Comparison of prediction methods for the uptake of As, Cd and Pb in carrot and lettuce.
The New Model Framework (NMF) for uptake into crops is based on particle deposition and Transfer factors from soil to plant calculated from the BAse de donnees sur les teneurs en Elements Traces metalliques de Plantes Potageres (BAPPET) database. Besides NMF, approaches developed by the National Institute of Public Health and the Environment (RIVM), Hough, and the United States Environmental Protection Agency (US EPA), and the Contaminated Land Exposure Assessment (CLEA) approach were tested. Experimental data were assembled from the BAPPET database and Danish background data of As, Cd and Pb in soil, air and crops was collected. None of the models proved able to estimate the measured concentrations in plants from the BAPPET database with an absolute normalized error smaller than 70%. On average, the predictions had an error of 80-250%. However, when applying the models to the rural Danish background scenario, the NMF and other models predicted the concentrations in carrot and lettuce within the range of measured values. Regressions considering soil pH, organic matter and clay content were not superior to simple transfer factors. The transfer from air to plant is significant, at least under background conditions, and should be considered in the prediction methods.


Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation.
Commensal bacteria that colonize mammalian barrier surfaces are reported to influence T helper type 2 (T(H)2) cytokine-dependent inflammation and susceptibility to allergic disease, although the mechanisms that underlie these observations are poorly understood. In this report, we find that deliberate alteration of commensal bacterial populations via oral antibiotic treatment resulted in elevated serum IgE concentrations, increased steady-state circulating basophil populations and exaggerated basophil-mediated T(H)2 cell responses and allergic inflammation. Elevated serum IgE levels correlated with increased circulating basophil populations in mice and subjects with hyperimmunoglobulinemia E syndrome. Furthermore, B cell-intrinsic expression of myeloid differentiation factor 88 (MyD88) was required to limit serum IgE concentrations and circulating basophil populations in mice. Commensal-derived signals were found to influence basophil development by limiting proliferation of bone marrow-resident precursor populations. Collectively, these results identify a previously unrecognized pathway through which commensal-derived signals influence basophil hematopoiesis and susceptibility to T(H)2 cytokine-dependent inflammation and allergic disease.


Calcitonin gene-related peptide: physiology and pathophysiology.
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biology, but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this molecule.


Single-frequency DBR Nd-doped fiber laser at 1120 nm with a narrow linewidth and low threshold.
We report a narrow linewidth and low threshold single-frequency distributed Bragg reflector (DBR) fiber laser at 1120 nm based on a short 1.5 cm long Nd-doped silica fiber which, to the best of our knowledge, is the first demonstration of a Nd-doped fiber-based single-frequency fiber laser with a wavelength greater than 1100 nm. A stable single-longitudinal-mode laser operation with a signal-to-noise ratio greater than 67 dB was verified by a scanning Fabry-Perot interferometer. The laser threshold is as low as 10 mW. The DBR fiber laser has a maximum output power of 15 mW and optical-to-optical efficiency for the launched pump power reaches more than 8%. The narrow linewidth of 71.5 kHz is obtained in such a single-frequency fiber laser (SFFL). Our result is expected to offer an exciting new opportunity to realize high-performance SFFLs above 1100 nm.


Effects of fathers' attendance to labor and delivery on the experience of childbirth in Turkey.
This study was planned to experimentally determine the effects of fathers' attendance to labor and delivery on the experience of childbirth. Fifty primigravidae low-risk women and their partners were recruited to the study. The first 25 women were included in the experimental group, and their partners were allowed to participate in birth. The remaining 25 women were included in the control group, and their partners were not allowed to participate in birth. Perception of Birth Scale and Father Interview Form were used to evaluate couples' experiences during labor and delivery. In conclusion, fathers' support in birth helped mothers to have more positive experiences in all aspects of childbirth. There was no relationship between fathers' support and length of labor, use of pain-relieving drugs, or obstetric interventions in birth. When mother and father were supported during labor and delivery, the rate of the fathers who adopted an active role was high.


Chronic fatigue development of modern human in the context of v. vernadsky's nosophere theory.
Introduction: The existence of the noosphere as a sphere of mind influences human life processes, particularly their physical and mental health, directly. That is why a need arises to consider the biosphere development in the context of the "boom" of scientific thought and noosphere with its processes affecting human health. The aim: The research purpose is to reveal the influence of noospheric processes on human health, in particular the information flow effects on human morphofunctional state expressed as chronic fatigue. Materials and methods: A complex of study methods was used in the research: general scientific (analysis, synthesis, comparison, correlation, systematization, generalization) and empirical (observation, conversation, questionnaire). The research was conducted within the framework of "Axia" international project (Innovation in Education). For the stated research purpose achievement subjective state diagnostic technique of "WAM" as used, intended for the qualitative subjective evaluation of three main functional psycho-emotional human states: well-being, activity and mood. Respondents of three age groups were involved in the research, 347 people in each group. The first group included the responders aged 14 to 19; the second group included the responders aged 19 to 35; the third group consisted of the respondents aged 35 to 60. Results: The research results confirmed that the noospheric processes are followed by the acceleration of human life pace, information pressure causing the development of human mental fatigue, energy depletion, tiredness and chronic fatigue. The results of empirical studies of the influence of the noospheric processes anthropoprice on the human well-being, activity and mood showed the dependence of the positive integral estimation of human subjective state on the orientation towards life-long learning, personal values regardless of the age. Conclusion: The proposed article reveals the influence of noospheric processes on human morphofunctional state, scientifically grounds the connection and dependence of human tiredness on the noospheric processes anthropoprice.


Coral luminescence identifies the Pacific Decadal Oscillation as a primary driver of river runoff variability impacting the southern Great Barrier Reef.
The Pacific Decadal Oscillation (PDO) is a large-scale climatic phenomenon modulating ocean-atmosphere variability on decadal time scales. While precipitation and river flow variability in the Great Barrier Reef (GBR) catchments are sensitive to PDO phases, the extent to which the PDO influences coral reefs is poorly understood. Here, six Porites coral cores were used to produce a composite record of coral luminescence variability (runoff proxy) and identify drivers of terrestrial influence on the Keppel reefs, southern GBR. We found that coral skeletal luminescence effectively captured seasonal, inter-annual and decadal variability of river discharge and rainfall from the Fitzroy River catchment. Most importantly, although the influence of El Niño-Southern Oscillation (ENSO) events was evident in the luminescence records, the variability in the coral luminescence composite record was significantly explained by the PDO. Negative luminescence anomalies (reduced runoff) were associated with El Niño years during positive PDO phases while positive luminescence anomalies (increased runoff) coincided with strong/moderate La Niña years during negative PDO phases. This study provides clear evidence that not only ENSO but also the PDO have significantly affected runoff regimes at the Keppel reefs for at least a century, and suggests that upcoming hydrological disturbances and ecological responses in the southern GBR region will be mediated by the future evolution of these sources of climate variability.


Soluble β-amyloid impaired the GABA inhibition by mediating KCC2 in early APP/PS1 mice.
Alzheimer's disease (AD) is a neurodegenerative disorder, which has become the leading cause of dementia cases globally. Synaptic failure is an early pathological feature of AD. However, the cause of synaptic failure in AD, especially the GABAergic synaptic activity remains unclear. Extensive evidence indicates that the presence of soluble amyloid-β is an early pathological feature in AD, which triggers synaptic dysfunction and cognitive decline. Our recent study explored the relation of GABAergic transmission and soluble Aβ in early APP/PS1 mice. Firstly, we found soluble Aβ42 levels were significantly increased in serum, hippocampus and prefrontal cortex in 3-4 months APP/PS1 mice, which was much earlier than Aβ plagues formation. In addition, we found TNF-α and BDNF expression levels were increased, while KCC2 and GABAAR expression were decreased in 3-4 months APP/PS1 hippocampus. When we treated 3-4 months APP/PS1 mice with a potent γ-secretase inhibitor, LY411575, which can reduce the soluble Aβ42 levels, the TNF-α and BDNF protein levels were decreased, while KCC2 and GABAAR levels were increased. In conclusion, our study suggested soluble Aβ may impaired the GABA inhibition by mediating KCC2 levels in early APP/PS1 mice. KCC2 may be served as a potential biomarker for AD.


Changes in Rat Adrenal Cortex and Pineal Gland in Inverted Light-Dark Cycle: A Biochemical, Histological, and Immunohistochemical Study.
Poor sleep standards are common in everyday life; it is frequently linked to a rise in stress levels. The adrenal gland interacts physiologically with the pineal gland in the stress response. Pineal gland is a small endocrine organ that modulates sleep patterns. This work aimed to evaluate the inverted light-dark cycle rhythm on the histological changes within the adrenal cortex and pineal gland in adult male albino rats. Twenty adult male albino rats were equally divided into two groups: For the first control group, animals were kept on daylight-darkness for 12-12 h. The second group was kept under an inverted 12- to 12-h light-darkness cycle for 4 weeks. Adrenal sections were subjected to biochemical, histological, and immunohistochemical study. Inverted light-dark cycle group recorded a significant elevation of plasma corticosterone, tissue malondialdehyde, tumor necrosis factor-α, and interleukin-1β (IL-1β) associated with a significant reduction of catalase and superoxide dismutase. Adrenal cortex showed biochemical and histological changes. Pineal glands also showed loss of lobular architecture. A significant upregulation in activated inducible nitric oxide synthase (iNOS) and B-cell lymphoma-associated X (Bax) immunohistochemical expression was recorded in adrenal cortex associating with downregulation in B-cell lymphoma 2 (Bcl-2). It could be concluded that subchronic inverted light-dark cycle exerted direct effects on adrenal cortex and the pineal glands.


Financial incentives to promote personalized medicine in Europe: an overview and guidance for implementation.
The implementation of adequate financing and reimbursement of personalized medicine (PM) in Europe is still turbulent. The views and experience of stakeholders about barriers in financing and reimbursing PM and potential solutions were elicited and supplemented with literature findings to draft a set of recommendations. Key recommendations to overcome the barriers for adequately financing and reimbursing PM in different healthcare systems in Europe included the provision of legal foundations and establishment of large pan-European databases, use of financial-based agreements and regulation of transparency of prices and reimbursement, and creating a business-friendly environment and attractive market for innovation. The recommendations could be used by health authorities for designing a sequence of policy steps to ensure the timely access to beneficial PM.


Discriminatory effect of cyclic alternating pattern in focal lesional and benign rolandic interictal spikes during sleep.
Twenty epileptic patients (10 male and 10 female) were polygraphically recorded during nocturnal sleep. Ten subjects, with a wide age range, were affected by focal lesional epilepsy, and 10 were children affected by benign epilepsy with rolandic spikes (BERS). In five cases a bihemispheric expression of the focal lesional bursts emerged occasionally during the night recordings. The behavior of interictal electroencephalographic (EEG) paroxysms were analyzed with respect to the two arousal states of non-rapid-eye-movement (REM) sleep: (a) the cyclic alternating pattern (CAP), expressed by biphasic EEG periodic activities and related to long-lasting fluctuations between greater (phase A) and lesser (phase B) arousal levels; and (b) the non-CAP (NCAP), manifested by EEG stationarities that reflect a sustained relative stability of arousal. The CAP/NCAP modality affected the spiking activity and distribution of the focal lesional EEG paroxysms, which appeared enhanced during CAP and which were mostly collected in phase A. The even more powerful influence of CAP and especially phase A on the secondary bisynchronous bursts suggests a crucial integration among thalamocortical circuits, arousal modulation, and epileptic generalization mechanisms. Conversely, in the BERS recordings no significant differences emerged throughout CAP and NCAP. The intense activity of the rolandic foci induced by sleep as such could be explained on the basis of the greater dependence of these functional cortical EEG abnormalities on the degree of synchronization during sleep.


Common binding sites for cholesterol and neurosteroids on a pentameric ligand-gated ion channel.
Cholesterol is an essential component of cell membranes, and is required for mammalian pentameric ligand-gated ion channel (pLGIC) function. Computational studies suggest direct interactions between cholesterol and pLGICs but experimental evidence identifying specific binding sites is limited. In this study, we mapped cholesterol binding to Gloeobacter ligand-gated ion channel (GLIC), a model pLGIC chosen for its high level of expression, existing crystal structure, and previous use as a prototypic pLGIC. Using two cholesterol analogue photolabeling reagents with the photoreactive moiety on opposite ends of the sterol, we identified two cholesterol binding sites: an intersubunit site between TM3 and TM1 of adjacent subunits and an intrasubunit site between TM1 and TM4. In both the inter- and intrasubunit sites, cholesterol is oriented such that the 3‑OH group points toward the center of the transmembrane domains rather than toward either the cytosolic or extracellular surfaces. We then compared this binding to that of the cholesterol metabolite, allopregnanolone, a neurosteroid that allosterically modulates pLGICs. The same binding pockets were identified for allopregnanolone and cholesterol, but the binding orientation of the two ligands was markedly different, with the 3‑OH group of allopregnanolone pointing to the intra- and extracellular termini of the transmembrane domains rather than to their centers. We also found that cholesterol increases, whereas allopregnanolone decreases the thermal stability of GLIC. These data indicate that cholesterol and neurosteroids bind to common hydrophobic pockets in the model pLGIC, GLIC, but that their effects depend on the orientation and specific molecular interactions unique to each sterol.


Is immunisation education in midwifery degrees adequate?
Maternal and childhood vaccination decisions begin during pregnancy, and midwives are an important information resource. Their role is set to increase with the expansion of maternal immunisations into new jurisdictions, and new maternal vaccines in development. Meanwhile, other health providers are orienting parents towards vaccine acceptance, using strategies at odds with midwifery norms around information provision and maternal autonomy. To better understand and address the implications of these developments, we conducted a pilot study to ascertain how midwifery students in Australian universities are taught about immunisation, including dedicated time, assessment, who teaches it, and when. We also analysed teaching materials, looking for messaging regarding the importance of vaccination and whether midwives should be advocating for it. We found that education on immunisation comprises less than four hours of the degree, and encountered the norm of midwives informing about rather than recommending vaccination. The considerations we brought to our small project, and what it illuminated, suggest that midwifery university education is an important arena for developing future vaccine advocates. However, midwifery ideology and professional practice mean that such efforts will be challenging, and must commence from a position of respect for the values midwives hold.


Effect of anti-PcrV antibody in a murine chronic airway Pseudomonas aeruginosa infection model.
Pseudomonas aeruginosa is one of the most important pathogens in patients with chronic airway conditions, such as cystic fibrosis and diffuse panbronchiolitis. Type III secretion system-mediated virulence factors contribute to the lung damage in chronic P. aeruginosa infection. The effects of the anti-PcrV immunoglobulin (Ig)G, which blocks the type III secretion system, were evaluated in a mouse model of chronic P. aeruginosa infection. On bacteriological examination, anti-PcrV IgG showed no bactericidal effects. On bronchoalveolar lavage fluid (BALF) analysis, total cell number and neutrophil ratios in the anti-PcrV IgG-treated groups were lower than those in the control group. In addition, macrophage inflammatory protein-2, tumour necrosis factor-alpha, and interleukin-beta concentrations in BALF were lower in the anti-PcrV IgG-treated groups when compared with controls. Plasma anti-PcrV IgG titre was elevated after administration of anti-PcrV IgG. Although plasma titre decreased gradually, a significant concentration was maintained during the experimental period. These data suggest that anti-PcrV immunoglobulin G reduces the inflammatory reaction caused by chronic Pseudomonas aeruginosa respiratory infection and may be useful in treating respiratory diseases.


A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS).
The optimal intensity of oral anticoagulation for the prevention of recurrent thrombosis in patients with antiphospholipid antibody syndrome is uncertain. Retrospective studies show that only high-intensity oral anticoagulation [target international normalized ratio (INR) >3.0] is effective but a recent randomized clinical trial comparing high (INR range 3.0-4.0) vs. moderate (INR 2.0-3.0) intensities of anticoagulation failed to confirm this assumption. We conducted a randomized trial in which 109 patients with antiphospholipid syndrome (APS) and previous thrombosis were given either high-intensity warfarin (INR range 3.0-4.5, 54 patients) or standard antithrombotic therapy (warfarin, INR range 2.0-3.0 in 52 patients or aspirin alone, 100 mg day(-1) in three patients) to determine whether intensive anticoagulation is superior to standard treatment in preventing symptomatic thromboembolism without increasing the bleeding risk. The 109 patients enrolled in the trial were followed up for a median time of 3.6 years. Mean INR during follow-up was 3.2 (SD 0.6) in the high-intensity warfarin group and 2.5 (SD 0.3) (P < 0.0001) in the conventional treatment patients given warfarin. Recurrent thrombosis was observed in six of 54 patients (11.1%) assigned to receive high-intensity warfarin and in three of 55 patients (5.5%) assigned to receive conventional treatment [hazard ratio for the high intensity group, 1.97; 95% confidence interval (CI) 0.49-7.89]. Major and minor bleeding occurred in 15 patients (two major) (27.8%) assigned to receive high-intensity warfarin and eight (three major) (14.6%) assigned to receive conventional treatment (hazard ratio 2.18; 95% CI 0.92-5.15). High-intensity warfarin was not superior to standard treatment in preventing recurrent thrombosis in patients with APS and was associated with an increased rate of minor hemorrhagic complications.


VIDEOFAR: an epidemiologic tool for drug utilization studies.
VIDEOFAR is a computerized drug prescription monitoring system oriented to gain an epidemiological insight into the phenomenon of "drug prescription". The set of activities carried out within the VIDEOFAR project were focused to: define methods of analysis of prescription data, which could be transferred to the peripherical operating settings of the National Health Service (Local Health Units, Epidemiologic Observatories, Regional Pharmaceutical Services, etc.); implement a Drug Data Base to allow a flexible utilization of information; implement software systems in different computer environments.


Factors promoting consistent adherence to safe needle precautions among hospital workers.
To examine organizational factors and occupational characteristics associated with adherence to occupational safety guidelines recommending never recapping needles. Mail surveys were conducted with healthcare workers (HCWs) and infection control professionals (ICPs). The surveys were conducted at all non-federal general hospitals in Iowa, except one tertiary-care hospital. Survey data were linked to annual survey data of the American Hospital Association (AHA). HCWs were sampled from statewide rosters of physicians, nurses, and laboratory workers in Iowa. Eligible HCWs worked in a setting and position in which they were likely to routinely handle needles. ICPs at all hospitals in the state were surveyed. Ninety-nine ICPs responded (79% response rate). AHA data were available for all variables from 84 (85%) of the hospitals. Analyses were based on 1,454 HCWs who identified one of these hospitals as their primary hospital (70% response rate). Analyses were conducted using multiple logistic regression. Positive predictors of consistent adherence included infection control personnel hours per full-time-equivalent employee (odds ratio [OR], 1.03), frequency of standard precautions education (OR, 1.11), facilities providing personal protective equipment (OR, 1.82), facilities using needleless intravenous systems (OR, 1.42), and management support for safety (OR, 1.05). Negative predictors were use of "blood and body fluid precautions" isolation category (OR, 0.74) and increased job demands (OR, 0.90). Healthcare organizations can improve staff safety by investing wisely in educational programs regarding approaches to minimize these risks, providing protective equipment, and eliminating the use of blood and body fluid precautions as an isolation policy.


Qualitative Methodology in Cardiovascular Outcomes Research: A Contemporary Look.
Qualitative research offers unique opportunities to contribute to cardiovascular outcomes research. Despite the growth in qualitative research over the last decade, outcomes investigators in cardiology still have relatively little guidance on when and how best to implement these methods in their investigations, leaving the full potential of these methods unrealized. We offer a contemporary look at qualitative methods, including publication trends of qualitative studies in cardiology journals from 1998 to 2018, novel emerging data collection and analytic methods, and current use and examples of cardiovascular outcomes research that apply qualitative methods such as user-centered design, preimplementation evaluation, implementation evaluation, effectiveness evaluation, and policy analysis.


A multi-modal sweat sensing patch for cross-verification of sweat rate, total ionic charge, and Na+ concentration.
Sweat sensors introduced in recent years have targeted a variety of sweat features and biomarkers for non-invasive health monitoring. Amongst these targets, reliable monitoring of sweat rate is crucial due to its modulation of sweat analyte concentrations and its intrinsic significance to numerous medical and physiological health conditions. Here we present a sweat rate sensor structure comprising of electrodes with interdigitated fingers in a microfluidic channel. Each time the accumulating sweat impinges on an electrode finger, the sensor reports a jump in admittance that can be simply and efficiently counted to estimate sweat rate, overcoming selectivity limitations of previously reported sweat rate sensors. We further integrate an impedimetric sensor for measuring total ionic charge concentration and an electrochemical Na+ sensor, together creating a multi-modal system for analyzing fluid and electrolyte secretion. We demonstrate how low analyte diffusion rates through this microfluidic device allow for multi-purpose sensor function, including utilizing the sweat rate sensor signal to corroborate total ionic sensor measurements. This cross-verification capability ensures data integrity in real time, satisfying a vital consideration for personalized healthcare technologies. We use the presented patch for continuous analysis of sweat rate, total ionic charge concentration, and Na+ concentration during exercise, while demonstrating how multi-modal cross-verification brings new trust to sensor readings.


Dunking rusk: innovative food soaking behaviour in Goffin's cockatoos (Cacatua goffiniana).
Foraging innovations in animals involving the processing of resources that are already edible in an unprocessed state, yet of improved quality in a processed state, are rare but important to study the evolution of food preparation. Here, we present the first scientific report of food dunking behaviours in parrots by Goffin's cockatoos, a model species for innovative problem solving. Observations during lunch showed seven out of 18 cockatoos placing their food into water and soaking it prior to consumption. This was largely done with dry rusk which was eaten almost exclusively when dunked. Furthermore, their transport effort and waiting times before retrieving food from the water indicate their willingness to invest considerable time to prepare a soaked rusk piece of a higher texture quality. Our present results suggest that the function of this behaviour is to soak the food. Because only some individuals dunked food and dunking has not been observed in the wild, we believe this to be a spontaneous foraging innovation either by one or multiple individuals.


Effects of drop sets with resistance training on increases in muscle CSA, strength, and endurance: a pilot study.
To investigate the effects of a single high-load (80% of one repetition maximum [1RM]) set with additional drop sets descending to a low-load (30% 1RM) without recovery intervals on muscle strength, endurance, and size in untrained young men. Nine untrained young men performed dumbbell curls to concentric failure 2-3 days per week for 8 weeks. Each arm was randomly assigned to one of the following three conditions: 3 sets of high-load (HL, 80% 1RM) resistance exercise, 3 sets of low-load [LL, 30% 1RM] resistance exercise, and a single high-load (SDS) set with additional drop sets descending to a low-load. The mean training time per session, including recovery intervals, was lowest in the SDS condition. Elbow flexor muscle cross-sectional area (CSA) increased similarly in all three conditions. Maximum isometric and 1RM strength of the elbow flexors increased from pre to post only in the HL and SDS conditions. Muscular endurance measured by maximum repetitions at 30% 1RM increased only in the LL and SDS conditions. A SDS resistance training program can simultaneously increase muscle CSA, strength, and endurance in untrained young men, even with lower training time compared to typical resistance exercise protocols using only high- or low-loads.


Refining Convolutional Neural Network Detection of Small-Bowel Obstruction in Conventional Radiography.
The purpose of this study was to evaluate improvement of convolutional neural network detection of high-grade small-bowel obstruction on conventional radiographs with increased training set size. A set of 2210 abdominal radiographs from one institution (image set 1) had been previously classified into obstructive and nonobstructive categories by consensus judgments of three abdominal radiologists. The images were used to fine-tune an initial convolutional neural network classifier (stage 1). An additional set of 13,935 clinical images from the same institution was reduced to 5558 radiographs (image set 2) primarily by retaining only images classified positive for bowel obstruction by the initial classifier. These images were classified into obstructive and nonobstructive categories by an abdominal radiologist. The combined 7768 radiographs were used to train additional classifiers (stage 2 training). The best classifiers from stage 1 and stage 2 training were evaluated on a held-out test set of 1453 abdominal radiographs from image set 1. The ROC AUC for the neural network trained on image set 1 was 0.803; after stage 2, the ROC AUC of the best model was 0.971. By use of an operating point based on maximizing the validation set Youden J index, the stage 2-trained model had a test set sensitivity of 91.4% and specificity of 91.9%. Classification performance increased with training set size, reaching a plateau with over 200 positive training examples. Accuracy of detection of high-grade small-bowel obstruction with a convolutional neural network improves significantly with the number of positive training radiographs.


Expression of TFH Markers and Detection of RHOA p.G17V and IDH2 p.R172K/S Mutations in Cutaneous Localizations of Angioimmunoblastic T-Cell Lymphomas.
Skin biopsies of 41 angioimmunoblastic T-cell lymphoma patients were retrospectively analyzed for the expression of follicular helper T-cell (TFH) markers, Epstein-Barr virus (EBV), and the presence of RHOA (p.G17V) and IDH2 (p.R172K/S) mutations using allele-specific polymerase chain reaction. We categorized cases into 4 distinctive patterns: (1) low-density lymphocytic perivascular infiltrates (n=11), (2) dense perivascular infiltrates with atypical cells and occasional inflammatory cells (n=13), (3) diffuse infiltrates reminiscent of angioimmunoblastic T-cell lymphoma (n=4), or (4) other aspects (n=13). Two EBV and 2 plasmacytoid lymphoproliferative disorders were seen. We observed variable expression of TFH markers (CD10 [50%], BCLB6 [84%], PD1 [94%], CXCL13 [84%], and ICOS [97.5%]), and EBV B-blasts (26%). A TFH phenotype was identified in 82% and 73%, respectively, of cases with the most challenging patterns 1 and 2. TFH markers and EBV can thus help for diagnosis and are detected in samples with low-density infiltrates. We found RHOA G17V and IDH2 R172K/S mutations in the skin in 14/18 (78%) and 3/16 (19%) cases, respectively. The RHOA G17V mutation was identified in a proportion of biopsies with patterns 1 and 2, which represent a diagnostic challenge. The RHOA G17V mutation was detected both in the skin and lymph node (LN) biopsies in 7/9 (64%) cases, and in only the skin or the LN of 1 sample each. The frequency of RHOA G17V mutation was similar to that reported in LNs. It may represent a sensitive diagnostic marker in the skin, helpful in cases with low-density infiltrates.


Single-Crystalline Aluminum Nanostructures on a Semiconducting GaAs Substrate for Ultraviolet to Near-Infrared Plasmonics.
Aluminum, as a metallic material for plasmonics, is of great interest because it extends the applications of surface plasmon resonance into the ultraviolet (UV) region and is superior to noble metals in natural abundance, cost, and compatibility with modern semiconductor fabrication processes. Ultrasmooth single-crystalline metallic films are beneficial for the fabrication of high-definition plasmonic nanostructures, especially complex integrated nanocircuits. The absence of surface corrugation and crystal boundaries also guarantees superior optical properties and applications in nanolasers. Here, we present UV to near-infrared plasmonic resonance of single-crystalline aluminum nanoslits and nanoholes. The high-definition nanostructures are fabricated with focused ion-beam milling into an ultrasmooth single-crystalline aluminum film grown on a semiconducting GaAs substrate with a molecular beam epitaxy method. The single-crystalline aluminum film shows improved reflectivity and reduced two-photon photoluminescence (TPPL) due to the ultrasmooth surface. Both linear scattering and nonlinear TPPL are studied in detail. The nanoslit arrays show clear Fano-like resonance, and the nanoholes are found to support both photonic modes and localized surface plasmon resonance. We also found that TPPL generation is more efficient when the excitation polarization is parallel rather than perpendicular to the edge of the aluminum film. Such a counterintuitive phenomenon is attributed to the high refractive index of the GaAs substrate. We show that the polarization of TPPL from aluminum preserves the excitation polarization and is independent of the crystal orientation of the film or substrate. Our study gains insight into the optical property of aluminum nanostructures on a high-index semiconducting GaAs substrate and illustrates a practical route to implement plasmonic devices onto semiconductors for future hybrid nanodevices.


Combination of alkaline and enzymatic treatments as a process for upgrading sisal paper-grade pulp to dissolving-grade pulp.
A sequence of treatments consisting of an initial xylanase treatment followed by cold alkaline extraction and a final endoglucanase treatment was investigated as a process for upgrading non-wood paper-grade pulps to dissolving-grade pulps for viscose production. Five commercial dried bleached non-wood soda/AQ paper pulps, from flax, hemp, sisal, abaca, and jute, were studied for this purpose. Commercial dried bleached eucalyptus dissolving pulp was used as reference sample. Sisal pulp showed the highest improvement in Fock's reactivity, reaching levels nearly as high or even higher than that of eucalyptus dissolving pulp (65%), and a low hemicellulose content (3-4%) when was subjected to this sequence of treatments. The viscosity, however, decreased considerably. A uniform and narrow molecular weight distribution was observed by size exclusion chromatography. (13)C nuclear magnetic resonance spectroscopy and Raman microspectroscopy revealed that the cellulose structure consisted of cellulose I.


Antiovulatory and estrogenic activity of Plumbago rosea leaves in female albino rats.
To evaluate the effect of petroleum ether (60-80 degrees ), chloroform, acetone, ethanol and aqueous extracts of Plumbago rosea leaves on the estrous cycle and to identify the estrogenic activity of active acetone and ethanol extracts in female albino rats. PLANT EXTRACTS WERE TESTED FOR THEIR EFFECT ON THE ESTROUS CYCLE AT TWO DOSE LEVELS: 200 and 400 mg/kg, respectively. The effective acetone and ethanol extracts were further studied on estrogenic activity in rats. Histological studies of the uterus were carried out to confirm their estrogenic activity. The acetone and ethanol extracts were most effective in interrupting the normal estrous cycle of the rats (P<0.05, <0.01, <0.001). These later exhibited prolonged diestrous stage of the estrous cycle with consequent temporary inhibition of ovulation. The antiovulatory activity was reversible on discontinuation of treatment. Both the extracts showed significant estrogenic and antiestrogenic activity. The acetone and ethanolic extracts of P. rosea leaves have an antifertility activity.


A binary system based DNA tetrahedron and fluorogenic RNA aptamers for highly specific and label-free mRNA imaging in living cells.
Developing simple, rapid and specific mRNA imaging strategy plays an important role in the early diagnosis of cancer and the new drugs development. Herein, we have established a novel binary system based DNA tetrahedron and fluorogenic RNA aptamers for highly specific and label-free mRNA imaging in living cells. This developed system consisted of tetrahedron probe A (TPA) and tetrahedron probe B (TPB). TK1 mRNA was chosen as the study model. After TPA and TPB enter into the live cells, the TK1 mRNA induces TPA and TPB to approach and activate the fluorescent aptamer, resulting in enhanced fluorescent signal in the presence of small molecules of DFHBI-1T. By this design, the high specificity label-free detection of nucleic acids was achieved with a detection limit of 1.34 nM. Confocal fluorescence imaging experiments had proved that this strategy could effectively distinguish the TK1 mRNA expression level between normal cell and cancer cell. The developed method is expected to provide a new tool for early diagnosis of diseases and new drug development.


Real life condition evaluation of Inoserp PAN-AFRICA antivenom effectiveness in Cameroon.
Snakebites is a serious public health issue but remains a neglected tropical disease. Data on antivenom effectiveness are urgently needed in Africa. We assessed effectiveness of Inoserp PAN-AFRICA (IPA), the recommended antivenom available in Cameroon. We enrolled 447 patients presenting with snakebite in 14 health facilities across Cameroon. At presentation, cytotoxicity, coagulation troubles and neurotoxicity were graded. We administered two to four vials of antivenom to patients based on hemotoxic or neurotoxic signs. We renewed antivenom administration to patients with persistence of bleedings or neurotoxicity 2 hours after each injection. We defined early improvement as a reduction of the grade of envenomation symptoms 2 hours after first injection. Medium-term effectiveness was investigated looking at disappearance of symptoms during hospitalization. After hospital discharge, a home visit was planned to assess long-term outcomes. Between October 2019 and May 2021, we enrolled 447 (93.7%), including 72% from the savannah regions. The median [IQR] age was 25 [14-40]. Envenomation was diagnosed in 369 (82.6%) participants. The antivenom was administered to 356 patients (96.5%) of whom 256 (71.9%) received one administration. Among these patients, cytotoxic symptoms were observed in 336 (94.4%) participants, coagulation disorders in 234 (65.7%) participants and neurotoxicity in 23 (6.5%) participants. Two hours after the first administration of antivenom, we observed a decrease in coagulation disorders or neurotoxicity in 75.2% and 39.1% of patients, respectively. Complete cessation of bleedings and neurotoxicity occurred in 96% and 93% of patients within 24 hours, respectively. Sequelae have been observed in 9 (3%) patients at the home visit 15 days after hospital admission and 11 (3%) died including one before antivenom injection. We confirmed good effectiveness of the IPA and highlighted the rapid improvement in bleeding or neurotoxicity after the first administration. Sequential administrations of low doses of antivenom, rigorously assessed at short intervals for an eventual renewal, can preserve patient safety and save antivenom. NCT03326492.


Numerical method for correcting the series resistance error in voltage clamp experiments.
There is an inherent error in the voltage clamp, which is a major electrophysiological research tool. Current (I) flowing across the voltage-clamped membrane generates a drop in the resistance potential in series with the membrane (Rs) and thus an error in control of the potential. This error, which may be very significant, can only be partially corrected by electronic compensation during the experiment. Subsequent correction by computation is generally believed impossible for membrane potentials (Vm) for which the conductance parameters are voltage dependent. In the proposed method, which is based on the assumption that dI/dt is a function of I and Vm only, the reconstruction begins with very small sodium or potassium currents (for which the Rs error is negligible). The subsequent I value is calculated using a dI/dt value obtained under any set of conditions where Vm is known to have the desired value (as ensured by the experimental protocol) and where I equals the initial I value. By iterations, the correct I vs. t curve is reconstructed for the chosen potential. It is shown analytically that for squid giant axons, with an uncompensated Rs of 5 omega . cm2 the maximal error in INa is reduced from about 30% to under 3%. The validity of the reconstruction is demonstrated experimentally by corrected INa generated in artificial seawater and comparing it with INa obtained in a solution containing a low concentration of tetrodotoxin.


Environmental Gas Sensing with Cavitands.
Environmental gas sensing needs stringent sensor requirements in terms of sensitivity, selectivity and ruggedness. One of the major issues to be addressed is combining in a single device the conflicting requirements of molecular-level selectivity and low-ppb sensitivity. The exploitation of synthetic molecular receptors as sensing materials is particularly attractive to address the selectivity issue, to single out the desired analytes in the presence of overwhelming amounts of interferents. This minireview summarizes the strategies in environmental gas and vapor sensing using molecular receptors as selective hosts for specific analytes, with the main focus on cavitands. In particular, we highlight the use of these macrocycles as selective preconcentrator units to be integrated into portable devices for environmental monitoring. Depending on the class of analytes to be detected, the molecular recognition properties of cavitands can be manipulated through the proper choice of the bridging groups at the upper rim, and their transducer integration can be implemented through the manifold functionalization options at the lower rim.


Detection of humic acid in water using flat-sheet and folded-rod viscous alkaline glucose syrups.
The utility of a low-cost biocompatible material for the detection of pollutants in water is highly essential to ensure safety and economic efficiency. In this paper, solutions of two viscous alkaline glucose syrups (AGS@22-sheet and AGS@60-rod), obtained under two different temperature conditions (22 °C and 60 °C) were used to detect low levels of humic acid (HA), a carcinogen pro-molecule and metal-complexing agent in an aqueous solution. The AGS materials were characterized using ultraviolet-visible spectroscopy (UV-Vis), Fourier transform infrared spectroscopy and scanning electron microscopy (SEM). By evaluation, a detection limit (LOD) as low as 4.6 × 10-5 mg L-1 was obtained. The sensing capability of the new technology was further extended to the detection of HA in a real water sample (tap water) using the standard addition method with 98 and 100.05% recoveries. The sensing was improved in the presence of sodium acetate and sodium citrate and was found to follow a pseudo-first order reaction. These findings show that the as-synthesized glucose syrups have the potential to detect humic acid in water and thus may be employed for the quantification of HA in water treatment plants or textile industry.


Secretory immunoglobulin A: well beyond immune exclusion at mucosal surfaces.
At mucosal surfaces, secretory IgA (SIgA) antibodies serve as the first line of defense against microorganisms through a mechanism called immune exclusion that prevents interaction of neutralized antigens with the epithelium. In addition, SIgA plays a role in the immune balance of the epithelial barrier through selective adhesion to M cells in intestinal Peyer's patches. This mediates the transepithelial retro-transport of the antibody and associated antigens from the intestinal lumen to underlying gut-associated organized lymphoid tissue. In Peyer's patches, SIgA-based immune complexes are internalized by underlying antigen-presenting cells, leaving the antigen with masked epitopes, a form that limits the risk of overwhelming the local immune protection system with danger signals. This translates into the onset of mucosal and systemic responses associated with production of anti-inflammatory cytokines and limited activation of antigen-presenting cells. In the gastrointestinal tract, SIgA exhibits thus properties of a neutralizing agent (immune exclusion) and of an immunopotentiator inducing effector immune responses in a noninflammatory context favorable to preserve local homeostasis.


Human mammaglobin RT-PCR assay for detection of occult breast cancer cells in hematopoietic products.
The aim of this study was: (i) to evaluate the sensitivity and specificity of mammaglobin as a reverse transcriptase polymerase chain reaction (RT-PCR) marker of breast cancer cells; (ii) to determine the incidence of tumor cell contamination of hematopoietic samples from patients with breast cancer. A nested RT-PCR assay for mammaglobin was developed. Sensitivity was determined by serial dilution assays with breast cancer cell lines, human breast cancers and normal breast tissue. Specificity was evaluated in hematopoietic samples from healthy volunteers and patients with hematological malignancies or solid tumors other than breast cancer. The mammaglobin transcript was detected in all 15 breast cancers, one benign breast tumor and five normal breast tissues studied, as well as in three breast cancer cell lines, in dilutions as low as 10(-8). The transcript was not detected in any of 47 peripheral blood samples, 15 bone marrow aspirates and 28 peripheral blood progenitor cell samples from the three control populations. Mammaglobin mRNA was detected in 19 of 78 peripheral blood samples from patients with breast cancer starting systemic chemotherapy, as well as in five of 30 repeat samples collected before the fourth cycle of treatment. The transcript was also present in six of seven bone marrow aspirates from patients with metastatic disease, two of five with loco-regional disease, but not in the aspirate of two patients with thrombocytopenia and a previous history of breast cancer. Human mammaglobin mRNA is a sensitive and specific marker of breast cancer cells and should be further studied as a molecular marker of tumor cell contamination of hematopoietic tissues.


Blood brain barrier permeable gold nanocluster for targeted brain imaging and therapy: an in vitro and in vivo study.
Blood brain barrier (BBB) is a dynamic interface, comprising polarized endothelial cells, that separates the brain from the circulatory system. The highly protective nature of this tight junction impairs diagnosis and treatment of brain disorders. In this study, we designed a sub atomic size, near infrared emitting, dual function glutathione gold cluster with high fluorescence yield to facilitate permeability of BBB, for imaging applications and drug delivery. The gold cluster was then modified with Levodopa (l-dopa), to utilize the large amino acid transporter 1 (LAT1) pathways to enhance brain entry. Uptake and permeability of the nanoprobes were demonstrated using an established model of BBB, comprising brain endothelial cells (bEnd.3). The uptake and the clearance of l-dopa modified cluster was faster than the glutathione cluster. l-Dopa modified cluster supports the slow and sustained delivery of a model drug, pilocarpine, to the brain. Results of in vivo imaging and drug release in normal mice hold promise for considering the probe for early diagnosis of brain diseases, when the barrier is not disrupted, and for subsequent drug treatment.


Leukotrienes as mediators in tissue trauma.
A significant increase in the production of cysteinyl leukotrienes was observed after mechanical or thermal trauma in the anesthesized rat. The amount of biliary N-acetyl-leukotriene E4, which represents a suitable indicator for blood plasma leukotrienes, was used as a measure of leukotriene generation. Cysteinyl leukotrienes were rapidly eliminated from blood plasma into bile where N-acetyl-leukotriene E4 was the major metabolite. Leukotrienes were at a much lower concentration in blood plasma than in bile and differed in the pattern of metabolites. The detected amounts of leukotrienes were sufficient to induce known phenomena associated with trauma, such as tissue edema and circulatory and respiratory dysfunction. Increased leukotriene generation appears to play an important role in the pathophysiology of tissue trauma.


A subtractive approach to characterize genes with regionalized expression in the gliogenic ventral neuroepithelium: identification of chick sulfatase 1 as a new oligodendrocyte lineage gene.
To address the question of the origin of glial cells and the mechanisms leading to their specification, we have sought to identify novel genes expressed in glial progenitors. We adopted suppression subtractive hybridization (SSH) to establish a chick cDNA library enriched for genes specifically expressed at 6 days of incubation (E6) in the ventral neuroepithelium, a tissue previously shown to contain glial progenitors. Screens were then undertaken to select differentially expressed cDNAs, and out of 82 unique SSH clones, 21 were confirmed to display a regionalized expression along the dorsoventral axis of the E6 ventral neuroepithelium. Among these, we identified a transcript coding for the chick orthologue of Sulf1, a recently identified cell surface sulfatase, as a new, early marker of oligodendrocyte (OL) precursors in the chick embryonic spinal cord. This study provides groundwork for the further identification of genes involved in glial specification.


Distribution of HBV genotypes in Latin America.
Approximately 2 billion people worldwide are infected with HBV, and 350 million people are chronic carriers. HBV is classified into nine genotypes (A to I). Genotype F is the most prevalent in the Spanish-speaking countries and in the Amerindian population in South America. HBV genotype F was primarily found in indigenous populations from South America and is divided into four subgenotypes (F1 to F4). Subgenotype F1 is further divided into F1a (found in Costa Rica and El Salvador) and F1b (found in in Alaska, Argentina and Chile). Subgenotypes F2 and F3 cocirculate in the north of South America: F2a is found in Brazil and Venezuela, F2b is described only in Venezuela, F3 is frequent in Colombia, Venezuela and Panama, and F4 is reported from the central and south areas of South America, including Bolivia, Argentina and southern Brazil. HBV genotypes and subgenotypes have distinct geographical distributions. It is currently under discussion whether they are associated with different prognoses, considering the patterns of severity of liver diseases in various populations. Furthermore, global human migrations affect the pattern of genotype distribution, introducing genotypes differing from those found in the original inhabitants.


Gut microbiota and child behavior in early puberty: does child sex play a role?
A growing number of studies have indicated relations between the gut microbiota and mental health. However, to date, there is a scarcity of microbiota studies in community samples in early puberty. The current preregistered study (https://osf.io/wu2vt) investigated gut microbiota composition in relation to sex in low-risk children and explored behavioral associations with gut microbiota composition and metabolites in the same samples, together with the potential role of sex. Fecal microbiota composition was analyzed in 12-year-old children (N = 137) by 16S rRNA gene sequencing and quantitative PCR. Modest sex differences were observed in beta diversity. Generalized linear models showed consistent behavioral relations to both relative and absolute abundances of individual taxa, including positive associations between Parasutterella and mother-reported internalizing behavior, and negative associations between Odoribacter and mother-reported externalizing behavior. Additionally, Prevotella 9 was positively related to mother-reported externalizing behavior, confirming earlier findings on the same cohort at 5 years of age. Sex-related differences were found in behavioral relations to Ruminiclostridium 5, Alistipes, Streptococcus, Ruminiclostridium 9, Ruminococcaceae UCG-5, and Dialister, for relative abundances, as well as to Family XIII AD3011 group and an unidentified bacterium within the Tenericutes, for absolute abundances. Limited behavioral relations were observed regarding alpha diversity and fecal metabolites. Our findings describe links between the gut microbiota and child behavior, together with differences between child sexes in these relations, in low-risk early pubertal children. Importantly, this study confirmed earlier findings in this cohort of positive relations between Prevotella 9 and externalizing behavior at age 10 years. Results also show the merit of including absolute abundances in microbiota studies.


The frequency of short-chain acyl-CoA dehydrogenase gene variants in the US population and correlation with the C(4)-acylcarnitine concentration in newborn blood spots.
Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is a clinically heterogeneous disorder. The clinical phenotype varies from fatal metabolic decompensation in early life to subtle adult onset, some patients remain asymptomatic. Two mutations (511C>T; 625G>A) have been described in exons 5 and 6 of the SCAD gene. Although they alter the structural and catalytic properties of the SCAD protein, these variants are not true disease-causing mutations but confer disease susceptibility. Previous studies found these gene variants to be common in Europeans. We aimed to establish the frequency of these variants in the US population and to determine whether the presence of these variants correlates with elevated butyrylcarnitine (C(4)-acylcarnitine) concentrations in newborn blood spots. Based on the analysis of 694 samples, we found that the allele frequency of the 625G>A variant was significantly higher (22%) than that of the 511C>T variant (3%). These gene variants were detected in either homozygous or compound heterozygous form in 7% of the study population. Additionally, the frequency of the 625G>A allele in the Hispanic population (30%) was significantly higher than that of the African-American (9%) and Asian (13%) subpopulations. A previously unreported variant, IVS 5 (-10) C>T, was identified in three African-American newborns (0.3%). The C(4)-acylcarnitine concentration in blood spots was significantly higher in subjects homozygous for the 625A variant when compared to those homozygous for the wild type (p<0.0001). However, none of the observed genotypes was associated with a concentration of C(4)-acylcarnitine that would be consistent with a biochemical diagnosis of SCAD deficiency.


Responsiveness of isolated tracheal smooth muscle from normal and sensitized guinea pigs.
Studies of the responsiveness of strips of tracheal smooth muscle and the changes after sensitization of ovalbumin were carried out. The hypothesis that there might be a generalized or a selective change of airway smooth muscle responsiveness to sensitization was examined in vitro. Agonists acting on muscarinic receptors, alpha 1-, alpha 2-, and beta-adrenoceptors, purine receptors, histamine and serotonin receptors, and leukotriene and prostaglandin receptors were tested, as well as mediators released from local nerves by field stimulation and procedures such as elevation of potassium or addition of Ca2+ ionophores which do not involve specific receptors. Sensitivity to serotonin increased significantly in sensitized animals. Total magnitude of the contraction and subsequent relaxation responses to field stimulation also increased significantly. Neither of these changes was large in magnitude. Although there were a few minor changes in sensitivity (pD2) or in maximum responses, the hypothesis of important changes in responses of any sort in tracheal muscle after sensitization was rejected. The question was raised whether this general absence of changed responsiveness in vitro reflected (i) the failure of sensitization to induce generalized smooth muscle hyperresponsiveness, (ii) the loss of the mechanisms of such responsiveness in vitro, or (iii) the inadequacy of in vitro techniques to assess responsiveness present in vivo.


O2 free radicals: cause of ischemia-reperfusion injury to cardiac Na+-K+-ATPase.
The role of O2 free radicals in the reduction of sarcolemmal Na+-K+-ATPase, which occurs during reperfusion of ischemic heart, was examined in isolated guinea pig heart using exogenous scavengers of O2 radicals and an inhibitor of xanthine oxidase. Ischemia and reperfusion reduced Na+-K+-ATPase activity and specific [3H]ouabain binding to the enzyme in ventricular muscle homogenates and also markedly lowered sodium pump activity estimated from ouabain-sensitive 86Rb+ uptake by ventricular muscle slices. These effects of ischemia and reperfusion were prevented to various degrees by O2-radical scavengers, such as superoxide dismutase, catalase, dimethyl-sulfoxide, histidine, or vitamin E or by the xanthine oxidase inhibitor, allopurinol. The degree of protection afforded by these agents paralleled that of reduction in enhanced lipid peroxidation of myocardial tissue as estimated from malondialdehyde production. These results strongly suggest that O2 radicals play a crucial role in the injury to sarcolemmal Na+-K+-ATPase during reperfusion of ischemic heart.


Improved Sampling of Adaptive Path Collective Variables by Stabilized Extended-System Dynamics.
Because of the complicated multistep nature of many biocatalytic reactions, an a priori definition of reaction coordinates is difficult. Therefore, we apply enhanced sampling algorithms along with adaptive path collective variables (PCVs), which converge to the minimum free energy path (MFEP) during the simulation. We show how PCVs can be combined with the highly efficient well-tempered metadynamics extended-system adaptive biasing force (WTM-eABF) hybrid sampling algorithm, offering dramatically increased sampling efficiency due to its fast adaptation to path updates. For this purpose, we address discontinuities of PCVs that can arise due to path shortcutting or path updates with a novel stabilization algorithm for extended-system methods. In addition, we show how the convergence of simulations can be further accelerated by utilizing the multistate Bennett's acceptance ratio (MBAR) estimator. These methods are applied to the first step of the enzymatic reaction mechanism of pseudouridine synthases, where the ability of path WTM-eABF to efficiently explore intricate molecular transitions is demonstrated.


Ownership and hospital behaviour: Employment and local unemployment.
In this paper, we address two issues: i) how hospital employment changes with local unemployment, according to the type of hospital ownership, and ii) whether this relationship changed after the implementation of a pro-competitive reform that made hospitals more similar. A 2006-2010 French panel of 1695 hospitals over five waves allows us to consider within-hospital employment changes. We first find that higher local unemployment is associated with greater employment in State-owned hospitals, but not for any other hospital ownership type: French local authorities then seem to respond to depressed local labour markets by increasing employment in State-owned hospitals. After the full implementation of the pro-competitive reform hospital funding became based only on activity and no longer on some historical budget. Theoretically, the new reimbursement system should break the relationship between public-hospital employment and local unemployment. Our results reveal that the reform worked as expected in less-deprived areas: reducing employment and eliminating the correlation between local unemployment and State-owned hospital employment. However, in higher-unemployment areas, public-hospital employment remains counter-cyclical. Poor local labour-market health then seems to trump financial incentives in determining employment in public hospitals.


Shiga toxin-producing Escherichia coli isolated from patients with diarrhoea in Bangladesh.
The prevalence of Shiga toxin-producing Escherichia coli (STEC) and its characteristics were determined among hospitalized patients with diarrhoea and children with diarrhoea in an urban slum community of Dhaka city using sensitive culture and PCR methods. Stool samples were collected from 410 patients with diarrhoea enrolled in the 2% surveillance system (every 50th patient attending the hospital with diarrhoeal disease is included) at the ICDDR,B hospital and from 160 children of 2-5 years of age with diarrhoea living in an urban slum in Dhaka, between September 2004 and April 2005. Shiga toxin genes (stx) were detected by multiplex PCR in the enrichment broth of nine samples (2.2%) from hospitalized patients and 11 samples (6.9%) from the community patients. STEC was isolated from five stool samples with positive PCR results using a colony patch technique. All five isolates were positive in the Vero cell assay and PCR fragments of stx genes were confirmed by sequencing. Two isolates were positive for the E. coli attaching-and-effacing (eae) gene and four were positive for the enterohaemolysin (hlyEHEC) gene and enterohaemolysin production. The five isolates belonged to five different serotypes:O32:H25, O2:H45, O76:H19, ONT:H25 and ONT:H19. It can be concluded that STEC is not a common pathogen in Bangladesh among hospitalized patients with diarrhoea nor among mild cases of diarrhoea in the community.


Histopathological and ultrastructural examination of the rat conjunctiva after exposure to tobacco smoke.
Exposure to tobacco smoke can cause irritation of the conjunctiva. We conducted this study to identify the effect of tobacco on rat conjunctiva. Animals were divided into experimental and control groups and we exposed the experimental group to tobacco smoke. Control group rats inhaled only room air. Spectrophotometric analysis of the smoke-air mixture revealed that many toxic substances were present in this compound. We found very high levels of plasma thiocyanate after exposure to smoke in experimental group animals but no increase in the control group. So, this data indicates that these animals inhaled smoke effectively in our method. After 3 months conjunctivas were examined by light and electron microscopy. In the experimental group, conjunctivas were thinned, atrophied and microvillous projections and desmosomal connections were absent in comparison with the control conjunctivas. This pathologic change is very similar to conjunctival response to chronic irritants of any type.


Differential Bone Loss in Mouse Models of Colon Cancer Cachexia.
Cachexia is a distinctive feature of colorectal cancer associated with body weight loss and progressive muscle wasting. Several mechanisms responsible for muscle and fat wasting have been identified, however it is not known whether the physiologic and molecular crosstalk between muscle and bone tissue may also contribute to the cachectic phenotype in cancer patients. The purpose of this study was to clarify whether tumor growth associates with bone loss using several experimental models of colorectal cancer cachexia, namely C26, HT-29, and ApcMin/+. The effects of cachexia on bone structure and strength were evaluated with dual energy X-ray absorptiometry (DXA), micro computed tomography (μCT), and three-point bending test. We found that all models showed tumor growth consistent with severe cachexia. While muscle wasting in C26 hosts was accompanied by moderate bone depletion, no loss of bone strength was observed. However, HT-29 tumor bearing mice showed bone abnormalities including significant reductions in whole-body bone mineral density (BMD), bone mineral content (BMC), femoral trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th), but no declines in strength. Similarly, cachexia in the ApcMin/+ mice was associated with significant decreases in BMD, BMC, BV/TV, Tb.N, and Tb.Th as well as decreased strength. Our data suggest that colorectal cancer is associated with muscle wasting and may be accompanied by bone loss dependent upon tumor type, burden, stage and duration of the disease. It is clear that preserving muscle mass promotes survival in cancer cachexia. Future studies will determine whether strategies aimed at preventing bone loss can also improve outcomes and survival in colorectal cancer cachexia.


Recovery of dynamic visual acuity in unilateral vestibular hypofunction.
To determine the effect of vestibular exercises on the recovery of visual acuity during head movement in patients with unilateral vestibular hypofunction. Prospective, randomized, double-blind study. Ambulatory referral center. Twenty-one patients with unilateral vestibular hypofunction, aged 20 to 86 years. One group (13 patients) performed vestibular exercises designed to enhance the vestibulo-ocular reflex, and the other group (8 patients) performed placebo exercises. The placebo group was switched to vestibular exercises after 4 weeks. Measurements of dynamic visual acuity (DVA) during predictable (DVA-predictable) and unpredictable (DVA-unpredictable) head movements by means of a computerized test and measurement of intensity of oscillopsia by means of a visual analog scale. As a group, patients who performed vestibular exercises showed a significant improvement in DVA-predictable (P<.001) and DVA-unpredictable (P<.001), while those performing placebo exercises did not (P =.07). On the basis of stepwise regression analysis, the leading factor contributing to improvement was vestibular exercises. This reached significance for DVA-predictable (P =.009) but not DVA-unpredictable (P =.11). Other factors examined included age, time from onset, initial DVA, oscillopsia, and duration of treatment. Changes in oscillopsia did not correlate with DVA-predictable or DVA-unpredictable. Use of vestibular exercises is the main factor involved in recovery of DVA-predictable and DVA-unpredictable in patients with unilateral vestibular hypofunction. Exercises may foster the use of centrally programmed eye movements that could substitute for the vestibulo-ocular reflex. The DVA-predictable would benefit more from this than would DVA-unpredictable.


Historical background and aspects of the mechanism of leukocyte adherence inhibition.
The development of leukocyte adherence inhibition is traced from early experiments with murine tumors to recent applications in human cancer and in cell-mediated immunity in general. Arbitrary experimental conditions (serum in culture medium, preincubation, and tumor extracts at a single concentration) were initially set up and permitted detection of specific inhibition of adherence of sensitized leukocytes reacting with antigen of the tumor extracts. Blocking serum completely or partially restored adherence. It was readily demonstrated that leukocyte adherence inhibition was mediated by a soluble lymphokine-like factor [leukocyte adherence inhibition factor (LAIF)]. Recent studies suggest that serum is important in enabling detection of LAIF; this may explain the inability of some other workers to confirm our findings. Serum appears to protect LAIF from enzymatic destruction in mixtures containing tumor extracts. Complex cell interactions are involved in LAIF production. With mouse cells in vitro, macrophages are required for production by both T- and B-lymphocytes, and there is evidence for suppressor cells also.


The FTLD Risk Factor TMEM106B Regulates the Transport of Lysosomes at the Axon Initial Segment of Motoneurons.
Genetic variations in TMEM106B, coding for a lysosomal membrane protein, affect frontotemporal lobar degeneration (FTLD) in GRN- (coding for progranulin) and C9orf72-expansion carriers and might play a role in aging. To determine the physiological function of TMEM106B, we generated TMEM106B-deficient mice. These mice develop proximal axonal swellings caused by drastically enlarged LAMP1-positive vacuoles, increased retrograde axonal transport of lysosomes, and accumulation of lipofuscin and autophagosomes. Giant vacuoles specifically accumulate at the distal end and within the axon initial segment, but not in peripheral nerves or at axon terminals, resulting in an impaired facial-nerve-dependent motor performance. These data implicate TMEM106B in mediating the axonal transport of LAMP1-positive organelles in motoneurons and axonal sorting at the initial segment. Our data provide mechanistic insight into how TMEM106B affects lysosomal proteolysis and degradative capacity in neurons.


Reliability and Validity of the Behavioral Addiction Measure for Video Gaming.
Most tests of video game addiction have weak construct validity and limited ability to correctly identify people in denial. The purpose of the present research was to investigate the reliability and validity of a new test of video game addiction (Behavioral Addiction Measure-Video Gaming [BAM-VG]) that was developed in part to address these deficiencies. Regular adult video gamers (n = 506) were recruited from a Canadian online panel and completed a survey containing three measures of excessive video gaming (BAM-VG; DSM-5 criteria for Internet Gaming Disorder [IGD]; and the IGD-20), as well as questions concerning extensiveness of video game involvement and self-report of problems associated with video gaming. One month later, they were reassessed for the purposes of establishing test-retest reliability. The BAM-VG demonstrated good internal consistency as well as 1 month test-retest reliability. Criterion-related validity was demonstrated by significant correlations with the following: time spent playing, self-identification of video game problems, and scores on other instruments designed to assess video game addiction (DSM-5 IGD, IGD-20). Consistent with the theory, principal component analysis identified two components underlying the BAM-VG that roughly correspond with impaired control and significant negative consequences deriving from this impaired control. Together with its excellent construct validity and other technical features, the BAM-VG represents a reliable and valid test of video game addiction.


Glasses-type wearable computer displays: usability considerations examined with a 3D glasses case study.
This study presents usability considerations and solutions for the design of glasses-type wearable computer displays and examines their effectiveness in a case study. Design countermeasures were investigated by a four-step design process: (1) preliminary design analysis; (2) design idea generation; (3) final design selection; and (4) virtual fitting trial. Three design interventions were devised from the design process: (1) weight balance to reduce pressure concentrated on the nose, (2) compliant temples to accommodate diverse head sizes and (3) a hanger mechanism to help spectacle users hang their wearable display on their eye glasses. To investigate their effectiveness, in the case study, the novel 3D glasses adopting the three interventions were compared with two existing 3D glasses in terms of neck muscle fatigue and subjective discomfort rating. While neck muscle fatigue was not significantly different among the three glasses (p = 0.467), the novel glasses had significantly smaller discomfort ratings (p = 0.009). Relevance to Industry: A four-step design process identified usability considerations and solutions for the design of glasses-type wearable computer displays. A novel 3D glasses was proposed through the process and its effectiveness was validated. The results identify design considerations and opportunities relevant to the emerging wearable display industry.


Predominant polarity and hippocampal subfield volumes in Bipolar disorders.
Predominant polarity (PP) is a proposed course specifier for bipolar disorders (BD) based on patient lifetime mood episodes. Hippocampal subfield volumetric changes have been proposed as a neurobiological marker for BD and could be influenced by mood episodes. Our study aimed to test the hypothesis that patients with BD differ in hippocampal subfield volumes according to their PP. We assessed 172 outpatients, diagnosed with BD according to DSM-IV-TR criteria, and 150 healthy control (HC) participants. High-resolution magnetic resonance imaging was performed on all subjects and volumes of all hippocampal subfields were measured using FreeSurfer. Patients with depressive PP (BD-DP) and with uncertain PP (BD-UP) but not with manic/hypomanic PP (BD-MP) showed a global reduction on all hippocampal subfield volumes with respect to HCs. When directly compared, BD-DP presented with smaller bilateral presubiculum/subiculum volumes than BD-MP. Results support the potential utility of PP not only as a clinical but also as a neurobiological specifier of BD.


[Third ventricle meningioma in a child: case report].
Meningiomas in childhood are rare, and those located in the third ventricle are even rarer, with only 16 cases reported. A five-year-old girl was seen at our hospital with headache and bilateral papilledema. CT scan showed a large third ventricular mass and associated hydrocephalus. Transcallosal interfornical approach was performed with total removal of the tumor, that was attached to the choroid plexus of the anterior third ventricle. Histologically the lesion proved to be a transitional meningioma. The recovery was uneventful, a permanent shunt was not necessary. The diagnosis of these tumors can be done using CT scan or MRI, that usually are sufficient for surgical planning. Angiography usually is not required, unless a vascular lesion is concerned, or embolization is necessary. The treatment of these tumors is surgical, aiming the total removal of the lesion, usually curative once it is acomplished. We report this case, and add a brief review of the literature on third ventricle meningiomas.


Estimating genome conservation between crop and model legume species.
Legumes are simultaneously one of the largest families of crop plants and a cornerstone in the biological nitrogen cycle. We combined molecular and phylogenetic analyses to evaluate genome conservation both within and between the two major clades of crop legumes. Genetic mapping of orthologous genes identifies broad conservation of genome macrostructure, especially within the galegoid legumes, while also highlighting inferred chromosomal rearrangements that may underlie the variation in chromosome number between these species. As a complement to comparative genetic mapping, we compared sequenced regions of the model legume Medicago truncatula with those of the diploid Lotus japonicus and the polyploid Glycine max. High conservation was observed between the genomes of M. truncatula and L. japonicus, whereas lower levels of conservation were evident between M. truncatula and G. max. In all cases, conserved genome microstructure was punctuated by significant structural divergence, including frequent insertion/deletion of individual genes or groups of genes and lineage-specific expansion/contraction of gene families. These results suggest that comparative mapping may have considerable utility for basic and applied research in the legumes, although its predictive value is likely to be tempered by phylogenetic distance and genome duplication.


Effect of prevalence of alcohol consumption and tobacco use in Mexican municipalities on early childhood development.
One of the most critical time periods in childhood is from birth to five years of age. Children exposed to alcohol and/or tobacco via family members and neighborhood are at risk for childhood developmental delays. This study evaluated the association of early childhood development with the prevalence of alcohol consumption and tobacco use in Mexican municipalities. This is a cross-sectional study. Early childhood development information from 2,345 children aged from 36 to 59 months was obtained from the 2015 Mexican National Survey of Boys, Girls, and Women (ENIM). Data on alcohol consumption and tobacco use come from the 2016 Mexican National Survey on Drugs, Alcohol, and Tobacco Consumption (ENCODAT). Multilevel logistic models were fitted to evaluate the association of the prevalence of alcohol consumption and tobacco use with the inadequacy of early childhood development. Children living in municipalities with high prevalence of alcohol consumption (OR = 13.410; 95%CI: 2.986; 60.240) and tobacco use (OR = 15.080; 95%CI: 2.040; 111.400) were less likely to be developmentally on track regarding early childhood development after adjustment for individual variables related to the child's development and other environmental variables at municipal level. Childhood exposure to alcohol and tobacco in the neighborhood may directly contribute to inadequate early childhood development. These findings suggest that there is an urgent need to develop effective interventions aimed at reducing alcohol consumption and tobacco use in municipalities to ensure adequate early childhood development.


Intrinsic disorder prediction from the analysis of multiple protein fold recognition models.
Intrinsic protein disorder is functionally implicated in numerous biological roles and is, therefore, ubiquitous in proteins from all three kingdoms of life. Determining the disordered regions in proteins presents a challenge for experimental methods and so recently there has been much focus on the development of improved predictive methods. In this article, a novel technique for disorder prediction, called DISOclust, is described, which is based on the analysis of multiple protein fold recognition models. The DISOclust method is rigorously benchmarked against the top.ve methods from the CASP7 experiment. In addition, the optimal consensus of the tested methods is determined and the added value from each method is quantified. The DISOclust method is shown to add the most value to a simple consensus of methods, even in the absence of target sequence homology to known structures. A simple consensus of methods that includes DISOclust can significantly outperform all of the previous individual methods tested. http://www.reading.ac.uk/bioinf/DISOclust/. Supplementary data are available at http://www.reading.ac.uk/bioinf/DISOclust/suppl.pdf.


The potential of human induced pluripotent stem cells for modelling diabetic wound healing in vitro.
Impaired wound healing and ulceration caused by diabetes mellitus, is a significant healthcare burden, markedly impairs quality of life for patients, and is the major cause of amputation worldwide. Current experimental approaches used to investigate the complex wound healing process often involve cultures of fibroblasts and/or keratinocytes in vitro, which can be limited in terms of complexity and capacity, or utilisation of rodent models in which the mechanisms of wound repair differ substantively from that in humans. However, advances in tissue engineering, and the discovery of strategies to reprogramme adult somatic cells to pluripotency, has led to the possibility of developing models of human skin on a large scale. Generation of induced pluripotent stem cells (iPSCs) from tissues donated by diabetic patients allows the (epi)genetic background of this disease to be studied, and the ability to differentiate iPSCs to multiple cell types found within skin may facilitate the development of more complex skin models; these advances offer key opportunities for improving modelling of wound healing in diabetes, and the development of effective therapeutics for treatment of chronic wounds.


A probabilistic approach to discovering dynamic full-brain functional connectivity patterns.
Recent research shows that the covariance structure of functional magnetic resonance imaging (fMRI) data - commonly described as functional connectivity - can change as a function of the participant's cognitive state (for review see Turk-Browne, 2013). Here we present a Bayesian hierarchical matrix factorization model, termed hierarchical topographic factor analysis (HTFA), for efficiently discovering full-brain networks in large multi-subject neuroimaging datasets. HTFA approximates each subject's network by first re-representing each brain image in terms of the activities of a set of localized nodes, and then computing the covariance of the activity time series of these nodes. The number of nodes, along with their locations, sizes, and activities (over time) are learned from the data. Because the number of nodes is typically substantially smaller than the number of fMRI voxels, HTFA can be orders of magnitude more efficient than traditional voxel-based functional connectivity approaches. In one case study, we show that HTFA recovers the known connectivity patterns underlying a collection of synthetic datasets. In a second case study, we illustrate how HTFA may be used to discover dynamic full-brain activity and connectivity patterns in real fMRI data, collected as participants listened to a story. In a third case study, we carried out a similar series of analyses on fMRI data collected as participants viewed an episode of a television show. In these latter case studies, we found that the HTFA-derived activity and connectivity patterns can be used to reliably decode which moments in the story or show the participants were experiencing. Further, we found that these two classes of patterns contained partially non-overlapping information, such that decoders trained on combinations of activity-based and dynamic connectivity-based features performed better than decoders trained on activity or connectivity patterns alone. We replicated this latter result with two additional (previously developed) methods for efficiently characterizing full-brain activity and connectivity patterns.


Naringenin Improves Ovalbumin-Induced Allergic Asthma in Rats through Antioxidant and Anti-Inflammatory Effects.
Asthma is a chronic disease with eosinophilic inflammation and oxidative damages leading to airway obstruction. Naringenin is a phytochemical possessing strong antioxidant and anti-inflammatory activities against chronic destructive conditions. The current study is devoted to evaluating naringenin's effects on the attenuation of inflammation and oxidative stress in lung tissue in a rat model of ovalbumin-induced asthma. Male Wistar rats were allocated to five groups of six: normal control (NC, receiving 1 ml/day of normal saline, orally), asthmatic (AS, receiving ovalbumin (1 mg/mL), and alum (1 mg/mL in saline) on days 0 and 14. Then, on days 21, 22, and 23, they were sensitized with the inhalation of ovalbumin), AS treated with dexamethasone (AS, 1 mg/kg/day, orally) [AS + D1], AS treated with naringenin (20 mg/kg/day, orally) [AS + N20], and AS treated with naringenin (40 mg/kg/day, orally) [AS + N40]. All the groups received associated drugs/agents for 28 days. Finally, bronchoalveolar lavage fluid (BALF) and lung tissue samples were taken off from the animals. The eosinophil count in BALF and malondialdehyde (MDA), glutathione (GSH), interleukin-13 and -4 (IL-13 and IL-4) levels were measured. Besides, the expression of urocortin (UCN) and surfactant protein-D (SP-D) were evaluated in the lung tissue using immunohistochemistry (IHC) and western blotting methods, respectively. Hematoxylin and eosin (H&E) staining were utilized to conduct histopathological analysis. Naringenin treatment significantly reduced MDA, remarkably increased GSH, and meaningfully reduced IL-4 and IL-13 levels in lung tissue. The count of eosinophils in the BALF of AS + N20 and AS + N40 was significantly reduced in comparison with the AS group. The UCN and SP-D protein levels were significantly decreased in the AS + N20 and AS + N40 groups compared to the AS group, using the IHC and western blot methods, respectively. Histopathological analysis data also confirm the results. Naringenin improves the symptoms of allergic asthma through antioxidant and anti-inflammatory effects.


PM2.5-Bound Organophosphate Flame Retardants in Hong Kong: Occurrence, Origins, and Source-Specific Health Risks.
Organophosphate flame retardants (OPFRs) are emerging organic pollutants in PM2.5, which have caused significant public health concerns in recent years, given their potential carcinogenic and neurotoxic effects. However, studies on the sources, occurrence, and health risk assessment of PM2.5-bound OPFRs in Hong Kong are lacking. To address this knowledge gap, we characterized 13 OPFRs in one-year PM2.5 samples using gas chromatography-atmospheric pressure chemical ionization tandem mass spectrometry. Our findings showed that OPFRs were present at a median concentration of 4978 pg m-3 (ranging from 1924 to 8481 pg m-3), with chlorinated OPFRs dominating and accounting for 82.7% of the total OPFRs. Using characteristic source markers and positive matrix factorization, we identified one secondary formation and five primary sources of OPFRs. Over 94.0% of PM2.5-bound OPFRs in Hong Kong were primarily emitted, with plastic processing and waste disposal being the leading source (61.0%), followed by marine vessels (14.1%). The contributions of these two sources to OPFRs were more pronounced on days influenced by local pollution emissions (91.9%) than on days affected by regional pollution (44.2%). Our assessment of health risks associated with human exposure to PM2.5-bound OPFRs indicated a low-risk level. However, further source-specific health risk assessment revealed relatively high noncarcinogenic and carcinogenic risks from chlorinated OPFRs emitted from plastic processing and waste disposal, suggesting a need for more stringent emission control of OPFRs from these sources in Hong Kong.


An AU-rich sequence in the 3'-UTR of plasminogen activator inhibitor type 2 (PAI-2) mRNA promotes PAI-2 mRNA decay and provides a binding site for nuclear HuR.
The plasminogen activator inhibitor type 2 (PAI-2) gene is regulated by transcriptional and post-transcriptional processes. We have previously shown that insertion of the 3'-untranslated region (3'-UTR) of PAI-2 mRNA into the 3'-UTR of a beta-globin reporter mRNA reduces constitutive beta-globin mRNA expression and that this requires, at least in part, an AU-rich motif. Here we have directly assessed the role of this motif in PAI-2 mRNA stability using both chimeric and non-chimeric reporter systems. We first show that the full-length PAI-2 mRNA is indeed unstable with a half-life of 1 h. Using the c-fos promoter-driven human growth hormone (HGH) mRNA as a reporter, we demonstrate that the 580 nt 3'-UTR of PAI-2 accelerates chimeric HGH mRNA decay in a process which is dependent on the intact AU-rich sequence. Furthermore, disruption of this motif within a constitutively expressed PAI-2 cDNA produces a 2.5- and 2. 7-fold increase in PAI-2 mRNA and protein levels in HT-1080 cells, respectively. RNA electrophoretic mobility shift and supershift assays indicate that this motif provides a specific binding site for cellular proteins that include nuclear HuR. Taken together, these data show that a correlation exists between the binding of HuR to the AU-rich motif in vitro and the destabilizing properties conferred by this sequence in vivo.


pp60c-src has less affinity for the detergent-insoluble cellular matrix than do pp60v-src and other viral protein-tyrosine kinases.
A difference in affinity for a Nonidet P-40-insoluble cellular matrix was observed between the products of the viral and cellular src genes. It has previously been demonstrated that pp60v-src is associated with a detergent-insoluble matrix containing the cellular cytoskeleton (J. G. Burr, G. Dreyfuss, S. Penman, and J. M. Buchanan, Proc. Natl. Acad. Sci. USA 77:3484-3488, 1980). We observed a similar association of the transforming proteins of Fujinami sarcoma virus (P130gag-fps) and Yamaguchi 73 avian sarcoma virus (P90gag-yes), both of which are tyrosine-specific protein kinases. However, we found that the endogenous c-src product, pp60c-src, was not tightly bound to the detergent-insoluble matrix. This does not appear to have been due to differences in the cytoskeleton between transformed and nontransformed cells since pp60c-src was also solubilized by nonionic detergent in cells transformed by Rous sarcoma virus. This difference in the affinities of the v-src and c-src products for cytoskeletal proteins may contribute to the inability of pp60c-src to transform cells.


A quantitative analgesic assay in the rabbit based on the response to tooth pulp stimulation.
A DC ramp voltage was used to stimulate rabbit tooth pulps. Thresholds to elicit chewing movements were extremely stable in the absence of drug treatment. Using cumulative dosing of analgesic drugs, potency and efficacy measurements could be readily obtained. Narcotic analgesics were the most effective analgesics on this test, followed by two centrally acting non-narcotics (nefopam and baclofen). Antipyretic/anti-inflammatory analgesics and centrally acting non-analgesic drugs elevated thresholds by lesser amounts or were inactive. It is concluded that the rabbit tooth pulp assay is suitable for the qualitative and quantitative determination of analgesic activity.


In vivo Raman spectroscopy for detection of oral neoplasia: a pilot clinical study.
We report a pilot study carried out to evaluate the applicability of in vivo Raman spectroscopy for differential diagnosis of malignant and potentially malignant lesions of human oral cavity in a clinical setting. The study involved 28 healthy volunteers and 171 patients having various lesions of oral cavity. The Raman spectra, measured from multiple sites of normal oral mucosa and of lesions belonging to three histopathological categories, viz. oral squamous cell carcinoma (OSCC), oral submucous fibrosis (OSMF) and leukoplakia (OLK), were subjected to a probability based multivariate statistical algorithm capable of direct multi-class classification. With respect to histology as the gold standard, the diagnostic algorithm was found to provide an accuracy of 85%, 89%, 85% and 82% in classifying the oral tissue spectra into the four tissue categories based on leave-one-subject-out cross validation. When employed for binary classification, the algorithm resulted in a sensitivity and specificity of 94% in discriminating normal from the rest of the abnormal spectra of OSCC, OSMF and OLK tissue sites pooled together.


Required warfarin dose and time in therapeutic range in patients with diagnosed Nonalcoholic Fatty Liver Disease (NAFLD) or Nonalcoholic Steatohepatitis (NASH).
Warfarin has been widely used to treat thromboembolism. The effect of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH), on warfarin dosing remains unknown. This study aims to examine the effects of NAFLD/NASH on the average daily dose (ADD) of warfarin and the time in therapeutic range (TTR). This is a retrospective study utilizing an administrative data. We included patients with at least 2 months of warfarin dispensing and two subsequent consecutive INR measures. The ADD of warfarin to achieve therapeutic range INR levels, and TTR were compared between patients with and without NAFLD/NASH in four subgroups of patients accounting for the presence of obesity and diabetes. Generalized linear models (GLM) with Propensity score (PS) fine stratification were applied to evaluate the relative differences (RD) of warfarin ADD and TTR (>60%) in four subgroups. A total of 430 NAFLD/NASH patients and 38,887 patients without NAFLD/NASH were included. The ADD and TTR, were not significant in the overall cohort between those with and without NAFLD/NASH. However, GLM results in patients without diabetes or obesity (N = 26,685) showed a significantly lower warfarin ADD (RD: -0.38; 95%CI: -0.74--0.02) and shorter TTR (OR: 0.71; 95%CI: 0.52-0.97) in patients diagnosed with NAFLD/NASH. The effects of NAFLD/NASH on warfarin dose or TTR were observed in patients without obesity and diabetes. Obesity and diabetes appear to be significant modifiers for the effects of NAFLD/NASH on warfarin dose and TTR.


Trends, patterns and cause-specific neonatal mortality in Tanzania: a hospital-based retrospective survey.
Globally, large numbers of children die shortly after birth and many of them within the first 4 wk of life. This study aimed to determine the trends, patterns and causes of neonatal mortality in hospitals in Tanzania during 2006-2015. This retrospective study involved 35 hospitals. Mortality data were extracted from inpatient registers, death registers and International Classification of Diseases-10 report forms. Annual specific hospital-based neonatal mortality rates were calculated and discussed. Two periods of 2006-2010 and 2011-2015 were assessed separately to account for data availability and interventions. A total of 235 689 deaths were recorded and neonatal deaths accounted for 11.3% (n=26 630) of the deaths. The majority of neonatal deaths (87.5%) occurred in the first week of life. Overall hospital-based neonatal mortality rates increased from 2.6 in 2006 to 10.4 deaths per 1000 live births in 2015, with the early neonates contributing 90% to this rate constantly over time. The neonatal mortality rate was 3.7/1000 during 2006-2010 and 10.4/1000 during 2011-2015, both periods indicating a stagnant trend in the years between. The leading causes of early neonatal death were birth asphyxia (22.3%) and respiratory distress (20.8%), while those of late neonatal death were sepsis (29.1%) and respiratory distress (20.0%). The majority of neonatal deaths in Tanzania occur among the early newborns and the trend over time indicates a slow improvement. Most neonatal deaths are preventable, hence there are opportunities to reduce mortality rates with improvements in service delivery during the first 7 d and maternal care.


Changes in IDH2, TET2 and KDM2B Gene Expression After Treatment With Classic Chemotherapeutic Agents and Decitabine in Myelogenous Leukemia Cell Lines.
Hematological malignancies are a heterogeneous group of tumors with increased proliferative and auto-replicative capacity. Despite treatment advances, post-treatment quality of life remains highly affected. Studies addressing the molecular mechanisms of these diseases are critical for the development of effective, rapid and selective therapies, since few therapeutic strategies succeed in being effective without triggering high-grade toxicities or debilitating late effects. Our aim of this study was to verify changes in the expression of genes involved in the malignant phenotype of hematological malignancies, by treating human cell lines in vitro with classic chemotherapeutic agents and the demethylating agent, decitabine. KASUMI-1 and K-562 human myeloid leukemia cell lines were plated at a density of 3 × 104 cells/well and treated with increasing concentrations of different chemotherapeutic agents commonly used in the clinical setting. After 24 and 48 h of treatment, cell viability was tested, and RNA was extracted. Complementary DNA (cDNA) was synthesized and quantitative real-time polymerase chain reaction (qPCR) was performed to evaluate the gene expression of IDH2, TET2 and KDM2B. A modulation in gene expression was observed before and after treatment with classic chemotherapeutic agents. It was possible to demonstrate a difference in gene expression when cells were treated with chemotherapeutic agents or decitabine alone when compared to chemotherapeutic agents in association with decitabine. The genes tested, and the modulation of their expression during in vitro treatments suggest that IDH2, TET2, and KDM2B should be further investigated as potential biomarkers for ongoing treatment response and follow-up for patients diagnosed with hematological malignancies of the myeloid lineage.