Assessment of halotolerant bacterial and fungal consortia for augmentation of wheat in saline soils.
Adaptations of green technologies to counter abiotic stress, including salinity for crops like wheat by using halotolerant microbes, is a promising approach. The current study investigated 17 salt-affected agroecological zones from the Punjab and Sindh provinces of Pakistan to explore the potential of indigenous microbial flora, with their multiple biochemical characteristics in addition to plant growth promoting (PGP) traits, for enhanced wheat production in saline areas. Initially, 297 isolated pure bacterial colonies were screened for salt tolerance, biochemical, and PGP traits. Three bacterial strains belonging to Pantoea spp. and Erwinia rhaphontici with possession of multiple characteristics were selected for the development of the halotolerant bacterial consortium. Inoculation of two local wheat varieties, Faisalabad 2008 and Galaxy 2013, with the consortium for in vitro seed germination assay and sand microcosm experiments exhibited significant improvement of selected plant growth parameters like germination percentage and root structure. Two previously reported PGP fungal strains of Trichoderma harzianum and T. viridae were also used as fungal consortium separately for pot experiments and field trials. The pot experiments exhibited a positive correlation of consortia with metabolic viz. catalase, peroxidase, and proline and agronomical parameters including shoot length, dry weight, number of spikes, spike length, and 100 grain weight. To evaluate their performance under natural environmental conditions, field trials were conducted at three salt-affected sites. Agronomical attributes including days of flowering and maturity, flag leaf weight, length and width, shoot length, number of spikes, spike length, spike weight, number of seeds spike-1, 1,000 grain weight, and plot yield indicated the efficiency of these microbes to enhance wheat growth. Concisely, the bacterial consortium showed better performance and Faisalabad 2008 was a more resistant variety as compared to Galaxy 2013. Initial promising results indicate that further extensive research on indigenous microbes might lead to the development of Pakistan's first saline-specific biofertilizers and sustainable eco-friendly agriculture practices.


Immune myocarditis related to sintilimab treatment in a patient with advanced lung adenocarcinoma: A case report.
Immune checkpoint inhibitors (ICI) have improved clinical outcomes of patients with advanced lung cancer, but may lead to fatal cardiac injury. We describe a 66-year-old man with advanced lung adenocarcinoma who presented with chest pain and dyspnea 3 weeks after the first dose of sintilimab. The initial electrocardiogram (ECG) demonstrated ST-elevation in leads V5-V9, and a high-sensitivity troponin level was significantly elevated. However, coronary angiography did not reveal any significant stenosis. The patient was successfully treated with methylprednisolone and immunoglobulin. Cardiac MRI was carried out before discharge and late gadolinium enhancement (LGE) was found to be in the mid layer of the septal segment and the subepicardial layer of the inferolateral wall. Due to the high fatality, ICI-related myocarditis requires close surveillance, prompt management and long-term follow-up.


Preliminary evidence for a race-based stress reduction intervention for Black women at risk for cardiovascular disease.
Despite evidence that chronic stress, racism, and discrimination impact the well-being and the risk for cardiovascular disease (CVD) in Black women, there are few evidence-based interventions that improve well-being and reduce the risk for CVD in women of minority groups. The purpose of this pilot study was to evaluate the psychobehavioral and anti-inflammatory benefit of a race-based stress reduction program "Resilience, Stress, and Ethnicity (RiSE) for Black women at risk for CVD. Black women were recruited from the Chicagoland community and randomized to either the 8-week RiSE intervention (n = 40) or control group (n = 34). Participants were assessed for coping strategies, psychological distress, and blood levels of TNF-alpha and high sensitivity C-reactive protein (hsCRP) at baseline and at 4 and 8 weeks after baseline. Participation in RiSE was associated with a more rapid decline in the use of avoidance coping (b = -0.3585, SE = 0.1705, p < .01). Reductions over time in TNF-alpha (b = -0.0163, SE = .0087, p = .08) and hsCRP (b= -0.4064, SE = 0.2270, p = .08) approached statistical significance. Findings provide preliminary evidence in Black women at risk for CVD that RiSE contributes to decreases in avoidance coping. Although preliminary, these results suggest RiSE to be an effective intervention to promote improved coping associated with racism and discrimination in minorities.


Risk factors for injuries in young children in four developing countries: the Young Lives Study.
To assess the occurrence of child injury in four developing country settings and to explore potential risk factors for injury. Injury occurrence was studied in cohorts of 2000 children of age 6-17 months at enrolment, in each of Ethiopia, Peru, Vietnam and India (Andhra Pradesh). Generalized estimating equation models were used to explore potential risk factors for child injury. Occurrence of child injury was high in all countries. Caregiver depression emerged as a consistent risk factor for all types of injury measured (burns, serious falls, broken bones and near-fatal injury) across all countries. Other risk factors also showed consistent associations, including long-term child health problems, region of residence and the regular care of the child by a non-household member. This report provides further evidence of the importance of childhood injury in developing countries and emphasizes the importance of including infants in injury research and prevention strategies. It provides strong evidence of an association between caregiver mental health and child injury risk and contributes to the limited knowledge base on risk factors for child injury in developing countries.


Kinetics of Supercritical Drying of Gels.
Supercritical drying of gels is considered as the most important step of aerogel production since it enables preservation of the three-dimensional pore structure which lead to unique material properties such as high porosity, low density, and large surface area. An understanding of the kinetics of supercritical drying is necessary to provide insight into material development, scale-up, and optimization of the aerogel manufacturing process. Thus, investigation of supercritical drying is gaining increased attention in recent years. This review paper covers the experimental considerations and techniques to study the kinetics of supercritical drying, fundamental mass transfer mechanisms during the drying process and modeling efforts to predict the drying kinetics for varying operating conditions and gel properties. Transport phenomena involving diffusion, convection, spillage by volume expansion, and axial dispersion are discussed by providing the fundamental equations and empirical correlations to predict transfer coefficients. A detailed review of literature covering experimental and theoretical studies on kinetics of supercritical drying is presented.


Dihydrooxazine N-Oxide Intermediates as Resting States in Organocatalytic Kinetic Resolution of Functionalized Nitroallylic Amines with Aldehydes.
Kinetic resolution of nitroallylic amines was established using chiral α,α-l-diphenylprolinol silyl ether auxiliary through isolation of the dihydrooxazine N-oxide intermediates. Further hydrolyzing the resting states provided tetrahydropyridines in high chemical yields and high to excellent stereoselectivities (up to >20:1 dr and 98% ee). A detailed mechanistic explanation for stereoselective protonation in the dihydrooxazine was probed computationally. In addition, the probable intermediates in α-halogenation of aldehydes (masked with enamines) were isolated to provide crystallographic evidence.


[CT, MRI].
Coronary arterial lesions (CAL) due to Kawasaki disease (KD) should be monitored by conventional coronary angiography(CAG) throughout their lives. However, recently multi detector row computed tomography(MDCT) and magnetic resonance coronary angiography (MRCA) have developed remarkably. We performed MRCA in 1,200 cases of KD (age at 4 month to 41 years: medium 8 years) since 1999. MR myocardial imaging is also performed simultaneously in patients with severe stenotic lesions. Noninvasive MRCA is useful to monitor CAL in young children. MDCT is efficient at screening of CAL and at making a diagnosis of no acute coronary syndromes in adults with chest pain. These examinations are very useful to decrease CAG to the least times as possible.


Matter-wave dromions in a disk-shaped dipolar Bose-Einstein condensate with the Lee-Huang-Yang correction.
We investigate, both analytically and numerically, the nonlinear dynamics of (2+1)-dimensional [(2+1)D] matter waves excited in a disk-shaped dipolar Bose-Einstein condensate (BEC) when quantum fluctuations described by the Lee-Huang-Yang (LHY) correction are taken into consideration. By using a method of multiple scales, we derive Davey-Stewartson I equations that govern the nonlinear evolution of matter-wave envelopes. We demonstrate that the system supports (2+1)D matter-wave dromions, which are superpositions of a short-wavelength excitation and a long-wavelength mean flow. We found that the stability of the matter-wave dromions can be enhanced by the LHY correction. We also found that such dromions display interesting behaviors of collision, reflection, and transmission when they interact with each other and are scattered by obstacles. The results reported here are useful not only for improving the understanding on the physical property of the quantum fluctuations in BECs, but also for possible experimental findings of new nonlinear localized excitations in systems with long-ranged interactions.


Comparison of treatment costs and outcome in public orthodontic services in Finland.
The objectives of the study were to compare the costs and outcome of orthodontic treatment in eight municipal health centres in Finland. A random sample of the age groups of 16- and 18-year-olds (n = 1109) living in these municipalities was clinically examined by two calibrated orthodontists. The acceptability of the morphology and function of the occlusion were assessed with the Occlusal Morphology and Function Index (OMFI). The data concerning previous orthodontic treatment were collected from the patient records of all subjects (n = 608) who reported previous or ongoing orthodontic treatment or who could not recall if they had received orthodontic treatment. The health centres were grouped into an early and a late timing group according to the mean age of starting the treatment. The mean age for starting orthodontic treatment was 8.0 years (SD 1.9) in the early group and 10.7 years (SD 2.3) in the late group. The visit costs and the costs of orthodontic appliances without overheads comprised the operating costs. The cost-effectiveness of orthodontic services was measured by estimating how much each health centre had to have paid for one per cent unit of acceptable morphology and acceptable function of occlusion. The mean appliance costs were higher in the late timing group and the mean visit costs higher in the early timing group. The mean operating costs per case were €720 in the early and €649 in the late timing group. However, there was a great variation within both groups. The cost of one per cent unit of acceptable morphology was the same in the two timing groups, while the cost of one per cent unit of acceptable function was lower in the early timing group. The low operating costs as such did not totally explain the better cost-effectiveness of orthodontic care. Furthermore, the cost-effectiveness was not directly connected with the timing of treatment.


RSSALib: a library for stochastic simulation of complex biochemical reactions.
Stochastic chemical kinetics is an essential mathematical framework for investigating the dynamics of biological processes, especially when stochasticity plays a vital role in their development. Simulation is often the only option for the analysis of many practical models due to their analytical intractability. We present in this article, the simulation library RSSALib, implementing our recently developed rejection-based stochastic simulation algorithm (RSSA) and a wide range of its improvements, to accelerate the simulation and analysis of biochemical reactions. RSSALib supports reactions with complex kinetics and time delays, necessary to model complexities of reaction mechanisms. Our library provides both an application program interface and a graphic user interface to ease the set-up and visualization of the simulation results. RSSALib is freely available at: https://github.com/vo-hong-thanh/rssalib. Supplementary data are available at Bioinformatics online.


[Expression of peroxisome proliferators-activated receptor-gamma and cyclooxygenase-2 in Helicobacter pylori infection-associated diseases and significance thereof].
To investigate the expression of peroxisome proliferators-activated receptor-gamma (PPAR-gamma) and cyclooxygenase-2 (COX-2) in Helicobacter pylori (Hp)-associated gastric mucosal lesions and the relations among them. Two-step immunohistochemical staining was used to detect the expression of PPAR-gamma and COX-2 proteins in the gastric biopsy specimens from 209 patients with lesions of gastric mucosa, including 75 cases of chronic superficial gastritis (CSG), 24 cases of chronic atrophic gastritis (CAG), and 90 cases of intestinal metaplasia (MI) and dysplasia (DYS), and from 20 subjects with normal gastric mucosa negative in Hp as controls. In addition, 36 CSG patients were followed up for 10 years to observe the changes of expression of PPAR-gamma and COX-2. (1) The expression of COX-2 protein in the glandular cells of the CSG, CAG, and IM + DYS groups were 42.7%, 45.8%, and 61.1% respectively, all significantly higher than that of the control group (20%, P < 0.01 or 0.05). The expression of COX-2 protein in the inflammatory cells of the CSG, CAG, and IM + DYS groups were 32%, 29.2%, and 36.7% respectively, all significantly higher than that of the control group (0%, all P < 0.05). (2) In the CSG and IM + DYS groups the expression levels of COX-2 in both the inflammatory and glandular cells were both significantly higher in the Hp-positive patients than in the Hp-negative patients (P < 0.05 or 0.01). (3) The expression of PPAR-gamma protein in the glandular cells of the CSG, CAG, and IM + DYS groups were 18.7%, 29.2%, and 45.6% respectively, all significantly higher than that of the control group (0%, all P < 0.01); and the expression levels of PPAR-gamma protein in the inflammatory cells of the CSG, CAG, and IM + DYS groups were 22.5%, 20.8%, and 22.2% respectively, all significantly higher than that of the control group (0%, P < 0.05 or 0.01). (4) In the CSG and IM + DYS groups the expression levels of PPAR-gamma in the inflammatory cells of the Hp-positive patients were both significantly higher than those of the Hp-negative patients (both P < 0.01); and the. expression levels of PPAR-gamma in the glandular cells of the Hp-positive patients were both significantly higher than those of the Hp-negative patients (both P < 0.01). (5) The expression level of COX-2 in the inflammatory cells of the CSG patients with a persistent Hp infection after a period of ten years was 33.3%, significantly lower than that a decade before (38.9%, P < 0.05). However, the expression level of PPAR-gamma in the inflammatory cells of the patients with a persistent Hp infection after a period of ten years was 30.6%, not significantly different from that a decade before (33.3%, P > 0.05). (6) The expression levels of COX-2 and PPAR-gamma in the glandular cells of the CSG patients with a persistent Hp infection after a period of ten years were 55.6% and 30.6% respectively, both significantly higher than those a decade before (47.2% and 22.2%, both P < 0.01). (7) In all Hp-negative disease groups the expression level of COX-2 in the inflammatory cells was not significantly correlated with the expression level of PPAR-gamma in the inflammatory cells(r = 0.006 and 0.149, P > 0.05) In the Hp-negative disease groups, the expression level of COX-2 in the glandular cells was significantly positively correlated with the expression level of PPAR-gamma in the glandular cells in the IM + DYS group (r = 0.336, P < 0.05), however, not significantly correlated with the expression level of PPAR-gamma in the glandular cells in both CAG and CSG groups (r = 0.035 and 0.126, both P > 0.05). (8) In both the inflammatory cells and glandular cells the COX-2 expression was significantly positively correlated with the PAR-gamma expression in all disease groups with Hp positivity (r = 0.348 and 0.645, P < 0.05 or 0.01). (1) Hp infection induces the overexpression of COX-2 and PPAR-gamma in the inflammatory and glandular cells within gastric mucosa, thus participating in the pathogenesis of gastric cancer (2) The expression of COX-2 induces by Hp is related to acute inflammation caused by Hp infection. In the glandular cells, significant increase of COX-2 and PPAR-gamma expression implies that along with time the expression of COX-2 and PPAR-gamma may change in advance of the morphological changes of the gastric mucosa.


Level of serum undercarboxylated osteocalcin correlates with bone quality assessed by calcaneal quantitative ultrasound sonometry in young Japanese females.
The diagnostic criteria of osteoporosis were established based on bone mineral density (BMD). Therefore, BMD measured by dual energy X-ray absorptiometry has been recognized as the gold standard to diagnose osteoporosis. However, discrepancies between fracture risk and BMD have been recognized. Bone is composed of collagen scaffold reinforced by hydroxyapatite. Both protein scaffold and hydroxyapatite are involved in bone quality. BMD may indicate bone mineralization but potentially fail to assess the protein scaffold. Vitamin K contributes to bone mineralization and as a protein scaffold. A deficiency of vitamin K upregulates the level of serum undercarboxylated osteocalcin (ucOC), and serum ucOC correlates with fracture risk. However, direct association of ucOC and bone quality has not been demonstrated. For the present study, a total of 49 healthy young Japanese female college students underwent calcaneal; quantitative ultrasound sonometry (QUS) and determination of serological bone metabolic markers. QUS parameters were significantly correlated with serum 25-hydroxyvitamin D (25-OH-D) concentrations (P<0.05). A significant negative correlation was also identified between log transformed serum ucOC concentrations [Ln(ucOC)] and a QUS parameter, speed of sound (SOS) (P<0.05). Stepwise multiple regression analysis indicated that Ln(ucOC) was an independent determinant of SOS, and 25-OH-D was an independent determinant of the other two QUS parameters, transmission index (TI) and synthetic parameter osteo-sono-assessment index. As vitamin D is involved in bone mineralization, TI may reflect the mineralization. Correlation of vitamin K status, indicated by ucOC, with SOS may clarify the correlation between vitamin K status and bone quality, although the material factors that connect them have not been identified.


Effect of serum sample inactivation on the performance of latex agglutination test for paracoccidioidomycosis serodiagnosis.
Paracoccidioidomycosis is diagnosed from the direct observation of the causative agent, but serology can facilitate and decrease the time required for diagnosis. The objective of this study was to determine the influence of serum sample inactivation on the performance of the latex agglutination test (LAT) for detecting antibodies against Paracoccidioides brasiliensis. The sensitivity of LAT from inactivated or non-inactivated samples was 73% and 83%, respectively and the LAT selectivity was 79% and 90%, respectively. The LAT evaluated here was no more specific than the double-immunodiffusion assay. We suggest the investigation of other methods for improving the LAT, such as the use of deglycosylated antigen.


Rheological profile in severe and morbid obesity. Preliminary results.
The association of hemorheological alterations with morbid obesity remains a question of debate. In order to ascertain whether morbid obese subjects show certain hemorheological alterations which might be involved in the higher thrombotic risk which characterizes these subjects, we determine glucose, plasma lipids, apolipoproteins, fibrinogen, hematocrit, blood viscosity (Brookfield DVIII viscosimeter), both at native and corrected hematocrit of 45%, plasma viscosity (Fresenius capillary viscosimeter), erythrocyte aggregation (Myrenne aggregometer), both at stasis and at 3 s(-1) at 45% hematocrit and erythrocyte indexes in 41 morbid obese subjects (32 female, 9 male aged 33+/-10 years), and in a well matched non-obese control group (40 female, 15 male, aged 32+/-10 years). Mean BMI in the morbid obese group was 44.9+/-6.7 kg/m2 vs 23.5+/-4.8 kg/m2 in the control group (p<0.001). Morbid obese subjects when compared with the control group showed a statistically higher glucose level (p<0.001), LDL-cholesterol (p=0.019), triglycerides (p<0.001), apoB (p=0.019), apoB/A1 (p<0.001), fibrinogen (p<0.001), erythrocyte aggregation (p<0.001), and a statistically lower HDL-cholesterol (p<0.001). No differences between both groups were observed regarding total-cholesterol, plasma viscosity, blood viscosity and hematocrit (p=0.109; p=0.690; p=0.510; p=0.950), respectively. After the adjustment for BMI, differences in glucose, LDL-cholesterol, triglycerides, apoB, apoB/A1, and erythrocyte aggregation did not reach the statistical significance, and differences in fibrinogen were borderline significant (p=0.051), showing a direct effect of BMI on the detected differences between obese and non-obese. Our results suggest that in morbid obese subjects the increased fibrinogen levels and the altered lipid profile associated with their higher BMI, could in addition to its known mechanisms on haemostasis, favour both venous and arterial thrombotic events by enhancing erythrocyte aggregation.


Expert supervisors' views of clinical supervision: a study of factors promoting and inhibiting the achievements of multiprofessional team supervision.
Only a few studies are available of team supervision and its challenges to supervisors. A multiprofessional team supervision project was accomplished in 1995-1998 in one university hospital in Finland. Eighty-two practitioners from five wards participated in the project and 10 experienced supervisors implemented their team supervision. The aim of this qualitative study is to describe the experiences of five supervisor pairs (n=10) of multiprofessional team supervision. Data were collected by semi-structured interviews from the supervisor pairs. The interviewing style was open and followed that of a guided conversation between supervisors and researcher. Interview data were analysed using thematic content analysis. The factors that influenced team supervision were as follows: advanced knowledge of supervision and confidence in supervisors, commitment and motivation, interaction and collaborative relationships and the arrangements of team supervision. The positive effects of team supervision as identified by the supervisors were as follows: influence on interaction and human relationships in the work community, supervisees' strengthened professional identity and the development of multiprofessional practice. Several factors can promote or inhibit the achievements of team supervision. Regardless of all the difficulties related to team supervision, its effects on a work community are positive. For the supervisors, team supervision is a demanding and challenging but also a rewarding process.


Attenuation of PM2.5-induced alveolar epithelial cells and lung injury through regulation of mitochondrial fission and fusion.
Exposure to particulate matter (PM) with an aerodynamic diameter less than 2.5 μm (PM2.5) is a risk factor for developing pulmonary diseases and the worsening of ongoing disease. Mitochondrial fission and fusion are essential processes underlying mitochondrial homeostasis in health and disease. We examined the role of mitochondrial fission and fusion in PM2.5-induced alveolar epithelial cell damage and lung injury. Key genes in these processes include dystrophin-related protein 1 (DRP1) and optic atrophy 1 (OPA1) respectively. Alveolar epithelial (A549) cells were treated with PM2.5 (32 µg/ml) in the presence and absence of Mdivi-1 (10µM, a DRP1 inhibitor) or BGP-15 (10µM, an OPA1 activator). Results were validated using DRP1-knockdown (KD) and OPA1-overexpression (OE). Mice were injected intraperitoneally with Mdivi-1 (20 mg/kg), BGP-15 (20 mg/kg) or distilled water (control) one hour before intranasal instillation of PM2.5 (7.8 mg/kg) or distilled water for two consecutive days. PM2.5 exposure of A549 cells caused oxidative stress, enhanced inflammation, necroptosis, mitophagy and mitochondrial dysfunction indicated by abnormal mitochondrial morphology, decreased mitochondrial membrane potential (ΔΨm), reduced mitochondrial respiration and disrupted mitochondrial fission and fusion. Regulating mitochondrial fission and fusion pharmacologically using Mdivi-1 and BGP-15 and genetically using DRP1-KD and OPA1-OE prevented PM2.5-induced celluar damage in A549 cells. Mdivi-1 and BGP-15 attenuated PM2.5-induced acute lung injury in mice. Increased mitochondrial fission and decreased mitochondrial fusion may underlie PM2.5-induced alveolar epithelial cell damage in vitro and lung injury in vivo.


NLRR1 enhances EGF-mediated MYCN induction in neuroblastoma and accelerates tumor growth in vivo.
Neuronal leucine-rich repeat protein-1 (NLRR1), a type-1 transmembrane protein highly expressed in unfavorable neuroblastoma, is a target gene of MYCN that is predominately expressed in primary neuroblastomas with MYCN amplification. However, the precise biological role of NLRR1 in cell proliferation and tumor progression remains unknown. To investigate its functional importance, we examined the role of NLRR1 in EGF and insulin growth factor-1 (IGF-1)-mediated cell viability. We found that NLRR1 positively regulated cell proliferation through activation of extracellular signal-regulated kinase mediated by EGF and IGF-1. Interestingly, EGF stimulation induced endogenous MYCN expression through Sp1 recruitment to the MYCN promoter region, which was accelerated in NLRR1-expressing cells. The Sp1-binding site was identified on the promoter region for MYCN induction, and phosphorylation of Sp1 was important for EGF-mediated MYCN regulation. In vivo studies confirmed the proliferation-promoting activity of NLRR1 and established an association between NLRR1 expression and poor prognosis in neuroblastoma. Together, our findings indicate that NLRR1 plays an important role in the development of neuroblastoma and therefore may represent an attractive therapeutic target for cancer treatment.


The representation of feared outcomes.
A list of negative outcomes (harmful events) was constructed to investigate the nature and organization of outcome concerns in anxiety. In Study 1, analysis of worry frequency ratings for the 116 negative outcomes revealed two major correlated factors corresponding to physical outcomes (harm or misfortune) and social outcomes (negative evaluation). These higher-order factors could be further subdivided into smaller discrete categories of related concerns. Ratings of worry frequency were higher for social outcomes. Trait anxiety was associated with both physical and social concerns, but stress and depression were primarily associated with social concerns. In Study 2, aversiveness ratings for the 116 negative outcomes followed the same physical-social organization and formed similar lower-order categories. Unlike the worry frequency ratings, aversiveness ratings were higher for physical than social categories, and did not correlate substantially with trait measures of depression, anxiety or stress. In Study 3, a short (24-item) negative outcome questionnaire was developed to discriminate between concerns about physical and social outcomes. The Physical Scale correlated substantially with the Anxiety Sensitivity Index (ASI) but not the Fear of Negative Evaluation (FNE), whereas the Social Scale correlated with the FNE but not the ASI. The Penn State Worry Questionnaire (PSWQ), which assesses worry frequency but not content, correlated only with the Social Scale. Implications for theories of normal and clinical anxiety are discussed.


MicroRNAs contribute to postnatal development of laminar differences and neuronal subtypes in the rat medial entorhinal cortex.
The medial entorhinal cortex (MEC) is important in spatial navigation and memory formation and its layers have distinct neuronal subtypes, connectivity, spatial properties, and disease susceptibility. As little is known about the molecular basis for the development of these laminar differences, we analyzed microRNA (miRNA) and messenger RNA (mRNA) expression differences between rat MEC layer II and layers III-VI during postnatal development. We identified layer and age-specific regulation of gene expression by miRNAs, which included processes related to neuron specialization and locomotor behavior. Further analyses by retrograde labeling and expression profiling of layer II stellate neurons and in situ hybridization revealed that the miRNA most up-regulated in layer II, miR-143, was enriched in stellate neurons, whereas the miRNA most up-regulated in deep layers, miR-219-5p, was expressed in ependymal cells, oligodendrocytes and glia. Bioinformatics analyses of predicted mRNA targets with negatively correlated expression patterns to miR-143 found that miR-143 likely regulates the Lmo4 gene, which is known to influence hippocampal-based spatial learning.


Effect of pH, competitive anions and NOM on the leaching of arsenic from solid residuals.
Implementation of the new arsenic MCL in 2006 will lead to the generation of an estimated 6 million pounds of arsenic-bearing solid residuals (ABSRs) every year, which will be disposed predominantly in non-hazardous landfills. The Toxicity Characteristic Leaching Procedure (TCLP) is typically used to assess whether a waste is hazardous and most solid residuals pass the TCLP. However, recent research shows the TCLP significantly underestimates arsenic mobilization in landfills. A variety of compositional dissimilarities between landfill leachates and the TCLP extractant solution likely play a role. Among the abiotic factors likely to play a key role in arsenic remobilization/leaching from solid sorbents are pH, and the concentrations of natural organic matter (NOM) and anions like phosphate, bicarbonate, sulfate and silicate. This study evaluates the desorption of arsenic from actual treatment sorbents, activated alumina (AA) and granular ferric hydroxide (GFH), which are representative of those predicted for use in arsenic removal processes, and as a function of the specific range of pH and concentrations of the competitive anions and NOM found in landfills. The influence of pH is much more significant than that of competing anions or NOM. An increase in one unit of pH may increase the fraction of arsenic leached by 3-4 times. NOM and phosphate replace arsenic from sorbent surface sites up to three orders of magnitude more than bicarbonate, sulfate and silicate, on a per mole basis. Effects of anions are neither additive nor purely competitive. Leaching tests, which compare the fraction of arsenic mobilized by the TCLP vis-a-vis an actual or more realistic synthetic landfill leachate, indicate that higher pH, and greater concentrations of anions and NOM are all factors, but of varying significance, in causing higher extraction in landfill and synthetic leachates than the TCLP.


Biotransformation of the polycyclic musks HHCB and AHTN and metabolite formation by fungi occurring in freshwater environments.
Micropollutants found in aquatic environments have increasingly raised concerns with respect to their uncertain environmental fate and potentially adverse effects on human health and the environment. The biodegradability of two major representatives of the polycyclic musk fragrances, Galaxolide (HHCB) and Tonalide (AHTN), and the formation of biotransformation metabolites, were investigated with Myrioconium sp. strain UHH 1-13-18-4 and Clavariopsis aquatica, two mitosporic fungi derived from freshwater environments. A particular focus was to assess the effects of extracellular oxidoreductases such as laccases, which are produced by the investigated fungi under certain conditions, on HHCB and AHTN. The fungi converted HHCB and AHTN into various products via initial hydroxylation at different carbon positions. Further metabolism resulted in the subsequent formation of diketone, peroxide, and O-methylated derivatives. Isolated laccases of the investigated fungi were able to oxidize HHCB and AHTN and catalyzed the formation of the metabolite HHCB-lactone from HHCB. At particular environmental situations also specified within the present study, biotransformations catalyzed by fungi occurring in freshwater environments may be considered when addressing the fate of polycyclic musks in freshwater systems and potential biological effects of their degradation metabolites.


Proteasome inhibitor lactacystin ablates liver injury induced by intestinal ischaemia-reperfusion.
1. The aim of the present study was to investigate the role of proteasome in the pathogenesis of liver injury induced by intestinal ischaemia-reperfusion (I/R) and the effect of the proteasome inhibitor lactacystin on neutrophil infiltration, intracellular adhesion molecule (ICAM)-1 and nuclear factor (NF)-kappaB expression in the liver tissues of rats. 2. Thirty-two Wistar rats were randomly divided into four groups (n = 8 in each group) as follows: (i) a control, sham-operated group; (ii) an I/R group subjected to 1 h intestinal ischaemia and 4 h reperfusion; (iii) a group pretreated with 0.2 mg/kg lactacystin 1 h before intestinal I/R; and (iv) a group pretreated with 0.6 mg/kg lactacystin 1 h before intestinal I/R. Liver and intestine histology were observed. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), as well as 20S proteasome activity in circulating white blood cells, were measured. Myeloperoxidase (MPO) activity in liver tissues and the immunohistochemical expression of liver NF-kappaB and ICAM-1 were assayed. In addition, a western blot of liver NF-kappaB was performed. 3. Compared with the sham-operated control group, liver and intestine injury was induced by intestinal I/R, characterized as histological damage including oedema, haemorrhage and infiltration by inflammatory cells, as well as a significant increase in serum AST (365 +/- 121 vs 546 +/- 297 IU/L, respectively; P < 0.05), ALT (65 +/- 23 vs 175 +/- 54 IU/L, respectively; P < 0.01) and LDH levels (733 +/- 383 vs 1434 +/- 890 IU/L, respectively; P < 0.05). Compared with the control group, MPO activity in the liver tissues increased significantly in the I/R group (2.05 +/- 0.69 vs 3.42 +/- 1.11 U/g, respectively; P < 0.05). Strong positive expression of liver ICAM-1 and NF-kappaB p65 was observed. 4. Compared with the intestinal I/R group, administration of 0.6 mg/kg lactacystin markedly reduced 20S proteasome activity in circulating white blood cells (15.47 +/- 4.00 vs 2.07 +/- 2.00 pmol 7-amino-4-methylcoumarin (AMC)/s per mg, respectively; P < 0.01) and ameliorated liver injury, which was demonstrated by decreased levels of serum AST (546 +/- 297 vs 367 +/- 86 IU/L, respectively; P < 0.05), ALT (175 +/- 54 vs 135 +/- 26 IU/L, respectively; P < 0.05) and LDH (1434 +/- 890 vs 742 +/- 218 IU/L, respectively; P < 0.05) and a reduced liver pathological score (2.13 +/- 0.64 vs 1.25 +/- 0.46, respectively; P < 0.01). Compared with the intestinal I/R group, MPO activity in liver tissues decreased significantly following lactacystin pretreatment (3.42 +/- 1.11 vs 2.58 +/- 0.61 U/g, respectively; P < 0.05) and the expression of liver NF-kappaB and ICAM-1 was markedly ameliorated. 5. The present study reveals that the proteasome inhibitor lactacystin ablates liver injury induced by intestinal I/R. One possible mechanism responsible for this effect is the inhibition of enhanced ICAM-1 and neutrophil infiltration by inhibition of NF-kappaB activity. The results suggest the feasibility of using proteasome inhibitor clinically in the treatment of intestinal I/R.


[Urogenital tuberculosis: problems of present-day diagnosis and treatment].
The analysis of 4904 cases with tuberculosis admitted to the urological department of Moscow tuberculosis hospital N 7 in 1996-2002 showed increased incidence of new-onset and recurrent urogenital tuberculosis--the share has risen from 2.1 to 7.8%. Of 267 new cases, 49.4% had severe destructive forms. The disease manifested with chronic cystitis in 35 (13.11%), subacute orchoepidydimitis in 35 (13.11%), anatomofunctional alterations of the kidneys (hydronephrotic transformation, non-functioning kidney, ureteritis, etc.) in 76 (28.46%) patients. Bacterial discharge occurred in 52% of new cases. The diagnosis was based on clinical and x-ray data in 48%. Isolated genital tuberculosis, isolated nephrotuberculosis and their combination were revealed in 14.23, 59.57 and 26.2% patients, respectively. Among the patients with advanced destructive forms 75% got disabled completely. This fact indicates the importance of early diagnosis and adequate etiotropic therapy. Active urogenital tuberculosis was treated surgically in 51% patients, most of the operations were made for marked destructive processes in the kidneys. The organ-removing operations were conducted in 73% of them. Preoperative tuberculostatic therapy reduced frequency of postoperative complications. In early diagnosis, the organ was saved in operations in 9.38%. It is recommended to refer patients to the phthisiourologist to be examined for urogenital tuberculosis if they have long-standing urogenital infection, destructive lesions of the upper urinary tracts, calculous prostatitis.


Anterior dislocation of the radial head in children: aetiology, natural history and management.
The results of operation for traumatic anterior dislocation of the head of the radius in eight children have been reviewed. We are satisfied on the basis of the results obtained and the outcome in one untreated patient that operative reduction is fully justified, provided that the annular ligament is reconstructed and internal fixation employed. We have not seen unilateral congenital dislocation and doubt its existence. Secondary subluxation of the distal radio-ulnar joint has been noted in an untreated patient.


Pragmatical access to the viscous flow of undercooled liquids.
The paper derives a relation for the viscosity of undercooled liquids on the basis of the pragmatical model concept of Eshelby relaxations with a finite lifetime. From accurate shear relaxation data in the literature, one finds that slightly less than half of the internal stresses relax directly via single Eshelby relaxations; the larger part dissolves at the terminal lifetime, which is a combined effect of many Eshelby relaxations.


Emergency Absentee Voting for Hospitalized Patients and Voting During COVID-19: A 50-State Study.
Voters facing illness or disability are disproportionately under-represented in terms of voter turnout. Earlier research has indicated that enfranchisement of these populations may reinforce the implementation of policies improving health outcomes and equity. Due to the confluence of the coronavirus 2019 (COVID-19) pandemic and the 2020 election, we aimed to assess emergency absentee voting processes, which allow voters hospitalized after regular absentee deadlines to still obtain an absentee ballot, and election changes due to COVID-19 in all 50 states. We performed a cross-sectional study collecting 34 variables pertaining to emergency voting processes and COVID-19-related election changes, including deadlines, methods of submission for applications and ballots, and specialized services for patients. Data were obtained from, in order of priority, state boards of elections websites, poll worker manuals, application forms, and state legislation. We verified all data through direct correspondence with state boards of elections. Emergency absentee voting processes are in place in 39 states, with the remaining states having universal vote-by-mail (n = 5) or extended regular absentee voting deadlines (n = 6). The emergency absentee period most commonly began within 24 hours following the normal absentee application deadline, which was often seven days before an election (n = 11). Unique aspects of emergency voting processes included patients designating an "authorized agent" to deliver their applications and ballots (n = 38), electronic ballot delivery (n = 5), and in-person teams that deliver ballots directly to patients (n = 18). Documented barriers in these processes nationwide include unavailable online information (n = 11), restrictions mandating agents to be family members (n = 7), physician affidavits or signatures (n = 9), and notary or witness signature requirements (n = 15). For the November 2020 presidential election, 12 states expanded absentee eligibility to allow COVID-19 as a reason to request an absentee ballot, and 18 states mailed absentee ballot applications or absentee ballots to all registered voters. While 39 states operate emergency absentee voting processes for hospitalized voters, there are considerable areas for improvement and heterogeneity in guidelines for these protocols. For future election cycles, information on emergency voting and broader election reforms due to COVID-19 may be useful for emergency providers and patients alike to improve the democratic participation of voters experiencing illness.


Antiproliferative effects of different plant parts of Panax notoginseng on SW480 human colorectal cancer cells.
The chemical constituents and antiproliferative effects on SW480 human colorectal cancer cells of different plant parts of P. notoginseng were evaluated. The contents of saponins in extracts from root, rhizome, flower and berry of P. notoginseng were determined using high performance liquid chromatography. The contents and proportions of saponins were different among the four plant parts. Using the cell counting method, the antiproliferative effects were evaluated and the results indicated all four extracts, at 0.05-1.0 mg/mL, showed concentration-related antiproliferative effects on the cancer cells. The flower extract had stronger effects compared with the other three extracts; at 1.0 mg/mL, it inhibited the cell growth by 93.1% (p < 0.01). The antiproliferative effects of major saponins in notoginseng, notoginsenoside R1, ginsenosides Rb1, Rb3 and Rg1, were also evaluated, and the observed effects of major constituents support the pharmacological activities of extracts. The effects of notoginseng extracts on cell cycle and apoptosis of SW480 cells were determined using flow cytometry. Notoginseng extract can arrest the cells in S and G2/M phases. Remarkably apoptosis induction activities of notoginseng extracts were observed with the flower extract possessing the most potent effect, supporting the antiproliferative effect.


Rapid and enantioselective synthetic approaches to germanicol and other pentacyclic triterpenes.
Two exceedingly short synthetic routes to the key intermediate 2 for the synthesis of the pentacyclic triterpene germanicol 1 have been developed. In the first, the ( S)-epoxide of farnesyl bromide is transformed in just three steps to the tetracyclic intermediate 7, which is converted to chiral 2 by treatment with polyphosphoric acid. The second synthetic route to 2 involves the coupling of the ( S)-epoxide 8 with vinyl iodide 9 to give 10 and two-stage acid-catalyzed cyclization of 10 to form 2. During the course of this work we have also discovered a very unusual intramolecular 1,5-proton shift from a carbocation to a C-C double bond. The details of the process have been confirmed by (2)H-labeling experiments.


Musicians' Online Performance during Auditory and Visual Statistical Learning Tasks.
Musicians' brains are considered to be a functional model of neuroplasticity due to the structural and functional changes associated with long-term musical training. In this study, we examined implicit extraction of statistical regularities from a continuous stream of stimuli-statistical learning (SL). We investigated whether long-term musical training is associated with better extraction of statistical cues in an auditory SL (aSL) task and a visual SL (vSL) task-both using the embedded triplet paradigm. Online measures, characterized by event related potentials (ERPs), were recorded during a familiarization phase while participants were exposed to a continuous stream of individually presented pure tones in the aSL task or individually presented cartoon figures in the vSL task. Unbeknown to participants, the stream was composed of triplets. Musicians showed advantages when compared to non-musicians in the online measure (early N1 and N400 triplet onset effects) during the aSL task. However, there were no differences between musicians and non-musicians for the vSL task. Results from the current study show that musical training is associated with enhancements in extraction of statistical cues only in the auditory domain.


Absorbable pulmonary artery banding: a strategy for reducing reoperations.
Pulmonary artery banding (PAB) remains in the armamentarium of techniques for several congenital cardiac anomalies, but necessitates a reoperation for eventual removal. We sought to assess the efficacy of an absorbable PAB in obviating the requirement for reoperation. From 2003 to 2015, 45 consecutive patients with a median age of 1.6 months (2 days-11 months) underwent placement of a polydioxanone absorbable PAB. In 28 patients (62%), the band was placed concomitantly to a ventricular septal defect (VSD) closure and in 17 (38%), the band was the sole procedure for the VSDs. Fourteen patients had additional cardiac anomalies and 9 patients had aortic arch anomalies, which were repaired at the time of absorbable PAB placement. There was 1 hospital death. The band was removed early in 3 patients. Mean time to follow-up was 5.2 ± 3.5 years. Overall, 32 of the 41 patients discharged from hospital with absorbable PABs did not require reoperation on the VSDs or the band, resulting in a single-stage definitive repair of 78%. Median time to absorbable PAB resorption was 7.2 months (interquartile range, 5.0-10.4). Freedom from reoperation related to residual VSDs or PAB obstruction was 78% (95% CI: 61-87%) at 10 years. The use of absorbable polydioxanone PABs is an effective method of reducing reoperations for multiple VSDs. Their use should be incorporated in the surgical strategy for repair of muscular and residual VSDs.


Maximal rate of the left ventricular pressure fall (peak negative dP/dt) in early stage of myocardial ischemia following experimental coronary occlusion.
Short-term, repeated myocardial ischemia was produced in 20 opened-chest anesthetized dogs by left anterior descending (LAD) branch occlusion. Left ventricular pressure (LVP) and its dP/dt were recorded by Satham SF-1 transducer, and isometric local force (F) was measured by a Walton-Brodie strain gauge arch sewn onto LV free wall. In all experiments, within a few beats after LAD occlusion, peak negative dP/dt started to diminish its amplitude, reaching a nadir after 20-30 sec (63 +/- 5% of control, 9 dogs). It recovered to 83 +/- 3% of control level in 45 sec and remained essentially unchanged thereafter. This change preceded those of LVP and max dP/dt, which showed only minor falls. In 6 dogs, changes by occluding root of LAD were compared with those by its branch occlusion. The greater the extent of ischemia, the more marked and prolonged were the changes. While F in the ischemic center (Fc) rapidly lost its contractile activity following LAD occlusion, F in marginal zone between infarcted and non-infarcted region (Fm) showed variable extent and different time-course of its diminution. Thus, it was concluded that the change in peak negative dP/dt following LAD occlusion was one of the sensitive signs of early ischemic changes, and was attributed at least in part to characteristic changes in contractile activity of myocardium surrounding the ischemic injury.


General anesthesia type does not influence serum levels of neutrophil gelatinase-associated lipocalin during the perioperative period in video laparoscopic bariatric surgery.
Video laparoscopic bariatric surgery is the preferred surgical technique for treating morbid obesity. However, pneumoperitoneum can pose risks to the kidneys by causing a decrease in renal blood flow. Furthermore, as in other surgical procedures, laparoscopic bariatric surgery triggers an acute inflammatory response. Neutrophil gelatinase-associated lipocalin is an early and accurate biomarker of renal injury, as well as of the inflammatory response. Anesthetic drugs could offer some protection for the kidneys and could attenuate the acute inflammatory response from surgical trauma. The objective of this study was to compare the effects of two types of anesthetics, propofol and sevoflurane, on the serum levels of neutrophil gelatinase-associated lipocalin during the perioperative period in laparoscopic bariatric surgery. Sixty-four patients scheduled for laparoscopic bariatric surgery were randomized into two anesthesia groups and were administered either total intravenous anesthesia (propofol) or inhalation anesthesia (sevoflurane). In the perioperative period, blood samples were collected at three time points (before anesthesia, 6 hours after pneumoperitoneum and 24 hours after pneumoperitoneum) and urine output was measured for 24 hours. Acute kidney injuries were evaluated by examining both the clinical and laboratory parameters during the postoperative period. The differences between the groups were compared using non-parametric tests. ReBEC (http://www.ensaiosclinicos.gov.br/rg/recruiting/): RBR-8wt2fy None of the patients developed an acute kidney injury during the study and no significant differences were found between the serum neutrophil gelatinase-associated lipocalin levels of the groups during the perioperative period. The choice of anesthetic drug, either propofol or sevoflurane, did not affect the serum levels of neutrophil gelatinase-associated lipocalin during the perioperative period in laparoscopic bariatric surgery.


Early retinal pigment epithelium dysfunction is concomitant with hyperglycemia in mouse models of type 1 and type 2 diabetes.
In the diabetic retina, cellular changes in the retinal pigment epithelium (RPE) and neurons occur before vision loss or diabetic retinopathy can be identified clinically. The precise etiologies of retinal pathology are poorly defined, and it remains unclear if the onset and progression of cellular dysfunction differ between type 1 and type 2 diabetes. Three mouse models were used to compare the time course of RPE involvement in type 1 and type 2 diabetes. C57BL/6J mice injected with streptozotocin (STZ mice) modeled type 1 diabetes, whereas Lepr(db/db) mice on both BKS and B6.BKS background strains modeled type 2 diabetes. Electroretinogram (ERG)-based techniques were used to measure light-evoked responses of the RPE (direct current-coupled ERG, dc-ERG) and the neural retina (a-wave, b-wave). Following onset of hyperglycemia, a-wave and b-wave amplitudes of STZ mice declined progressively and by equivalent degrees. Components of the dc-ERG were also altered, with the largest reduction seen in the c-wave. Lepr(db/db) mice on the BKS strain (BKS.Lepr) displayed sustained hyperglycemia and a small increase in insulin, whereas Lepr(db/db) mice on the B6.BKS background (B6.BKS.Lepr) were transiently hyperglycemic and displayed severe hyperinsulinemia. BKS.Lepr mice exhibited sustained reductions in the dc-ERG c-wave, fast oscillation, and off response that were not attributable to reduced photoreceptor activity; B6.BKS.Lepr mice displayed transient reductions in the c-wave and fast oscillation that correlated with hyperglycemia and magnitude of photoreceptor activity. In summary, all mouse models displayed altered RPE function concomitant with the onset of hyperglycemia. These results suggest that RPE function is directly reduced by elevated blood glucose levels. That RPE dysfunction was reversible and mitigated in hyperinsulinemic B6.BKS.Lepr mice provides insight into the underlying mechanism.


Modified external needle drainage of subretinal fluid in the management of rhegmatogenous retinal detachment using a "guarded needle" approach.
External needle drainage of subretinal fluid is a useful technique to assist with retinal detachment surgery. This technique provides the ability to directly visualize the removal of subretinal fluid in a controlled manner. The major difficulty in learning this technique is the potential for overpenetration with the needle. Using a "guarded needle" approach can reduce this risk and increase the adoption of this useful method.


The Dutch famine of 1944-45: mortality and morbidity in past and present generations.
During the last months of the Second World War the Western Netherlands was affected by an acute famine, known as the Hunger Winter. Food intake from all sources was reduced to extremely low levels. The effect on mortality at all ages was very large and immediate. By making use of unpublished data from the Dutch Central Bureau of Statistics, estimates could be made of the changes in mortality by cause of death and age for both sexes. Mortality due to hunger was most common in the very young and the very old whereas the effects in males were more pronounced than in females. Hunger was a contributing factor to the increased mortality due to infectious diseases and diseases of the digestive system. In several follow-up studies on selected populations, long-term consequences of the famine could be studied. They related to reproductive outcomes of women who gave birth during the Hunger Winter, to birth weight, malformations, and perinatal mortalitiy of the newborn who were exposed to the famine during gestation, and to the long-term effects of the famine on the medical and psychological situation of infants born during the famine. Several studies on reproductive outcomes in the subsequent generation are also discussed.


Eating frequency and weight and body composition: a systematic review of observational studies.
The present review aimed to examine the association of eating frequency with body weight or body composition in adults of both sexes. PubMed, EMBASE and Scopus databases were searched. PRISMA and MOOSE protocols were followed. Observational studies published up to August 2016 were included. The methodological quality of the studies was assessed with the Downs and Black checklist. A systematic review of the literature. Adults (n 136 052); the majority of studies were developed in the USA and Europe. Thirty-one articles were included in the review: two prospective and twenty-nine cross-sectional studies. Thirteen per cent of the studies received quality scores above 80 %. The assessment of eating frequency and body composition or body weight varied widely across the studies. Potential confounders were included in 73 % of the studies. Fourteen studies reported an inverse association between eating frequency and body weight or body composition, and seven studies found a positive association. The majority of studies applied multiple analyses adjusted for potential confounders, such as sex, age, education, income, smoking, physical activity and alcohol intake. Six studies took into account under-reporting of eating frequency and/or energy intake in the analysis, and one investigated the mediation effect of energy intake. There is not sufficient evidence confirming the association between eating frequency and body weight or body composition when misreporting bias is taken into account. However, in men, a potential protective effect of high eating frequency was observed on BMI and visceral obesity.


Model building of a thermolysin-like protease by mutagenesis.
The present study concerns the use of site-directed mutagenesis experiments to optimize a three-dimensional model of the neutral protease of Bacillus subtilis (NP-sub). An initial model of NP-sub was constructed using the crystal structures of the homologous neutral proteases of Bacillus thermoproteolyticus (thermolysin) and Bacillus cereus as templates. The largest portion of NP-sub could be modelled satisfactorily, using standard techniques, but several surface-located regions could only be modelled with a high degree of uncertainty. In order to make the model more reliable in these regions a 'model building by mutagenesis' approach was adopted. Mutations were designed such that their effect on thermal stability could indicate how their local environment should be modelled. This approach provided insight in the local structure of several regions in NP-sub that were hard to model on the basis of homology with the two known structures alone.


Quetiapine add-on therapy improves the depressive behaviors and hippocampal neurogenesis in fluoxetine treatment resistant depressive rats.
Quetiapine, an atypical antipsychotic, may have efficacy as augmentation therapy in treatment resistant depression (TRD), but evidence is limited and the underlying mechanism remains poorly understood. Therefore, this study was aimed to investigate whether and how quetiapine can be served as an augmentation agent in fluoxetine treatment resistant depressive rats induced by chronic unpredictable mild stress (CUMS). In this study, the effects of CUMS regimen and antidepressant treatment were assessed by behavioral tests and hippocampal neurogenesis. Approximately 20-30% of depressive rats respond poorly to fluoxetine treatment. In their hippocampus, a significant decrease of neurogenesis was also observed. However, quetiapine add-on therapy significantly improved the depressive behaviors and increased the number of the newborn neurons in the hippocampus of fluoxetine treatment resistant depressive rats. Thus, our results suggest that quetiapine may be used as an augmentation agent in the treatment resistant depression partly mediated by increasing the number of newborn neurons in the hippocampus.


Focus prediction of medical microscopic images based on Lightweight Densely Connected with Squeeze-and-Excitation Network.
Due to the demand for sample observation, optical microscopy has become an essential tool in the fields of biology and medicine. In addition, it is impossible to maintain the living sample in focus over long-time observation. Rapid focus prediction which involves moving a microscope stage along a vertical axis to find an optimal focus position, is a critical step for high-quality microscopic imaging of specimens. Current focus prediction algorithms, which are time-consuming, cannot support high frame rate imaging of dynamic living samples, and may introduce phototoxicity and photobleaching on the samples. In this paper, we propose Lightweight Densely Connected with Squeeze-and-Excitation Network (LDSE-NET). The results of the focusing algorithm are demonstrated on a public dataset and a self-built dataset. A complete evaluation system was constructed to compare and analyze the effectiveness of LDSE-NET, BotNet, and ResNet50 models in multi-region and multi-multiplier prediction. Experimental results show that LDSE-NET is reduced to 1E-05 of the root mean square error. The accuracy of the predicted focal length of the image is increased by 1 ~ 2 times. Training time is reduced by 33.3%. Moreover, the volume of the model only reaches the KB level, which has the characteristics of being lightweight.


Absence of photoreceptor rescue with D-cis-diltiazem in the rd mouse.
Because of a previous report suggesting that D-cis-diltiazem slows retinal degeneration in rd mice, this study was undertaken to examine the effect of D-cis-diltiazem on photoreceptor structure and function in this line of mice. Mice were randomly assigned to daily intraperitoneal injections of D-cis-diltiazem or saline between postnatal days 9 and 24. On postnatal day 26 or 27, retinal function was assessed by recording dark-adapted bright-flash ERGs in all animals. Retinal morphology was examined in fixed sections and in immunolabeled frozen sections. Examiners were masked to the treatment group assignment. On postnatal days 26 and 27, diltiazem- and saline-treated mice had only one row of remaining photoreceptor cells throughout most of the central retina. Cone cells in the periphery had remnants of inner segments. Total cell counts and separate counts of rod and cone photoreceptor cells by immunostaining were similar in the diltiazem- versus saline-treated mice. Both groups of mice had, on average, comparable subnormal ERG amplitudes. D-cis-Diltiazem had no detectable effect on preservation of photoreceptor structure and function in rd mice.


Bronchiolitis obliterans organizing pneumonia secondary to amiodarone: clinical, radiological and histological pattern.
The most common lung tissue reaction to amiodarone toxicity is a nonspecific pulmonary chronic interstitial pneumonia. In a minority of patients diffuse alveolar damage, alveolar haemorrhage or bronchiolitis obliterans organizing pneumonia (BOOP) is encountered. We report the case of a patient with clinical, functional, radiological and histological signs of BOOP secondary to amiodarone. The condition was partially reversible after suspending drug treatment, and resolved after corticosteroid treatment without relapse after a 14 month follow-up.


Toothache with a multifactorial etiology: a case report.
A case report of orofacial pain originating from both dental and nondental conditions is presented. The spontaneous throbbing pain initiated from the left maxillary second premolar and spread throughout the entire upper part of the face to the frontoparietal area. Root canal treatment of the maxillary second premolar did not resolve the chief complaint. Magnetic resonance imaging examination revealed hypertrophy of the left inferior turbinate and soft tissue haziness in the left maxillary sinus floor. After antrostomy, submucosal turbinectomy, and endodontic treatment, the patient was free from pain. The final diagnosis of this case, in addition to pulpitis, was maxillary sinusitis with chronic rhinitis. The multiple factors associated with the etiology made the diagnosis difficult. The mechanism of referred pain from the maxillary sinus and paranasal mucosa to the maxillary teeth and face is discussed.


Control of B lymphocyte apoptosis by the transcription factor NF-kappaB.
B cells maintain homeostasis by balancing cell viability and cell death. B lymphocytes are susceptible to mitochondria- and receptor-initiated cell death at various stages of peripheral differentiation and during immune responses. The inducible transcription factor NF-kappaB enhances cell viability by activating genes that counteract both cell-death pathways. This review uses characteristic features of NF-kappaB activation and downregulation to provide insight into the regulation of B cell apoptosis in the periphery. In particular, the temporal patterns of NF-kappaB induction, differences between Rel family members, and the intersection between canonical and noncanonical signaling pathways in keeping B cells alive are discussed.


The presence of antibodies to lymphotoxin and tumor necrosis factor in normal serum.
Lymphotoxin (LT) and tumor necrosis factor (TNF) are cytokines that probably play a role in several autoimmune diseases. In this report, we describe the detection, in normal nonimmune serum, of naturally occurring antibodies that bind to recombinant human LT and TNF. The naturally occurring antibodies that bind to LT and TNF could explain why normal immunoglobulin is effective therapy in idiopathic thrombocytopenic purpura and Kawasaki syndrome.


Thrombin-receptor occupancy initiates a transient increase in cAMP levels in mitogenically responsive hamster (NIL) fibroblasts.
Previous studies from our laboratory have shown that thrombin mitogenesis requires both high-affinity receptor occupancy and enzymic activity. Combined addition of DIP-inactivated-thrombin, which retains the ability to bind to thrombin receptors, and enzymically active gamma-thrombin generates a complete set of signals sufficient to initiate cell proliferation. Several possible signals, including stimulation of ion fluxes and phosphoinositide turnover, appear to be stimulated by thrombin's enzymic activity, but not by receptor occupancy. We now report that alpha-thrombin and DIP-thrombin stimulate an early, transient increase of 60 to 200% in intracellular levels of cAMP. This stimulation occurs at low mitogenic concentrations of alpha-thrombin where less than half the receptors are occupied. Enzymically active gamma-thrombin, which stimulates other types of signals, has no stimulatory effects on cAMP. Thus, this effect appears to be generated by high-affinity interaction of thrombin with its cell-surface receptors. Artificially increasing cAMP levels within these cells, however, cannot replace the requirement for thrombin-receptor occupancy in completing the mitogenic stimulation. Therefore, thrombin-receptor occupancy may generate additional, as yet unidentified, required signals.


Three-dimensional helical CT angiography.
CT angiography can accurately depict vascular lesions in less time, with less patient morbidity, and at a lower cost than conventional angiography. Meticulous attention to scan technique is required for achieving diagnostic images. Regardless of the three-dimensional rendering techniques employed, a review of the original axial sections is always required to ensure the detection of any unsuspected parenchymal lesions present and to exclude inaccuracies in segmentation and three-dimensional rendering.


Flat Graphene-Enhanced Electron Transfer Involved in Redox Reactions.
Graphene is easily warped in the out-of-plane direction because of its high in-plane Young's modulus, and exploring the influence of wrinkled graphene on its properties is essential for the design of graphene-based materials for environmental applications. Herein, we prepared wrinkled graphene (WGN-1 and WGN-2) by thermal treatment and compared their electrochemical properties with those of flat graphene nanosheets (FGN). FGN exhibit activities that are much better than those of wrinkled graphene nanosheets (WGN), not only in the electrochemical oxidation of methylene blue (MB) but also in the electrochemical reduction of nitrobenzene (NB). Transformation ratios of MB and NB in FGN, WGN-1, and WGN-2 were 97.5, 80.1, and 57.9% and 94.6, 92.1, and 81.2%, respectively. Electrochemical impedance spectroscopy and the surface resistance of the graphene samples increased in the following order: FGN < WGN-1 < WGN-2. This suggests that the reaction charges transfer faster across the reaction interfaces and along the surface of FGN than that of WGN, and wrinkles restrict reaction charge transfer and reduce the reaction rates. This study reveals that the morphology of the graphene (flat or wrinkle) greatly affects redox reaction activities and may have important implications for the design of novel graphene-based nanostructures and for our understanding of graphene wrinkle-dependent redox reactions in environmental processes.


An empirical charge transfer potential with correct dissociation limits.
The empirical valence bond (EVB) method [J. Chem. Phys. 52, 1262 (1970)] has always embodied charge transfer processes. The mechanism of that behavior is examined here and recast for use as a new empirical potential energy surface for large-scale simulations. A two-state model is explored. The main features of the model are: (1) explicit decomposition of the total system electron density is invoked; (2) the charge is defined through the density decomposition into constituent contributions; (3) the charge transfer behavior is controlled through the resonance energy matrix elements which cannot be ignored; and (4) a reference-state approach, similar in spirit to the EVB method, is used to define the resonance state energy contributions in terms of "knowable" quantities. With equal validity, the new potential energy can be expressed as a nonthermal ensemble average with a nonlinear but analytical charge dependence in the occupation number. Dissociation to neutral species for a gas-phase process is preserved. A variant of constrained search density functional theory is advocated as the preferred way to define an energy for a given charge.


Distinguishing the preparation and roles of Doctor of Philosophy and Doctor of Nursing Practice graduates: national implications for academic curricula and health care systems.
Although the American Association of Colleges of Nursing was clear in defining the role of individuals with the Doctor of Nursing Practice (DNP) degree when it endorsed the DNP as the single-entry degree for advanced practice nurses in 2004, confusion about educational curricula to prepare DNPs continues to exist in academic programs throughout the United States. Further, health care systems are unsure about the role DNP graduates should fulfill in comparison with PhD-prepared individuals. This article discusses the importance of DNP- and PhD-prepared individuals in improving the quality of health care and the health of Americans, how best to resolve the confusion in preparation of DNP and PhD students, and the various roles DNP and PhD graduates should fulfill in real-world settings. A national call to action and future implications for research, academia, and health care settings are highlighted.


Protective efficacy of recombinant exotoxin A--flagellin fusion protein against Pseudomonas aeruginosa infection.
Pseudomonas aeruginosa is an opportunistic bacterium that causes serious nosocomial infection in immunocompromised patients. The aim of this study was to prepare a fusion protein consisting of exotoxin A (ExoA) and flagellin (Fla) from P. aeruginosa and to evaluate its potential as a vaccine candidate against P. aeruginosa infection. The genes encoding for ExoA and Fla proteins were cloned in-frame and expressed in Escherichia coli. The recombinant ExoA-Fla fusion protein was purified by Ni-NTA affinity chromatography. Mice were immunized subcutaneously with ExoA, Fla, and ExoA-Fla fusion proteins, and the humoral immune response was evaluated by ELISA method. The immunized and control group mice were challenged with a 2× LD50 (7.5 × 10(7) CFU) of P. aeruginosa for the protection assay. The results indicated that vaccination with Fla, ExoA, and ExoA-Fla fusion proteins produced a significant amount of specific immunoglobulin G antibodies. Immunization of mice with ExoA-Fla fusion protein showed significant protection against intraperitoneal challenge with 7.5 × 10(7) CFU (2× LD50) P. aeruginosa. Results of this study suggest that recombinant ExoA-Fla fusion protein is a highly immunogenic protective protein showing promise as a vaccine candidate against P. aeruginosa.


Determination of S-phenylmercapturic acid by GC-MS and ELISA: a comparison of the two methods.
S-phenylmercapturic acid (PMA) is a specific urinary biomarker of benzene at exposure levels lower than 1 ppm. However, measuring PMA in urine is an expensive task by either GC or HPLC due to the necessity of extensive sample pretreatment. In the present study, a commercial chemiluminescence enzyme-linked immunosorbent assay (ELISA) test for PMA and GC-MS were used for screening urine samples of 60 workers employed in petrochemical settings. The ELISA results were evaluated by comparison with the GC-MS. Overall, the ELISA test proved sensitive (limit of detection=0.1 microg l(-1)), rapid, robust and reliable, affording results in good agreement with the GC-MS (54% of measurements) and no false-negatives. On the other hand, 46% of the ELISA assays were assigned as false-positives (arbitrarily established when ELISA >5 microg l(-1), GC-MS <5 microg l(-1) and a correlation coefficient of 0.687 was calculated between the two methods. It appears that urinary PMA routine biomonitoring on large numbers of samples is carried out in a cost-effective and rapid approach by preliminary screening with the ELISA assay followed by GC-MS confirmation of concentrations exceeding the biological exposure index for PMA.


Ostomy care and management: a systematic review.
The frequency of ostomy surgery in Canada is not known, but it is estimated that approximately 13,000 ostomy surgeries are performed annually in Canada. This systematic review incorporates evidence for the assessment and management of colostomies, ileostomies, and urostomies, as well as the peristomal skin. The review was completed as part of a best practice guideline document generated by a task force appointed by the Registered Nurses' Association of Ontario.


GPA33 is expressed on multiple human blood cell types and distinguishes CD4+ central memory T cells with and without effector function.
The Ig superfamily protein glycoprotein A33 (GPA33) has been implicated in immune dysregulation, but little is known about its expression in the immune compartment. Here, we comprehensively determined GPA33 expression patterns on human blood leukocyte subsets, using mass and flow cytometry. We found that GPA33 was expressed on fractions of B, dendritic, natural killer and innate lymphoid cells. Most prominent expression was found in the CD4+ T cell compartment. Naïve and CXCR5+ regulatory T cells were GPA33high , and naïve conventional CD4+ T cells expressed intermediate GPA33 levels. The expression pattern of GPA33 identified functional heterogeneity within the CD4+ central memory T cell (Tcm) population. GPA33+ CD4+ Tcm cells were fully undifferentiated, bona fide Tcm cells that lack immediate effector function, whereas GPA33- Tcm cells exhibited rapid effector functions and may represent an early stage of differentiation into effector/effector memory T cells before loss of CD62L. Expression of GPA33 in conventional CD4+ T cells suggests a role in localization and/or preservation of an undifferentiated state. These results form a basis to study the function of GPA33 and show it to be a useful marker to discriminate between different cellular subsets, especially in the CD4+ T cell lineage.


Recruitment of phosphoinositide 3-kinase defines a positive contribution of tyrosine kinase signaling to E-cadherin function.
Classical cadherin adhesion molecules can function as adhesion-activated cell-signaling receptors. One key target for cadherin signaling is the lipid kinase phosphoinositide (PI) 3-kinase, which is recruited to cell-cell contacts and activated by E-cadherin. In this study, we sought to identify upstream factors necessary for E-cadherin to activate PI 3-kinase signaling. We found that inhibition of tyrosine kinase signaling blocked recruitment of PI 3-kinase to E-cadherin contacts and abolished the ability of E-cadherin to activate PI 3-kinase signaling. Tyrosine kinase inhibitors further perturbed several parameters of cadherin function, including cell adhesion and the ability of cells to productively extend nascent cadherin-adhesive contacts. Notably, the functional effects of tyrosine kinase blockade were rescued by expression of a constitutively active form of PI 3-kinase that restores PI 3-kinase signaling. Finally, using dominant negative Src mutants and Src-null cells, we identified Src as one key upstream kinase in the E-cadherin/PI 3-kinase-signaling pathway. Taken together, our findings indicate that tyrosine kinase activity, notably Src signaling, can contribute positively to cadherin function by supporting E-cadherin signaling to PI 3-kinase.


[Complex regional pain syndrome type I induced by phenobarbital].
Complex regional pain syndrome type I (CRPS-I) requires the presence of regional pain and sensory changes associated with findings such as abnormal skin color, temperature change, sudomotor activity, or edema, following a noxious event. Complex regional pain syndrome type I induced by phenobarbital (PB) is not well known, although several reports have strengthened the association between PB and CRPS-I. I reviewed the charts of 99 patients treated with PB to assess the incidence, clinical characteristics, investigations, dosage and plasma concentration of PB, and risk factors in the development of CRPS-I. Six patients developed CRPS-I. Pain was severe and allodynia, swelling, discoloration, sweating were present in all patients. This syndrome manifested bilaterally in some patients. Affected patients included 5 men and 1 woman between the ages of 52 and 78 (average 64.2 years). A radiograph showed demineralization in one patient. Thermography showed temperature differences between affected and unaffected limbs, although in a few patients the differences were little because of bilateral affected limbs. 99Technetium methlyene diphosphonate bone scan showed increased periarticular changes in most of the patients. The patients developed CRPS-I at 9.7 weeks (average) after PB was begun. The average time was 7.5 months between CPRS-I and PB reduction. Neither sympathetic ganglion blockade nor physical therapy was effective. Treatment of CRPS-I consists of PB reduction and prednisone and/or Neurotropin. In all patients clinical symptoms and signs such as pain and edema, and range of motion of their shoulders were improved after PB discontinuation. One patient was followed longitudinally, documenting improvement following discontinuation, reexacerbation with PB rechallenge, and remission once more when PB were discontinued. The higher incidence should depend on the coexistence of separate risk factors such as age and PB dosage. Recognition of CRPS-I induced PB, early diagnosis, and withdrawal of PB are important for symptomatic relief and improvement of QOL.


A variant of human growth differentiation factor-9 that improves oocyte developmental competence.
Growth differentiation factor-9 (GDF9) and bone morphogenetic protein-15 (BMP15) are co-expressed exclusively in oocytes throughout most of folliculogenesis and play central roles in controlling ovarian physiology. Although both growth factors exist as homodimers, recent evidence indicates that GDF9 and BMP15 can also heterodimerize to form the potent growth factor cumulin. Within the cumulin complex, BMP15 "activates" latent GDF9, enabling potent signaling in granulosa cells via type I receptors (i.e. activin receptor-like kinase-4/5 (ALK4/5)) and SMAD2/3 transcription factors. In the cumulin heterodimer, two distinct type I receptor interfaces are formed compared with homodimeric GDF9 and BMP15. Previous studies have highlighted the potential of cumulin to improve treatment of female infertility, but, as a noncovalent heterodimer, cumulin is difficult to produce and purify without contaminating GDF9 and BMP15 homodimers. In this study we addressed this challenge by focusing on the cumulin interface formed by the helix of the GDF9 chain and the fingers of the BMP15 chain. We demonstrate that unique BMP15 finger residues at this site (Arg301, Gly304, His307, and Met369) enable potent activation of the SMAD2/3 pathway. Incorporating these BMP15 residues into latent GDF9 generated a highly potent growth factor, called hereafter Super-GDF9. Super-GDF9 was >1000-fold more potent than WT human GDF9 and 4-fold more potent than cumulin in SMAD2/3-responsive transcriptional assays in granulosa cells. Our demonstration that Super-GDF9 can effectively promote mouse cumulus cell expansion and improve oocyte quality in vitro represents a potential solution to the current challenges of producing and purifying intact cumulin.


The dMi-2 chromodomains are DNA binding modules important for ATP-dependent nucleosome mobilization.
Drosophila Mi-2 (dMi-2) is the ATPase subunit of a complex combining ATP-dependent nucleosome remodelling and histone deacetylase activities. dMi-2 contains an HMG box-like region, two PHD fingers, two chromodomains and a SNF2-type ATPase domain. It is not known which of these domains contribute to nucleosome remodelling. We have tested a panel of dMi-2 deletion mutants in ATPase, nucleosome mobilization and nucleosome binding assays. Deletion of the chromodomains impairs all three activities. A dMi-2 mutant lacking the chromodomains is incorporated into a functional histone deacetylase complex in vivo but has lost nucleosome-stimulated ATPase activity. In contrast to dHP1, dMi-2 does not bind methylated histone H3 tails and does not require histone tails for nucleosome binding. Instead, the dMi-2 chromodomains display DNA binding activity that is not shared by other chromodomains. Our results suggest that the chromodomains act at an early step of the remodelling process to bind the nucleosome substrate predominantly via protein-DNA interactions. Furthermore, we identify DNA binding as a novel chromodomain-associated activity.


MEK Inhibitors in the Treatment of Metastatic Melanoma and Solid Tumors.
The mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells. Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation. These mutations have become targets for new therapeutic strategies in melanoma and other cancers. Selective MEK inhibitors have the ability to inhibit growth and induce cell death in BRAF- and NRAS-mutant melanoma cell lines. MEK inhibitor therapy in combination with a BRAF inhibitor is more effective and less toxic than treatment with a BRAF inhibitor alone, and has become the standard of care for patients with BRAF-mutated melanoma. Trametinib was the first MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma not previously treated with BRAF inhibitors, and is also approved in combination with the BRAF inhibitor dabrafenib. Furthermore, cobimetinib is another MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma in combination with a BRAF inhibitor, vemurafenib. The MEK inhibitor binimetinib in combination with the BRAF inhibitor encorafenib is in clinical development. The addition of an anti-PD-1/PD-L1 agent, such as pembrolizumab, durvalumab or atezolizumab, to combined BRAF and MEK inhibition has shown considerable promise, with several trials ongoing in metastatic melanoma. Binimetinib has also shown efficacy in NRAS-mutated melanoma patients. Future possibilities for MEK inhibitors in advanced melanoma, as well as other solid tumors, include their use in combination with other targeted therapies (e.g. anti-CDK4/6 inhibitors) and/or various immune-modulating antibodies.


Carbohydrate epitope structural elucidation by 1H-NMR spectroscopy of a new Mycobacterium kansasii phenolic glycolipid antigen.
The complete primary structure of the carbohydrate moiety of a new phenolic glycolipid antigen namely PheGl K-IV from Mycobacterium kansasii was successfully established from only one- and two-dimensional 1H-NMR data. Among the scalar two-dimensional techniques, correlated spectroscopy with a 45 degree mixing pulse and phase-sensitive double-quantum-filtered correlated spectroscopy were selected, combined with two-dimensional dipolar techniques (nuclear Overhauser effect). These techniques using milligram of quantities native PheGl K-IV allowed the following monoacetylated tetrasaccharide to be proposed for its carbohydrate part: 4-O-Me-alpha-Manp-(1----3)-4-O-Ac-2-O-Me-alpha-Fucp-(1----3) -2-O-Me-alpha-Rhap- (1----3)-2,4-di-O-Me-alpha-Rhap. The PheGl K-IV shares, with the other phenolic glycolipids isolated from M. kansasii (K-I, K-II), a common core assigned to the lipid aglycone glycosylated by the monoacetylated trisaccharide part. It differs in the structure of the distal monosaccharide residue.


[Evaluation on the impacts of environmental changes and Three-Gorge engineering on the population of Yangtze voles (Microtus forits) in the Dongting Lake region].
The relationships between the population of Yangtze voles (Microtus fortis) and the evolvement of the Dongting Lake beaches were analyzed based on historical data, and the impacts of the Three-Gorge Engineering on beach environment and water level of the lake were assessed according to the regulation scheme on downward discharge flux of the Three-Gorge dam. The results indicated that the population of the voles has been increasing since 1950's, owing to the continuous enlargement of the lake beach and prolonging successional emergence of the beach. The emergence date of the beach in Autumn would be earlier, its emergence area would be going up, the population of the voles would be also expanded at the initial post-construction stage, which would still increase with the continuous expansion of beach area in a middle and long period after the establishment of the dam. More voles would thus move to the farmland, and heavily harm crops.


Addressing Adverse Childhood Experiences in Primary Care: Challenges and Considerations.
This article draws attention to the overlapping literature on social determinants of health and adverse childhood experiences, and the growing clinical interest in addressing them to promote children's and parents' health and well-being. We address important considerations and suggest solutions for leaders and practitioners in primary care to address social determinants of health/adverse childhood experiences. Priorities include: begin with a few prevalent conditions for which there are helpful resources; focus on conditions that are current or recent and where parents may be more apt to engage in services; focus initially on families with children aged <6 given the frequency of well-child visits and the especially strong relationships between primary care professionals and parents during this period; ensure training of primary care professionals and staff to help them play this role competently and comfortably; and have good referral processes to facilitate additional evaluation or help.


Persistence of Bacillus thuringiensis israelensis (Bti) in the environment induces resistance to multiple Bti toxins in mosquitoes.
The simultaneous production of six different toxins by Bacillus thuringiensis israelensis (Bti) is thought to delay the evolution of resistance in treated mosquito populations. Recent studies have shown that Bti can persist and proliferate in the environment, thereby imposing continuous selective pressure on mosquito populations, raising concerns about the long-term effectiveness of this bioinsecticide. In order to evaluate the effect of Bti persistence on the evolution of resistance, the authors selected a laboratory Aedes aegypti L. strain with field-collected leaf litter containing Bti toxins. It is shown that resistance to each individual Bti toxin (up to 30-fold) can be obtained after only a few generations of selection. However, the resistance to commercial Bti and to environmental Bti remains low (twofold and 3.4-fold respectively) in the selected strain. Furthermore, some selected individuals exhibited resistance to Cry4B but not to Cry4A, suggesting that two distinct resistance mechanisms are involved in the resistance to these two toxins. Considering that resistance to Cry toxins might act as a first step to resistance to a complete Bti toxin mixture, the present results highlight the importance of testing each toxin individually in order accurately to monitor Bti toxin resistance evolution in field populations.


[Initial osteoblast functions on a type of near β-type titanium alloys surfaces modified by the double glow plasma nitriding technology].
Objective: To evaluate the adhesion, proliferation, alkaline phosphatase (ALP) activity and the expression of osteogenesis-related genes and osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) of osteoblast-like cells on a type of near β-type titanium alloys (Ti-5Zr-3Sn-5Mo-15Nb, TLM) surfaces modified by the double glow plasma nitriding technology, and to investigate the effect of the modified surfaces on the initial functions of osteoblast-like cells. Methods: The surfaces of TLM were modified by the double glow plasma nitriding technology. TLM surfaces without modification were used as control. Cell morphology was observed with scanning electron microscopy (SEM). Methyl thiazolyl tetrazolium (MTT) method was used to measure cell proliferation. Cell ALP activity was evaluated by using reagent kits. The mRNA expression of Runt-related transcription factor-2 (RUNX2), typeⅠcollagen alpha 1 chain (COLⅠ α1) and OPG/RANKL were examined by quantitative real-time PCR(qRT-PCR). Results: Four hour following cell alture, cells on modified surfaces extend filopodia and intercellular junction was tight. Three days later, cell proliferation (0.277±0.007) was significantly higher than that in control group (0.249±0.004) (P<0.01). After two weeks, ALP activity on TLM modified layer (173.6±1.89) was significantly higher than that on unmodified TLM (162.6±2.4) (P<0.01). The mRNA expression of osteoblast marker RUNX2, COLⅠα1 were stronger than that in control group (P<0.05). The expression of OPG mRNA was higher than that in control group (P<0.01), and RANKL mRNA expression was significantly lower than that in control group (P<0.05). Conclusions: The TLM surface modified by the double glow plasma nitriding technology has a positive effect on osteoblasts initial adhesion, proliferation and differentiation, and it can also improve expression of OPG mRNA and has an inhibitory effect on RANKL mRNA expression of osteoblasts.


Optimal estimator model for human spatial orientation.
A model is presented to predict human dynamic spatial orientation in response to multisensory stimuli. Motion stimuli are first processed by dynamic models of the visual, vestibular, tactile, and proprioceptive sensors. Central nervous system function is modeled as a steady state Kalman filter that optimally blends information from the various sensors to form an estimate of spatial orientation. Where necessary, nonlinear elements preprocess inputs to the linear central estimator in order to reflect more accurately some nonlinear human response characteristics. Computer implementation of the model has shown agreement with several important qualitative characteristics of human spatial orientation.


Factors Associated with Adherence to and Treatment Duration of Erlotinib Among Patients with Non-Small Cell Lung Cancer.
In lung cancer, there is an increasing number of oral agents available for patients; however, little is known about the factors associated with adherence to and treatment duration on oral medications in non-small cell lung cancer (NSCLC). To evaluate the clinical and demographic factors associated with adherence and treatment discontinuation, respectively, to oral oncolytics among patients with NSCLC. A retrospective, claims-based analysis of the Humana Research Database supplemented with medical chart review was conducted among patients with NSCLC who started an oral oncolytic between January 1, 2008, and June 30, 2013. Patients were required to be enrolled at least 1 year before the start of oral oncolytics and have no evidence of any oral oncolytic use during this period. Logistic regression models and Cox proportional hazard models were used to identify predictors associated with medication adherence and treatment duration, respectively. Among all oral oncolytics, only the cohort starting on erlotinib had sufficient sample size (n = 1,452). A wide variety of factors were found to be associated with adherence. Low-income subsidy status, previous use of intravenous chemotherapy, and lower total baseline health care costs were significantly related to decreasing adherence (each P < 0.05). Additionally, increasing patient out-of-pocket cost was associated with decreasing adherence to erlotinib (P < 0.0001). Factors significantly related to longer treatment duration included low-income subsidy status (P < 0.001) and having Medicare insurance, (P = 0.0004), dual eligibility (Medicare and Medicaid, P = 0.007), and higher erlotinib out-of-pocket costs (P < 0.0001). There is a need for mechanisms to be in place to identify and address barriers to care. Future research should focus on evaluating and reducing any potential risk to patient outcomes that may be associated with low adherence to or shorter treatment duration on oral chemotherapy. This study was supported by funding from Eli Lilly and Company to Comprehensive Health Insights, a Humana company, as a collaborative research project involving employees of both companies. Hess, Winfree, Zhu, and Oton are employees of Eli Lilly and Company. Louder and Nair are employees of Comprehensive Health Insights, which received funding to complete this research. Study concept and design were contributed by Hess, Zhu, Winfree, and Oton. Nair and Louder collected the data, and data interpretation was performed by all the authors. The manuscript was written primarily by Hess, along with Nair, and revised by Hess, Nair, Louder, and Winfree, with assistance from Zhu and Louder.


Multidisciplinary Management of Diabetic Foot Ulcers in Primary Cares in Quebec: Can We Do Better?
A growing body of evidence supports the presence of integrated foot care based on multidisciplinary and interdisciplinary teams in the management and prevention of diabetic foot ulcer (DFU) worldwide. This model of care is however rare in the clinical setting in Quebec, Canada. Many best practice gaps are identified as well as probable causal hypothesis are listed in this commentary. We support our opinions with a pilot audit conducted as part of a continuous quality improvement process in managing patients with DFU in our area and on Canadian facts and data. Our pilot study (n = 27 hospitalized patients) included a typical DFU population with neuropathy, peripheral arterial disease and previous amputation. It highlights underachievement of best practice recommendations implementation such as multidisciplinary DFU management and offloading interventions in our establishment. Due the high morbidity and mortality associated with DFU patients, four died during the studied hospitalization episode. Several barriers were encountered in the pilot audit justifying that no robust conclusion can be raised. However, our observations are concerning. Even though data accessibility was limited, our observations are sadly coherent with what is found in the literature. Economic data of what this means for our health system is put forward in the overall discussion. We are preoccupied by the trends outlined by some facts and observations, and this commentary was written with this in mind. In the face of the diabetes crisis that is arising, a plea is made to reassess care pathway for this vulnerable population as we emphasize the importance of teamwork in managing DFU.


[Studies on As2O3-induced rabbit hypothermia and brain monoamines (author's transl)].
It has been suggested that hypothermia induced in rabbits by As2O3 3 mg/kg (i.v.) depends mostly on the blocking of the thermo-regulatory center. The relationship between hypothermia induced by As2O3 and brain monoamine levels in rabbits was investigated. To clarify the mechanism of the hypothermia, the influence of pretreatment with several agents on As2O3-induced hypothermia and on monoamine levels in the hypothalamus was examined. The core temperature was measured by inserting the thermister probe into the rectum and noradrenaline(NA), 5-hydroxytryptamine(5-HT) and 5-hydroxyindoleacetic acid(5-HIAA) levels in the hypothalamus were estimated fluorometrically. Pretreatment with p-chlorophenylalanine(PCPA), alpha-methyl-p-tyrosine(alpha-MPT) or 5-hydroxytryptophan(5-HTP) did not inhibit the hypothermia induced by As2O3 but did decrease NA levels in the hypothalamus. On the contrary, pretreatment with barbital sodium, pheniprazine, 1-DOPA and 1-tyrosine significantly inhibited the hypothermia or exhibited the hyperthermia. As2O3-induced hypothermia in rabbits was followed by a decrease in NA levels and an increase in 5-HT levels in the hypothalamus. On the other hand, when the hypothermia induced by As2O3 was inhibited by pretreatment with barbital sodium, pheniprazine, 1-DOPA and 1-tyrosine, both NA and 5-HT levels in the hypothalamus were significantly increased. These results suggest that As2O3-induced hypothermia is due to a decrease in NA levels and inhibition of the hypothermia is due to an increase in NA levels, in the rabbit hypothalamus.


Teriflunomide for the treatment of relapsing-remitting multiple sclerosis.
Teriflunomide, a once-daily, oral disease-modifying therapy, is a valuable new treatment option for the management of patients with relapsing-remitting multiple sclerosis. This article reviews key efficacy and safety data arising from pivotal teriflunomide studies that demonstrate the utility in treating both treatment-naïve patients and those previously treated with another disease-modifying therapy who, for a variety of reasons, may require an alternative treatment.


Factors affecting stabilometry recordings of single limb stance.
Stabilometry is an objective method for the quantitative study of postural equilibrium and has previously been shown to correlate to functional instability of the ankle joint. Stabilometric recordings of 25 soccer players did not confirm existing theories that an ankle joint injury itself produces a functional instability. Stabilometric recordings of 38 soccer players with and without ankle taping did not show that taping influenced the stabilometric values. In 10 soccer players with functional instability, a significant improvement of stabilometric results and subjective "giving way" feelings were found after 6 weeks of coordination on an ankle disk.