vulgaris, 2 lichen planus (LP), 1 bullous pemphigoid (BP), 6 clinical/histopathologically indeterminate rashes, and 7 healthy controls). Our data revealed active proliferative expansion of the Treg and Trm components and universal T cell exhaustion in human rashes, with a relative attenuation of antigen-presenting cells. Skin-resident memory T cells showed the greatest transcriptional dysregulation in both atopic dermatitis and psoriasis, whereas atopic dermatitis also demonstrated recurrent abnormalities in ILC and CD8+ cytotoxic lymphocytes. Transcript signatures differentiating these rash types included genes previously implicated in T helper cell (TH2)/TH17 diatheses, segregated in unbiased functional networks, and accurately identified disease class in untrained validation data sets. These gene signatures were able to classify clinicopathologically ambiguous rashes with diagnoses consistent with therapeutic response. Thus, we have defined major classes of human inflammatory skin disease at the molecular level and described a quantitative method to classify indeterminate instances of pathologic inflammation. To make this approach accessible to the scientific community, we created a proof-of-principle web interface (RashX), where scientists and clinicians can visualize their patient-level rash scRNA-seq-derived data in the context of our TH2/TH17 transcriptional framework.


Data science in drug discovery safety: Challenges and opportunities.
Early de-risking of drug targets and chemistry is essential to provide drug projects with the best chance of success. Target safety assessments (TSAs) use target biology, gene and protein expression data, genetic information from humans and animals, and competitor compound intelligence to understand the potential safety risks associated with modulating a drug target. However, there is a vast amount of information, updated daily that must be considered for each TSA. We have developed a data science-based approach that allows acquisition of relevant evidence for an optimal TSA. This is built on expert-led conventional and artificial intelligence-based mining of literature and other bioinformatics databases. Potential safety risks are identified according to an evidence framework, adjusted to the degree of target novelty. Expert knowledge is necessary to interpret the evidence and to take account of the nuances of drug safety, the modality, and the intended patient population for each TSA within each project. Overall, TSAs take full advantage of the most recent developments in data science and can be used within drug projects to identify and mitigate risks, helping with informed decision-making and resource management. These approaches should be used in the earliest stages of a drug project to guide decisions such as target selection, discovery chemistry options, in vitro assay choice, and end points for investigative in vivo studies.


Biochemical and functional characterization of a novel neuron-glia adhesion molecule that is involved in neuronal migration.
Adhesion molecule on glia (AMOG) is a novel neural cell adhesion molecule that mediates neuron-astrocyte interaction in vitro. In situ AMOG is expressed in the cerebellum by glial cells at the critical developmental stages of granule neuron migration. Granule neuron migration that is guided by surface contacts between migrating neurons and astroglial processes is inhibited by monoclonal AMOG antibody, probably by disturbing neuron-glia adhesion. AMOG is an integral cell surface glycoprotein of 45-50-kD molecular weight with a carbohydrate content of at least 30%. It does not belong to the L2/HNK-1 family of neural cell adhesion molecules but expresses another carbohydrate epitope that is shared with the adhesion molecules L1 and myelin-associated glycoprotein, but is not present on N-CAM or J1.


Connexin 30 Deficiency Ameliorates Disease Progression at the Early Phase in a Mouse Model of Amyotrophic Lateral Sclerosis by Suppressing Glial Inflammation.
Connexin 30 (Cx30), which forms gap junctions between astrocytes, regulates cell adhesion and migration, and modulates glutamate transport. Cx30 is upregulated on activated astroglia in central nervous system inflammatory lesions, including spinal cord lesions in mutant superoxide dismutase 1 (mSOD1) transgenic amyotrophic lateral sclerosis (ALS) model mice. Here, we investigated the role of Cx30 in mSOD1 mice. Cx30 was highly expressed in the pre-onset stage in mSOD1 mice. mSOD1 mice with knockout (KO) of the Cx30 gene (Cx30KO-mSOD1 mice) showed delayed disease onset and tended to have an extended survival period (log-rank, p = 0.09). At the progressive and end stages of the disease, anterior horn cells were significantly preserved in Cx30KO-mSOD1 mice. In lesions of these mice, glial fibrillary acidic protein/C3-positive inflammatory astroglia were decreased. Additionally, the activation of astrocytes in Cx30KO-mSOD1 mice was reduced compared with mSOD1 mice by gene expression microarray. Furthermore, expression of connexin 43 at the pre-onset stage was downregulated in Cx30KO-mSOD1 mice. These findings suggest that reduced expression of astroglial Cx30 at the early disease stage in ALS model mice protects neurons by attenuating astroglial inflammation.


[Constrictive pericarditis in children under 2 years of age].
Two cases of constrictive pericarditis, in children under 2 years of age, of non-tuberculosis aetiology, diagnosed from June 97 to May 98 are reported. This entity is rare in paediatrics and it may progress to severe condition. Surgical treatment has a low risk and is generally associated with good prognosis. Aetiology, clinic presentation, differential diagnosis with restrictive cardiomyopathy and treatment are discussed.


Diversity of metallothioneins in the American oyster, Crassostrea virginica, revealed by transcriptomic and proteomic approaches.
Metallothioneins are typically low relative molecular mass (6000-7000), sulfhydryl-rich metal-binding proteins with characteristic repeating cysteine motifs (Cys-X-Cys or Cys-X(n)-Cys) and a prolate ellipsoid shape containing single alpha- and beta-domains. While functionally diverse, they play important roles in the homeostasis, detoxification and stress response of metals. The originally reported metallothionein of the American oyster, Crassostrea virginica showed the canonical molluscan alphabeta-domain structure. Oyster metallothioneins have been characterized as cDNA and as expressed proteins, and here it is shown that the previously reported metallothionein is a prototypical member of a subfamily (designated as CvMT-I) of alphabeta-domain metallothioneins. A second extensive subfamily of oyster metallothioneins (designated as CvMT-II) has apparently arisen from (a) a stop mutation that truncates the protein after the alpha-domain, and (b) a subsequent series of duplication and recombination events that have led to the development of metallothionein isoforms containing one to four alpha-domains and that lack a beta-domain. Analysis of metallothioneins revealed that certain CvMT-I isoforms showed preferential association either with cadmium or with copper and zinc, even after exposure to cadmium. These data extend our knowledge of the evolutionary diversification of metallothioneins, and indicate differences in metal-binding preferences between isoforms within the same family.


Vocational choices made by alumni of the Leadership Program for Veterinary Students at Cornell University.
OBJECTIVE To compare vocational aspirations and outcomes of participants in the 10-week Leadership Program for Veterinary Students at Cornell University. DESIGN Survey. SAMPLE Veterinary students who participated in the program between 1990 and 2013. PROCEDURES Questionnaires that sought information about the career aspirations of participants at the beginning and end of the program were reviewed, along with records documenting the career progression of participants, audio recordings of interviews conducted with students, and notes of vocation-oriented counseling sessions held during each year's program. RESULTS At the conclusion of the program, 143 of 174 (82%) participants indicated they were more likely than not to undertake research training after completing their veterinary degree, compared with 106 of 174 (61%) at the beginning. Participation also stimulated interest in residency training and industry, but did little to promote interest in careers in government or the military. The percentage of participants who indicated they were more likely than not to pursue additional training in private practice decreased from 97 of 174 (56%) at the beginning of the program to 75 of 174 (43%) at the end. Information on career progression was available for 391 individuals, of whom 177 (45%) were pursuing careers of the kind envisioned by the program. However, 189 (48%) participants had a career in general or specialty clinical practice. CONCLUSIONS AND CLINICAL RELEVANCE The Leadership Program appeared to have a short-term influence on careers anticipated by program participants. However, a substantial proportion pursued careers in clinical practice after graduation.


Propofol-induced anesthesia in mice is mediated by gamma-aminobutyric acid-A and excitatory amino acid receptors.
To elucidate the role of gamma-aminobutyric acid (GABA)(A) receptor complex and excitatory amino acid receptors (N-methyl-D-aspartate [NMDA] and non-NMDA receptors) in propofol-induced anesthesia, we examined behaviorally the effects of GABAergic and glutamatergic drugs on propofol anesthesia in mice. All drugs were administered intraperitoneally. General anesthetic potencies were evaluated using a righting reflex assay. The GABA(A) receptor agonist muscimol potentiated propofol (140 mg/kg; 50% effective dose for loss of righting reflex) induced anesthesia. Similarly, the benzodiazepine receptor agonist diazepam and the NMDA receptor antagonist MK-801 augmented propofol anesthesia, but the non-NMDA receptor antagonist CNQX did not. In contrast, the GABA(A) receptor antagonist bicuculline antagonized propofol (200 mg/kg; 95% effective dose for loss of righting reflex) induced anesthesia. However, neither the benzodiazepine receptor antagonist flumazenil, the GABA synthesis inhibitor L-allylglycine, nor the NMDA receptor agonist NMDA reversed propofol anesthesia. Conversely, the non-NMDA receptor agonist kainate enhanced propofol anesthesia. These results suggest that propofol-induced anesthesia is mediated, at least in part, by both GABA(A) and excitatory amino acid receptors. We examined behaviorally the effects of GABAergic and glutamatergic drugs on propofol-induced anesthesia in mice. The results suggest that propofol anesthesia is mediated, at least in part, by both GABA(A) and excitatory amino acid receptors.