Air pollution and DNA methylation: interaction by psychological factors in the VA Normative Aging Study.
DNA methylation is a potential pathway linking air pollution to disease. Studies indicate that psychological functioning modifies the association between pollution and morbidity. The authors estimated the association of DNA methylation with ambient particulate matter less than 2.5 µm in diameter (PM(2.5)) and black carbon, using mixed models. DNA methylation of the inducible nitric oxide synthase gene, iNOS, and the glucocorticoid receptor gene, GCR, was measured by quantitative polymerase chain reaction pyrosequencing of 1,377 blood samples from 699 elderly male participants in the VA Normative Aging Study (1999-2009). The authors also investigated whether this association was modified by psychological factors including optimism or pessimism, anxiety, and depression. iNOS methylation was decreased after acute exposure to both black carbon and PM(2.5). A 1-μg/m(3) increase in exposure to black carbon in the 4 hours preceding the clinical examination was associated with a 0.9% decrease in 5-methylcytosine (95% CI: 0.4, 1.4) in iNOS, and a 10-μg/m(3) increase in exposure to PM(2.5) was associated with a 0.6% decrease in 5-methylcytosine (95% CI: 0.03, 1.1) in iNOS. Participants with low optimism and high anxiety had associations that were 3-4 times larger than those with high optimism or low anxiety. GCR methylation was not associated with particulate air pollution exposure.


The prevalence and clinical significance of perinuclear anti-neutrophil cytoplasmic antibody in Korean patients with ulcerative colitis.
Perinuclear anti-neutrophil cytoplasmic antibody (pANCA) is a serological marker associated with various immune-mediated diseases whose clinical significance and possible diagnostic roles in ulcerative colitis (UC) are still unclear. We aimed to evaluate the prevalence of pANCA expression and its association with clinical findings and disease course in Korean patients with UC. This study included 484 patients with UC who were diagnosed and treated between 1990 and 2006 at Severance Hospital, Yonsei University, Seoul, Korea, and were followed for at least 1 year. Clinical findings at diagnosis, disease extent, treatment modalities used, and cumulative relapse rates were analyzed and compared to pANCA expression. Of the 484 patients, 405 (83.7%) were evaluated for pANCA and were eligible for analysis. The overall pANCA prevalence was 22.1%, with a female preponderance (male, 21.5%; female, 31.6%; P < 0.05). Proctitis was more common in pANCA-negative patients (pANCA-negative, 37.6%; pANCA-positive, 25.2%, P < 0.05). UC activity index and cumulative relapse rates were higher in pANCA-positive patients. However, there were no significant differences in the cumulative probability of steroid and immunosuppressant use and operation rate between the two groups. The prevalence of pANCA expression in Korean patients with UC was relatively low compared to that in Western countries. Although UC patients with pANCA expression had more severe clinical findings at diagnosis and higher cumulative relapse rates in our study, further prospective studies are warranted to clarify whether pANCA positivity influences the initial clinical presentation or disease aggressiveness.


Inequitable impact of infection: social gradients in severe COVID-19 outcomes among all confirmed SARS-CoV-2 cases during the first pandemic wave in Sweden.
The backdrop of the ubiquitous social inequalities has increasingly come into foreground in research on the COVID-19 pandemic, but the lack of high-quality population-based studies limits our understanding of the inequitable outcomes of the disease. The present study seeks to estimate social gradients in COVID-19 hospitalisations, intensive care admissions and death by education, income and country of birth, while taking into account disparities in comorbidities. We used a register-based retrospective open cohort design enrolling all 74 659 confirmed SARS-CoV-2-positive cases aged >25 years in Sweden during the first wave of the pandemic (until 14 September 2020). Information was retrieved from multiple registers and linked by the unique Swedish personal identity number concerning COVID-19 case identification; COVID-19 hospitalisations, intensive care admissions and death; comorbidities as measured by the Charlson Comorbidity Index; and sociodemographic information. Social gradients were estimated by the Relative Index of Inequality (RII) using Cox regression. Adjusted analyses showed significant social gradients in COVID-19 hospitalisation, intensive care admission, across education, income and country of birth, which were unaffected by adjustment for comorbidities. Education and country of birth gradients were stronger for hospitalisation and intensive care admissions but small to non-existent for death. In contrast, income gradients were consistent across all three COVID-19 outcomes. Social gradients in severe COVID-19 outcomes are widespread in Sweden, but appear to be unrelated to pre-existing health disparities. Inequitable outcomes of SARS-CoV-2 infection may therefore be at least partially avoidable and could rely on equitable management of confirmed COVID-19 cases.


A novel survival rat model of hyperkalemia and landiolol induced cardioplegic arrest and resuscitation via cardiopulmonary bypass.
A small animal model would be an effective tool for research on the pathophysiology of cardiopulmonary bypass (CPB). However, numerous CPB models do not involve myocardial arrest and resuscitation. The aim of this research is to establish an easily achievable myocardial arrest and resuscitation CPB model through hyperkalemia and landiolol, simulating clinical cardiac surgery. Ten Sprague-Dawley rats were chosen for CPB. Rats underwent sevoflurane inhalation induction anesthesia and were sustained in an anesthesia state by intubation and intraperitoneal injection's of esketamine and propofol. The entire CPB circuit include a reservoir, a membrane oxygenator and a roller pump, which were connected into a complete loop via silicon tubes and infusion tube.After CPB was established through the tail artery and internal jugular vein, cardioplegic arrest was induced and maintained for 5 min at a rectum temperature of 28.5 ± 0.5°C with hyperkalemia and landiolol. Calcium chloride, epinephrine and insulin were then used for resuscitation. All rats successfully finished cardioplegic arrest, resuscitation procedure and survived 2 h postoperatively. Mean hematocrit during CPB was significantly lower than physiologic values of the baseline. The mean time of arrest-resuscitation and CPB was 5.4 ± 0.8 min and 98.5 ± 5.0 min. The blood gas at each detection point were in range with the normal standard requirement of CPB. The establishment of cardioplegic arrest and resuscitation procedure via hyperkalemia and landiolol during CPB of WD rat could be achieved successfully. This animal model could be an alternative organ injury research on organ injury of patients undergoing cardiac surgery.


Mutagenesis and functional analysis of the pore-forming toxin HALT-1 from Hydra magnipapillata.
Actinoporins are small 18.5 kDa pore-forming toxins. A family of six actinoporin genes has been identified in the genome of Hydra magnipapillata, and HALT-1 (Hydra actinoporin-like toxin-1) has been shown to have haemolytic activity. In this study, we have used site-directed mutagenesis to investigate the role of amino acids in the pore-forming N-terminal region and the conserved aromatic cluster required for cell membrane binding. A total of 10 mutants of HALT-1 were constructed and tested for their haemolytic and cytolytic activity on human erythrocytes and HeLa cells, respectively. Insertion of 1-4 negatively charged residues in the N-terminal region of HALT-1 strongly reduced haemolytic and cytolytic activity, suggesting that the length or charge of the N-terminal region is critical for pore-forming activity. Moreover, substitution of amino acids in the conserved aromatic cluster reduced haemolytic and cytolytic activity by more than 80%, suggesting that these aromatic amino acids are important for attachment to the lipid membrane as shown for other actinoporins. The results suggest that HALT-1 and other actinoporins share similar mechanisms of pore formation and that it is critical for HALT-1 to maintain an amphipathic helix at the N-terminus and an aromatic amino acid-rich segment at the site of membrane binding.


Purifying selection modulates the estimates of population differentiation and confounds genome-wide comparisons across single-nucleotide polymorphisms.
An improved understanding of the biological and numerical properties of measures of population differentiation across loci is becoming increasingly more important because of their growing use in analyzing genome-wide polymorphism data for detecting population structures, inferring the rates of migration, and identifying local adaptations. In a genome-wide analysis, we discovered that the estimates of population differentiation (e.g., F(ST), θ, and Jost's D) calculated for human single-nucleotide polymorphisms (SNPs) are strongly and positively correlated to the position-specific evolutionary rates measured from multispecies alignments. That is, genomic positions (loci) experiencing higher purifying selection (lower evolutionary rates) produce lower values for the degree of population differentiation than those evolving with faster rates. We show that this pattern is completely mediated by the negative effects of purifying selection on the minor allele frequency (MAF) at individual loci. Our results suggest that inferences and methods relying on the comparison of population differentiation estimates (F(ST), θ, and Jost's D) based on SNPs across genomic positions should be restricted to loci with similar MAFs and/or the rates of evolution in genome scale surveys.


How gaps in regulation of compounding pharmacy set the stage for a multistate fungal meningitis outbreak.
To provide an overview of the regulation issues surrounding compounding pharmacy that allowed the United States fungal meningitis outbreak to occur and the changes in regulation that ensued. In September 2012, a single case report sparked an investigation into a nationwide outbreak of fungal meningitis due to contaminated injectable drugs. The source of the contamination, New England Compounding Center (NECC), was in violation of several state and federal laws and had a history of such violations. The regulation of compounding pharmacies has historically been left to the states, while manufacturing fell under the jurisdiction of the Food and Drug Administration. However, as more compounders took part in large-scale interstate distribution of drugs, the current state-based regulatory system became less equipped to provide oversight. The lack of a clear definition of "compounding pharmacy" further obscures proper oversight and regulation. Congress and several states have taken steps to build safeguards against large-scale compounding by increasing inspections, adopting stricter licensing requirements, and enacting the Drug Quality and Security Act of 2013. While the current compounding regulation changes are a necessary step forward, it remains to be seen how effective they will be in safeguarding the public.


Considerations of radiofrequency induction heating for localised hyperthermia.
A finite difference technique for studying both spatial and temporal variations in temperature in tissues subjected to local hyperthermia is described. The calculation offers speed and simplicity whilst remaining stable. Its form is discussed in both 3-dimensional Cartesian coordinates and cylindrical coordinates. The technique is used to predict RF induction heating of a plane skin-fat-muscle model. Physical and physiological parameters are incorporated. These include the contributions to heating from both E and H fields associated with a plane coil, heat transfer across the skin surface for various environmental conditions, and an appropriate dependence of blood flow on temperature for each tissue layer. The effects on tissue temperature of varying each of a number of parameters in the model are considered.


Atomic White-Out: Enabling Atomic Circuitry through Mechanically Induced Bonding of Single Hydrogen Atoms to a Silicon Surface.
We report the mechanically induced formation of a silicon-hydrogen covalent bond and its application in engineering nanoelectronic devices. We show that using the tip of a noncontact atomic force microscope (NC-AFM), a single hydrogen atom could be vertically manipulated. When applying a localized electronic excitation, a single hydrogen atom is desorbed from the hydrogen-passivated surface and can be transferred to the tip apex, as evidenced from a unique signature in frequency shift curves. In the absence of tunnel electrons and electric field in the scanning probe microscope junction at 0 V, the hydrogen atom at the tip apex is brought very close to a silicon dangling bond, inducing the mechanical formation of a silicon-hydrogen covalent bond and the passivation of the dangling bond. The functionalized tip was used to characterize silicon dangling bonds on the hydrogen-silicon surface, which was shown to enhance the scanning tunneling microscope contrast, and allowed NC-AFM imaging with atomic and chemical bond contrasts. Through examples, we show the importance of this atomic-scale mechanical manipulation technique in the engineering of the emerging technology of on-surface dangling bond based nanoelectronic devices.


Effects of correlations and fees in random multiplicative environments: Implications for portfolio management.
Geometric Brownian motion (GBM) is frequently used to model price dynamics of financial assets, and a weighted average of multiple GBMs is commonly used to model a financial portfolio. Diversified portfolios can lead to an increased exponential growth compared to a single asset by effectively reducing the effective noise. The sum of GBM processes is no longer a log-normal process and has a complex statistical properties. The nonergodicity of the weighted average process results in constant degradation of the exponential growth from the ensemble average toward the time average. One way to stay closer to the ensemble average is to maintain a balanced portfolio: keep the relative weights of the different assets constant over time. To keep these proportions constant, whenever assets values change, it is necessary to rebalance their relative weights, exposing this strategy to fees (transaction costs). Two strategies that were suggested in the past for cases that involve fees are rebalance the portfolio periodically and rebalance it in a partial way. In this paper, we study these two strategies in the presence of correlations and fees. We show that using periodic and partial rebalance strategies, it is possible to maintain a steady exponential growth while minimizing the losses due to fees. We also demonstrate how these redistribution strategies perform in a phenomenal way on real-world market data, despite the fact that not all assumptions of the model hold in these real-world systems. Our results have important implications for stochastic dynamics in general and to portfolio management in particular, as we show that there is a superior alternative to the common buy-and-hold strategy, even in the presence of correlations and fees.


[Association of the hepatitis A virus with the membranes of infected cells].
"Light" viral antigen (HAAg) with buoyant density 1.20 g/cm2 and sedimentation coefficient 92S are accumulated together with mature viral particles in Hepatitis A virus (HAV) infected FRhK-4 cells. This HAAg is localized predominantly in endoplasmic reticulum fraction of infected cells, while nature virions are localized in cytosol. In contrast to mature virus, "light" HAAg is sensitive to trypsin digestion and is not able to hybridize with synthetic oligodeoxinucleotide which is complementary to structural part of HAV RNA. Antigenic properties of mature virus and "light" antigen are compared.


An event-triggered collaborative neurodynamic approach to distributed global optimization.
In this paper, we propose an event-triggered collaborative neurodynamic approach to distributed global optimization in the presence of nonconvexity. We design a projection neural network group consisting of multiple projection neural networks coupled via a communication network. We prove the convergence of the projection neural network group to Karush-Kuhn-Tucker points of a given global optimization problem. To reduce communication bandwidth consumption, we adopt an event-triggered mechanism to liaise with other neural networks in the group with the Zeno behavior being precluded. We employ multiple projection neural network groups for scattered searches and re-initialize their states using a meta-heuristic rule in the collaborative neurodynamic optimization framework. In addition, we apply the collaborative neurodynamic approach for distributed optimal chiller loading in a heating, ventilation, and air conditioning system.


Individual airway constrictor response heterogeneity to histamine assessed by high-resolution computed tomography.
We directly measured the range of individual airway responses to aerosol and intravenous administration of histamine by using high-resolution computed tomography and then compared the heterogeneity in constriction responses between these two routes. Seven dogs were used for a total of eleven studies. Six of the seven dogs received intravenous histamine (100-300 micrograms/min) and five of the seven dogs received aerosolized histamine (0.01-3.0 mg/ml for 5 breaths). Data were analyzed using linear regression models calculating residual mean square values for each route of histamine as a measure of variability in the change in airway size. The residual mean square values for the absolute airway size after the aerosol and intravenous histamine challenges were 17.73 and 15.42, respectively, which were not significantly different [F(331,166) = 1.15, P = 0.32]. Also, there were no significant differences when we compared the log or the percent change in airway area for the two routes of administration. We conclude that the route of histamine administration does not significantly affect the heterogeneity of airway response, suggesting that the heterogeneity observed after the histamine challenge is predominantly controlled by local mechanisms in the airways.


The effects of clonidine on postoperative analgesia after peripheral nerve blockade in children.
The effect of clonidine on the duration of sensory blockade after peripheral nerve blockade is controversial. We evaluated the effects of clonidine on the duration of sensory and motor block and analgesia time in children who underwent a variety of peripheral nerve blocks. We reviewed the regional anesthesia database that contains data on children who underwent an infraclavicular, lumbar plexus, femoral, fascia iliaca or sciatic nerve block for postoperative analgesia at The Children's Hospital of Philadelphia between October 2002 and December 2005. Patients were prospectively followed after the nerve block. Two hundred fifteen patients (47%) received either bupivacaine or ropivacaine local anesthetic (LA) and 220 (53%) a combination of local anesthetic and clonidine (LAC). The duration of sensory block was significantly longer in the LAC (17.2 +/- 5 h) compared with that in the LA group (13.2 +/- 5 h) (P = 0.0001). The increase in duration was independent from the type of peripheral nerve block, local anesthetic used and operation performed. The motor block duration was significantly longer in the LAC group (9.6 +/- 5 vs 4.3 +/- 4 h, P = 0.014). Two patients in the LAC and one in the LA group experience prolonged numbness (max 72 h). No paresthesia or dysesthesia was observed. The addition of clonidine to bupivacaine and ropivacaine can extend sensory block by a few hours, and increase the incidence of motor blocks.


Biomarkers of acute myocardial infarction in the elderly: troponin and beyond.
In the broadest context, biological markers, or biomarkers, are molecules that characterize a biological system or process. In the setting of cardiovascular disease, a number of biomarkers have become an integral part of diagnostic and risk stratification strategies. In this review, we will discuss classic and emerging biomarkers of cardiovascular disease and the role of these biomarkers in the diagnosis and prognosis of elderly patients presenting with acute myocardial infarction.


Live time-lapse dataset of in vitro wound healing experiments.
The wound healing assay is the common method to study collective cell migration in vitro. Computational analyses of live imaging exploit the rich temporal information and significantly improve understanding of complex phenomena that emerge during this mode of collective motility. Publicly available experimental data can allow application of new analyses to promote new discoveries, and assess algorithms' capabilities to distinguish between different experimental conditions. A freely-available dataset of 31 time-lapse in vitro wound healing experiments of two cell lines is presented. It consists of six different experimental conditions with 4-6 replicates each, gathered to study the effects of a growth factor on collective cell migration. The raw data is available at 'The Cell: an Image Library' repository. This Data Note provides detailed description of the data, intermediately processed data, scripts and experimental validations that have not been reported before and are currently available at GigaDB. This is the first publicly available repository of live collective cell migration data that includes independent replicates for each set of conditions. This dataset has the potential for extensive reuse. Some aspects in the data remain unexplored and can be exploited extensively to reveal new insight. The dataset could also be used to assess the performance of available and new quantification methods by demonstrating phenotypic discriminatory capabilities between the different experimental conditions. It may allow faster and more elaborated, reproducible and effective analyses, which will likely lead to new biological and biophysical discoveries.


Immunomodulatory Effects and Induction of Apoptosis by Different Molecular Weight Chitosan Oligosaccharides in Head Kidney Macrophages From Blunt Snout Bream (Megalobrama amblycephala).
Prophylactic administration of immunopotentiators has been tested and practiced as one of the most promising disease prevention methods in aquaculture. Chitosan oligosaccharide (COS), as an ideal immunopotentiator, is mainly used as feed additives in aquaculture, and the antimicrobial and immune enhancement effects are highly correlated with molecular weight (MW), but little is known about the mechanisms in teleost. Here, we isolated and purified macrophages in head kidney from blunt snout bream (Megalobrama amblycephala), stimulated them with three different MW (~500 Da, ~1000 Da and 2000~3000 Da) COSs, performed RNA-sequencing, global transcriptional analyses, and verification by quantitative real-time PCR (qRT-PCR) and immunofluorescent staining methods. Differential expression gene (DEG) analysis indicated that gene expression patterns are different and the proportion of unique genes are relatively high in different treatment groups. Biological process and gene set enrichment analysis (GSEA) demonstrated that all three COSs activate resting macrophages, but the degrees are different. Weighted gene co-expression network analysis (WGCNA) reflected gene modules correlated to MW, the module hub genes and top GO terms showed the activation of macrophage was positively correlated with the MW, and larger MW COS activated cell death associated GO terms. Further use of the screening and enrichment functions of STRING and Pfam databases discovered that apoptosis-related pathways and protein families were activated, such as the P53 pathway and caspase protein family. qRT-PCR results showed that as the stimulation time extends, the innate immune-related and P53 pathways are gradually activated, and the degree of activation is positively correlated with the stimulation time. In addition, apoptosis was detected by immunofluorescent staining in three groups. Therefore, the use of COS has two sides-it can activate the immune system against pathogen invasion, but with the increase in stimulation time and MW, macrophage apoptosis is induced, which may be caused by abnormal replication of DNA and excessive inflammation. This study provides a theoretical basis for the rational use of COS as an immunopotentiator in aquaculture.


Cardiovascular and metabolic response to acute normovolemic anemia. Effects of anesthesia.
The maintenance of adequate tissue oxygenation during acute anemia depends on an increase in both cardiac output and tissue oxygen extraction. This study tested the hypothesis that anesthesia blunts the cardiac output response associated with acute normovolemic hemodilution. Forty patients undergoing major abdominal surgery were prospectively randomized to undergo acute normovolemic hemodilution (ANH) either awake (awake group, n = 20) or with fentanyl-nitrous oxide-isoflurane anesthesia (anesthetized group, n = 20). Radial and pulmonary artery catheters were placed in all patients. After hemodynamic measurements were taken, patients in the two groups underwent hemodilution to decrease their hemoglobin concentration from 13 to 8 g/dl. A total of 1,875 +/- 222 ml (mean +/- SD) of blood was collected and simultaneously replaced by the same volume of medium molecular weight hydroxyethylstarch in both groups. In the awake group, ANH resulted in a significant increase in cardiac index (from 3.1 +/- 0.5 to 4.8 +/- 1.0 l. min-1. m-2) related to both an increase in heart rate and stroke index. Oxygen delivery remained unchanged, but oxygen consumption increased significantly, resulting in an increase in oxygen extraction ratio. In the anesthetized group, ANH resulted in a significantly smaller increase in cardiac index (from 2.3 +/- 0.5 to 3.1 +/- 0.7 l. min-1. m-2) related solely to an increase in stroke index. Oxygen delivery decreased but oxygen consumption was maintained as oxygen extraction increased. Anesthesia significantly reduces the cardiac output response associated with ANH. This could be related to the effects of the anesthetic drugs on the autonomic and the cardiovascular systems.


Behavioral Changes in General Practitioners towards Chronic Obstructive Pulmonary Disease Over Five Years: An Observational Study.
Early detection of chronic obstructive pulmonary disease (COPD) is critical for preventing progression; however, the disease is rarely detected in the early stages. One reason for this is that COPD is not generally recognized and diagnosed by general practitioners (GPs). The objective of this study was to observe changes in the knowledge and behavior of GPs regarding the diagnosis and treatment of COPD over a five-year period. The surveys were performed using identical and anonymous questionnaires in 2005, 2006 and 2010. During this period, various educational campaigns were conducted. All members of the Shiga Medical Association working as GPs in Shiga Prefecture. The number of questionnaires collected was 216 of 711, 269 of 731 and 326 of 856, respectively. Throughout the study period, the number of doctors who prescribed inhaled long-acting muscarinic antagonists (LAMAs) significantly increased (p<0.001). However, there were no significant changes in the rate of possession of spirometers or recognition of COPD guidelines. When we focused on the data for internists, the rate of recognition of the guidelines increased significantly (p<0.01), despite a lack of change in the rate of possession of spirometers. Furthermore, the results of the multivariate analysis revealed that increased knowledge concerning COPD was associated with the doctor's specialty, ownership of a spirometer, number of COPD patients attending their clinic and their level of recognition of the guidelines. During the study period, the GPs prescribed more inhaled LAMAs. The rate of recognition of COPD guidelines was also increased among internists. Educational campaigns may be more effective if the backgrounds of the GPs are taken into consideration.


Speciation of volatile selenium species in plants using gas chromatography/inductively coupled plasma mass spectrometry.
Gas chromatography/inductively coupled plasma mass spectrometry (GC/ICP-MS) coupled with solid phase micro-extraction can provide a simple, extremely selective and sensitive technique for the analysis of volatile sulfur and selenium compounds in the headspace of growing plants. In this work, the technique was used to evaluate the volatilization of selenium in wild-type and genetically-modified Brassica juncea seedlings. By converting toxic inorganic selenium in the soil to less toxic, volatile organic selenium, B. juncea might be useful in bioremediation of selenium contaminated soil.


Comparison of the effects of repetitive low-dose and single-dose antigen challenge on airway inflammation.
Airway allergen provocation provides a model to study allergic inflammation in relationship to pulmonary physiology. Allergen provocation is usually administered as a relatively large single-dose challenge that might not reflect a chronic, natural, low-dose airborne allergen exposure. We sought to compare the magnitude, characteristic features, and kinetics of airway inflammation induced by means of repetitive low-dose antigen challenges with those factors induced by means of an equivalent single-dose allergen challenge in allergic asthma. This was a 2-period crossover study. During separate phases, each subject was administered either a predetermined single-dose antigen challenge or 25% of that dose on each of 4 consecutive days. The airway response to allergen challenge was determined by means of measurement of pulmonary function and sputum features of inflammation, including eosinophil, eosinophil-derived neurotoxin, and fibronectin levels. Both models of antigen challenge caused significant and equivalent sputum eosinophilia. The immediate decrease in FEV(1) and the FEV(1)/forced vital capacity ratio and the increase in sputum eosinophilia, eosinophil-derived neurotoxin, and fibronectin levels occurred gradually over the first 3 low doses and then reached a plateau or tended to decrease with the fourth antigen exposure. Our data suggest that although the 2 challenge models had similar quantitative effects on lung function and sputum eosinophilia, the qualitative responses and kinetics of these changes were distinct. Repetitive low doses of antigen, as might mimic natural allergy exposure, produced an equivalent inflammatory response to the large single-dose challenge but with a smaller amount of antigen, suggesting that priming and accumulative effects might have occurred. Moreover, our limited data also suggest that immunologic tolerance might be induced by frequent challenges.


Effects of cell-type specific leptin receptor mutation on leptin transport across the BBB.
The functions of leptin receptors (LRs) are cell-type specific. At the blood-brain barrier, LRs mediate leptin transport that is essential for its CNS actions, and both endothelial and astrocytic LRs may be involved. To test this, we generated endothelia specific LR knockout (ELKO) and astrocyte specific LR knockout (ALKO) mice. ELKO mice were derived from a cross of Tie2-cre recombinase mice with LR-floxed mice, whereas ALKO mice were generated by a cross of GFAP-cre with LR-floxed mice, yielding mutant transmembrane LRs without signaling functions in endothelial cells and astrocytes, respectively. The ELKO mutation did not affect leptin half-life in blood or apparent influx rate to the brain and spinal cord, though there was an increase of brain parenchymal uptake of leptin after in situ brain perfusion. Similarly, the ALKO mutation did not affect blood-brain barrier permeation of leptin or its degradation in blood and brain. The results support our observation from cellular studies that membrane-bound truncated LRs are fully efficient in transporting leptin, and that basal levels of astrocytic LRs do not affect leptin transport across the endothelial monolayer. Nonetheless, the absence of leptin signaling at the BBB appears to enhance the availability of leptin to CNS parenchyma. The ELKO and ALKO mice provide new models to determine the dynamic regulation of leptin transport in metabolic and inflammatory disorders where cellular distribution of LRs is shifted.


The effects of ZD6474, an inhibitor of VEGF signaling, on cutaneous wound healing in mice.
ZD6474 is an inhibitor of the VEGFR-2 receptor tyrosine kinase with additional activity against EGFR-1 receptor tyrosine kinases that has been shown to inhibit tumor growth and wound-induced neovascularization in pre-clinical studies and phase I clinical trials. The purpose of this study was to determine the effects of ZD6474 on breaking strength in a murine model of cutaneous wound healing. Balb/C mice were given ZD6474 (50 or 100 mg/kg p.o.) or vehicle starting 7 days before wounding. Two full-thickness incisions were made in each mouse and closed using suture. On post-wounding day 7 or 28, laser Doppler blood flow measurements were made, and the breaking strength of the wounded skin was determined. Microvessel density measurements were performed using computer image analysis of CD31-stained sections. Compared with controls, mice treated with ZD6474 showed a significantly reduced dose-dependent decline in breaking strength, both at POD 7 (P < 0.001) and at POD 28 (P < 0.005). Histologically, the ZD6474-treated mice showed a qualitative reduction in the degree of fibrosis and epithelial proliferation at the wound site, but no significant difference was noted between the 50 mg/kg and 100 mg/kg ZD6474-treated groups. Also, microvessel density measurements demonstrated no significant difference between groups. In a murine model of wound healing, ZD6474 treatment did not prevent wound healing, but was associated with a reduced skin breaking strength compared with vehicle-treated controls at both 7 and 28 days post-wounding. These observations may have clinical relevance for the perioperative management of patients treated with inhibitors of angiogenesis.


Distinct Chiral Nematic Self-Assembling Behavior Caused by Different Size-Unified Cellulose Nanocrystals via a Multistage Separation.
Cellulose nanocrystals (CNCs) are perfect rodlike nanofibers that can self-assemble and form a chiral nematic phase. We found that different self-assembling morphologies could be formed by different size-unified CNCs. This study reported a facile and new approach of fractionating raw (unseparated) CNCs in a wide particle size distribution (9-1700 nm) into a series of narrower size ranges to obtain size-unified CNCs via a well-designed multistage separation process composed of layered filter membranes with different pore size cutoffs followed by a fast pressurized filtration. The smaller size-unified CNCs readily self-assembled into polish chiral nematic phases with larger pitch value as compared to larger size-unified CNCs. Such a distinction among different chiral nematic phases and pitch values as functions of size was addressed by a mathematical evaluation, which suggested that the reduced volume fraction of the anisotropic phase as a function of both increased ionic strength and reduced crystallinity of rigid-rod-like CNCs is a critical factor. In addition, Fourier-transform infrared spectroscopy, thermogravimetric analysis, and X-ray diffraction results revealed that different size-unified CNCs exhibited particular thermal stabilities and crystallinities even though their chemical and crystalline structures remained unchanged. The discrepancies in physicochemical characteristics and self-assembling chiral nematic behavior among different size-unified CNCs may benefit the specific functionalization of cellulose materials using size-unified fibers instead of raw CNCs containing mixed small and large fibers.


Cortical serotonin type-2 receptor density in parents of children with autism spectrum disorders.
Parents (N = 19) of children with autism spectrum disorders (ASD) and adult controls (N = 17) underwent positron emission tomography (PET) using [(18)F]setoperone to image cortical serotonin type-2 (5-HT2) receptors. The 5-HT2 binding potentials (BPs) were calculated by ratioing [(18)F]setoperone intensity in regions of interest (ROI) to cerebellar intensity. Cortical 5-HT2 BPs were significantly lower in parents compared to controls and platelet 5-HT levels were significantly negatively correlated with cortical 5-HT2 BP in parents. Lower cortical 5-HT2 receptor density in parents of children with ASD is consistent with reports of diminished 5-HT2 expression and functioning in individuals with ASD. Further research should examine the relationship of reduced 5-HT2 receptor expression to underlying causation and to clinical and neurochemical correlates of autistic behavior.


Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX.
In the POLLUX study, daratumumab plus lenalidomide/dexamethasone significantly reduced risk of progression/death versus lenalidomide/dexamethasone alone in relapsed/refractory multiple myeloma. We provide one additional year of follow up and include the effect on minimal residual disease and in clinically relevant subgroups. After 25.4 months of follow up, daratumumab plus lenalidomide/dexamethasone prolonged progression-free survival versus lenalidomide/dexamethasone alone (median not reached vs 17.5 months; hazard ratio, 0.41; 95% confidence interval, 0.31-0.53; P<0.0001). The overall response rate was 92.9% versus 76.4%, and 51.2% versus 21.0% achieved a complete response or better, respectively (both P<0.0001). At the 10-5 sensitivity threshold, 26.2% versus 6.4% were minimal residual disease-negative, respectively (P<0.0001). Post hoc analyses of clinically relevant patient subgroups demonstrated that progression-free survival was significantly prolonged for daratumumab plus lenalidomide/dexamethasone versus lenalidomide/dexamethasone regardless of number of prior lines of therapy. Patients previously treated with lenalidomide or thalidomide and those refractory to bortezomib received similar benefits (all P<0.01). Treatment benefit with daratumumab plus lenalidomide/dexamethasone was maintained in high-risk patients (median progression-free survival 22.6 vs 10.2 months; hazard ratio, 0.53; 95% confidence interval, 0.25-1.13; P=0.0921) and patients with treatment-free intervals of >12 and ≤12 months and >6 and ≤6 months. No new safety signals were observed. In relapsed/refractory multiple myeloma patients, daratumumab plus lenalidomide/dexamethasone continued to improve progression-free survival and deepen responses versus lenalidomide/dexamethasone. Trial Registration: clinicaltrials.gov identifier: 02076009.


Added Value of Using a CT Coronal Reformation to Diagnose Adnexal Torsion.
To evaluate the increased value of using coronal reformation of a transverse computed tomography (CT) scan for detecting adnexal torsion. This study included 106 woman suspected of having adnexal torsion who underwent CT with coronal reformations and subsequent surgical exploration. Two readers independently recorded the CT findings, such as the thickening of a fallopian tube, twisting of the adnexal pedicle, eccentric smooth wall thickening of the torsed adnexal mass, eccentric septal thickening of the torsed adnexal mass, eccentric poor enhancement of the torsed adnexal mass, uterine deviation to the twisted side, ascites or infiltration of pelvic fat, and the overall impression of adnexal torsion with a transverse scan alone or combined with coronal reformation and a transverse scan. The areas under the receiver operating characteristic curves (AUCs), sensitivity, specificity, and positive predictive value were used to compare diagnostic performance. Fifty-two patients were confirmed to have adnexal torsion. The addition of coronal reformations to the transverse scan improved AUCs for readers 1 and 2 from 0.74 and 0.75 to 0.92 and 0.87, respectively, for detecting adnexal torsion (p < 0.001 and p = 0.004, respectively). Sensitivity of CT for detecting twisting of the adnexal pedicle increased significantly for readers 1 and 2 from 0.27 and 0.29 with a transverse scan alone to 0.79 and 0.77 with a combined coronal reformation and a transverse scan, respectively (p < 0.001 and p < 0.001, respectively). Use of a coronal reformation with transverse CT images improves detection of adnexal torsion.


Effect of olive oil mill wastewater on extracellular ligninolytic enzymes produced by Phanerochaete flavido-alba.
Our previous results have demonstrated that Phanerochaete flavido-alba decoloration, dephenolization and detoxification of olive oil mill wastewater (OMW) were associated with changes in the ligninolytic major exoenzymes accumulated in the cultures. This paper describes the effect of the two main OMW components (monomeric aromatic compounds and a major brownish polymeric pigment), on extracellular P. flavido-alba ligninolytic enzymes. Laccase was the sole ligninolytic enzyme detected in cultures containing monomeric aromatic compounds. Laccase and an acidic manganese-dependent peroxidase (MnPA, pI<2.8) were accumulated in cultures with OMW or polymeric pigment. Also, modified manganese-dependent peroxidases were observed mainly in OMW-supplemented cultures. Laccase was more stable to the effect of OMW toxic components and was accumulated in monomeric aromatic-supplemented cultures, suggesting a more important role than manganese-dependent peroxidases in OMW detoxification. Alternatively, MnPA accumulated in cultures containing the polymeric pigment seems to be more essential than laccase for degradation of this recalcitrant macromolecule by P. flavido-alba.


Tiotropium in the treatment of patients with asthma.
Asthma is a chronic disease with a significant disease burden, and many patients fail to achieve disease control despite recommended medical therapy. Recent evidence suggests that there may be benefits to the use of the long-acting anticholinergic agent tiotropium in patients with asthma. We performed a systematic review of the literature to determine the role of tiotropium in management of adult patients with asthma. In six studies, 1773 patients were randomized and 1057 received tiotropium as an intervention. The mean prebronchodilator forced expiratory volume in 1 second was 60.1%. All six studies reported a small but statistically significant improvement in spirometry when using tiotropium as compared with the control. Improvement was reported in patients with both moderate and severe asthma, patients uncontrolled on previous regimens, patients treated with low- to high-dose inhaled corticosteroids regimens, and patients treated with and without long-acting β-agonist therapy. Five studies evaluated clinical outcomes with tiotropium with variable success rates. Although a large randomized trial demonstrated a reduction in the frequency of severe asthma exacerbation with tiotropium, there is insufficient evidence to support the argument that tiotropium therapy leads to improvements in asthma symptom measures, asthma control days, asthma-related quality-of-life-scores, or rescue inhaler use. There is strong evidence supporting improvement in spirometry and asthma exacerbations with tiotropium in patients with moderate and severe asthma; therefore, tiotropium may be an effective intervention in patients with asthma.


A Heterostructure Coupling of Bioinspired, Adhesive Polydopamine, and Porous Prussian Blue Nanocubics as Cathode for High-Performance Sodium-Ion Battery.
Prussian blue (PB) and its analogues are recognized as promising cathodes for rechargeable batteries intended for application in low-cost and large-scale electric energy storage. With respect to PB cathodes, however, their intrinsic crystal regularity, vacancies, and coordinated water will lead to low specific capacity and poor rate performance, impeding their application. Herein, nanocubic porous Nax FeFe(CN)6 coated with polydopamine (PDA) as a coupling layer to improve its electrochemical performance is reported, inspired by the excellent adhesive property of PDA. As a cathode for sodium-ion batteries, the Nax FeFe(CN)6 electrode coupled with PDA delivers a reversible capacity of 93.8 mA h g-1 after 500 cycles at 0.2 A g-1 , and a discharge capacity of 72.6 mA h g-1 at 5.0 A g-1 . The sodium storage mechanism of this Nax FeFe(CN)6 coupled with PDA is revealed via in situ Raman spectroscopy. The first-principles computational results indicate that FeII sites in PB prefer to couple with the robust PDA layer to stabilize the PB structure. Moreover, the sodium-ion migration in the PB structure is enhanced after coating with PDA, thus improving the sodium storage properties. Both experiments and computational simulations present guidelines for the rational design of nanomaterials as electrodes for energy storage devices.


Pre-employment examinations for preventing occupational injury and disease in workers.
Many employers and other stakeholders believe that health examinations of job applicants prevent occupational diseases and sickness absence. To evaluate the effectiveness of pre-employment examinations of job applicants in preventing occupational injury, disease and sickness absence compared to no intervention or alternative interventions. We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE, CINAHL, PsycINFO and PEDro (to December 2009) not restricted by date, language or publication type. We included randomised controlled trials (RCTs), controlled before-after studies (CBA), and interrupted time-series (ITS) of health examinations to prevent occupational diseases and injuries in job applicants. Four review authors (NM, ML, JV, ES) independently selected studies, extracted data, and determined study quality. The studies were too heterogeneous for statistical pooling of results. We included two RCTs, five CBA studies and two ITS. Seven studies with 5872 participants evaluated the screening process of pre-employment examinations and two studies with 2164 participants evaluated the measures to mitigate the risks found following the screening process.Of those studies that evaluated the screening process, one study found that a general examination did not reduce sick leave (Mean Difference -0.1 95% CI -0.5 to 0.3) but another study found that a more task focused examination did (MD -36 95% CI -68.3 to -3.8). One study found that incorporation of a bronchial challenge test decreased occupational asthma (trend change -2.6 95% CI -3.6 to -1.5). Three studies that included functional capacity evaluation found contradictory effects on injury rates and number of medical visits. The rates of rejecting job applicants varied from 2% to 35%.Neither of the two studies that evaluated risk mitigation found an increased injury rate after training or work accommodations had been implemented.We rated the evidence for all outcomes as very low quality. There is very low quality evidence that pre-employment examinations that are specific to certain jobs or health problems could reduce occupational disease, injury, or sickness absence. This supports the current policy to restrict pre-employment examinations to job-specific examinations. More studies are needed that take into account the harms of rejecting job applicants.


Adverse events associated with procedural sedation in pediatric patients in the emergency department.
To determine the agents used by emergency medicine (EM) physicians in pediatric procedural sedation and the associated adverse events (AEs) and to provide recommendations for optimizing drug therapy in pediatric patients. We conducted a prospective study at Stanford Hospital's pediatric emergency department (ED) from April 2007 to April 2008 to determine the medications most frequently used in pediatric procedural sedation as well as their effectiveness and AEs. Patients, 18 years old or younger, who required procedural sedation in the pediatric ED were eligible for the study. The data collected included medical record number, sex, age, height, weight, procedure type and length, physician, and agents used. For each agent, the dose, route, time from administration to onset of sedation, duration of sedation, AEs, and sedation score were recorded. Use of supplemental oxygen and interventions during procedural sedation were also recorded. We found that in a convenience sample of 196 children (202 procedures) receiving procedural sedation in a university-based ED, 8 different medications were used (ketamine, etomidate, fentanyl, hydromorphone, methohexital, midazolam, pentobarbital, and thiopental). Ketamine was the most frequently used medication (88%), regardless of the procedure. Only twice in the study was the medication that was initially used for procedural sedation changed completely. Fracture reduction was the most frequently performed procedure (41%), followed by laceration/suture repair (32%). There were no serious AEs reported. EM-trained physicians can safely perform pediatric procedural sedation in the ED. In the pediatric ED, the most common procedure requiring conscious sedation is fracture reduction, with ketamine as the preferred agent.


Protein structure prediction by threading methods: evaluation of current techniques.
This paper evaluates the results of a protein structure prediction contest. The predictions were made using threading procedures, which employ techniques for aligning sequences with 3D structures to select the correct fold of a given sequence from a set of alternatives. Nine different teams submitted 86 predictions, on a total of 21 target proteins with little or no sequence homology to proteins of known structure. The 3D structures of these proteins were newly determined by experimental methods, but not yet published or otherwise available to the predictors. The predictions, made from the amino acid sequence alone, thus represent a genuine test of the current performance of threading methods. Only a subset of all the predictions is evaluated here. It corresponds to the 44 predictions submitted for the 11 target proteins seen to adopt known folds. The predictions for the remaining 10 proteins were not analyzed, although weak similarities with known folds may also exist in these proteins. We find that threading methods are capable of identifying the correct fold in many cases, but not reliably enough as yet. Every team predicts correctly a different set of targets, with virtually all targets predicted correctly by at least one team. Also, common folds such as TIM barrels are recognized more readily than folds with only a few known examples. However, quite surprisingly, the quality of the sequence-structure alignments, corresponding to correctly recognized folds, is generally very poor, as judged by comparison with the corresponding 3D structure alignments. Thus, threading can presently not be relied upon to derive a detailed 3D model from the amino acid sequence. This raises a very intriguing question: how is fold recognition achieved? Our analysis suggests that it may be achieved because threading procedures maximize hydrophobic interactions in the protein core, and are reasonably good at recognizing local secondary structure.


The stability of insulin in solid formulations containing melezitose and starch. Effects of processing and excipients.
Solid insulin formulations obtained by different methods of preparation were compared with respect to chemical stability and morphology. Spray- and freeze-drying, solution enhanced dispersion by supercritical fluids (SEDS) and precipitation into starch microspheres were the methods used for preparation of solid powders. The excipients applied were melezitose, starch, and sodium taurocholate. The stability of the samples was evaluated after storage in open containers at 25 degrees C and 30% RH for 6 months. All samples were amorphous after processing and storage as detected by XRD, except for the starch microspheres which were semi-crystalline. The spray- and freeze-dried samples containing melezitose and sodium taurocholate experienced a significant water uptake during storage, resulting in changes in morphology and disappearance of Tg. However, the chemical stability of these samples did not seem to be affected by the water uptake. Changes in morphology were not observed for the SEDS powders and the starch microspheres. The chemical stability of the samples was assessed by HPLC. In general, conventional spray- and freeze drying resulted in samples with higher chemical stability compared to SEDS powders and starch microspheres. Nevertheless, the excipients applied were observed to be of major importance, and further optimization of the formulation as well as processing conditions may lead to slightly different conclusions.


In vitro and In vivo Studies on a Novel Bioadhesive Colloidal System: Cationic Liposomes of Ibuprofen.
The objective of this study was to develop an ocular drug delivery system built on the cationic liposomes, a novel bioadhesive colloidal system, which could enhance the precorneal residence time, ocular permeation, and bioavailability of ibuprofen. The optimal formulation of cationic liposomes prepared by ethanol injection method was ultimately confirmed by an orthogonal L9 (33) test design. In addition, γ-scintigraphic technology and the microdialysis technique were utilized in the assessment of in vivo precorneal retention capability and ocular bioavailability individually. In the end, we acquired the optimal formulation of ibuprofen cationic liposomes (Ibu-CL) by orthogonal test design, and the particle size and entrapment efficiency (EE%) were 121.0 ± 3.5 nm and 72.9 ± 3.4%, respectively. In comparison to ibuprofen eye drops (Ibu-ED), Ibu-CL could significantly prolong the T max to 100 min and the AUC to 1.53-folds, which indicated that the Ibu-CL could improve the precorneal retention time and bioavailability of ibuprofen. Consequently, these outcomes designated that the ibuprofen cationic liposomes we researched probably are a promising application in ocular drug delivery system.


Maintenance of the enteric stem cell niche by bacterial lipopolysaccharides? Evidence and perspectives.
The enteric nervous system (ENS) has to respond to continuously changing microenvironmental challenges within the gut and is therefore dependent on a neural stem cell niche to keep the ENS functional throughout life. In this study, we hypothesize that this stem cell niche is also affected during inflammation and therefore investigated lipopolysaccharides (LPS) effects on enteric neural stem/progenitor cells (NSPCs). NSPCs were derived from the ENS and cultured under the influence of different LPS concentrations. LPS effects upon proliferation and differentiation of enteric NSPC cultures were assessed using immunochemistry, flow cytometry, western blot, Multiplex ELISA and real-time PCR. LPS enhances the proliferation of enteric NSPCs in a dose-dependent manner. It delays and modifies the differentiation of these cells. The expression of the LPS receptor toll-like receptor 4 on NSPCs could be demonstrated. Moreover, LPS induces the secretion of several cytokines. Flow cytometry data gives evidence for individual subgroups within the NSPC population. ENS-derived NSPCs respond to LPS in maintaining at least partially their stem cell character. In the case of inflammatory disease or trauma where the liberation and exposure to LPS will be increased, the expansion of NSPCs could be a first step towards regeneration of the ENS. The reduced and altered differentiation, as well as the induction of cytokine signalling, demonstrates that the stem cell niche may take part in the LPS-transmitted inflammatory processes in a direct and defined way.


Peroxisomal fatty acid oxidation and inhibitors of the mitochondrial carnitine palmitoyltransferase I in isolated rat hepatocytes.
Fatty acid oxidation was studied in the presence of inhibitors of carnitine palmitoyltransferase I (CPT I), in normal and in peroxisome-proliferated rat hepatocytes. The oxidation decreased in mitochondria, as expected, but in peroxisomes it increased. These two effects were seen, in variable proportions, with (+)-decanoylcarnitine, 2-tetradecylglycidic acid (TDGA) and etomoxir. The decrease in mitochondrial oxidation (ketogenesis) affected saturated fatty acids with 12 or more carbon atoms, whereas the increase in peroxisomal oxidation (H2O2 production) affected saturated fatty acids with 8 or more carbon atoms. The peroxisomal increase was sensitive to chlorpromazine, a peroxisomal inhibitor. To study possible mechanisms, palmitoyl-, octanoyl- and acetyl-carnitine acyltransferase activities were measured, in homogenates and in subcellular fractions from control and TDGA-treated cells. The palmitoylcarnitine acyltransferase was inhibited, as expected, but the octanoyltransferase activity also decreased. The CoA derivative of TDGA was synthesized and tentatively identified as being responsible for inhibition of the octanoylcarnitine acyltransferase. These results show that inhibitors of the mitochondrial CPT I may also inhibit the peroxisomal octanoyl transferase; they also support the hypothesis that the octanoyltransferase has the capacity to control or regulate peroxisomal fatty acid oxidation.


Brain Derived Neurotropic Factors in Speed vs. Inclined Treadmill in Young Adult Healthy Male With Occult Balance Disorder.
Background: There is an increase in fall risk among elders and young adults consecutively due to various causes. Occult balance disorder may be among the abnormal causes of falling in young adults as well as elders. The One Leg Stance (OLS) test is used to diagnose this balance performance; it's a proven test to measure static balance function which would lead to dynamic balance function. It has been proven that aside from cardiopulmonary exercises, treadmill workout can be used as a dynamic balance exercise. The Brain Derived Neurotropic Factor (BDNF) increases balance function through the treadmill exercise (the inclination and speed). This hormone is one of the tropical hormones generated in neurons, muscles, hematopoietic tissue and it is characterized by neurons morphology regulation and neuroplasticity. Materials and Methods: We divided 20 healthy young adult men to work out on inclination and speed groups treadmill exercise. The workout lasted for 2 weeks. We immediately observed the effect of exercise on serum BDNF as two tests were taken on before and 30 min after the workout. Result: There were significant increases of pre-exercise serum BDNF level in speed group between the first and the last exercise (p = 0.001), post-exercise between the first day and the last exercise (p = 0.001). No significant increase of serum BDNF in speed group pre- and post-exercise on the first exercise (p = 0.159), pre- and post-exercise on the last exercise (p = 0.892). There was no significant increase in serum BDNF in inclination group on all parameters (p > 0.05). The serum BDNF is actually a neurotropic factor that affects not just the neuronal system, but also molecular energy and metabolism regulation. This serum is dependent on the aerobic capacity, lactate production, muscle calcium uptake, and muscle fiber type used in exercises. Furthermore, the serum BDNF is increased by treadmill exercises in escalated speed. Conclusion: Treadmill exercises with average speed escalation increase the serum BDNF.


Multiorgan involvement due to cytomegalovirus infection in AIDS.
Cytomegalovirus (CMV) infection is a relatively late complication of AIDS. Like other viruses contributing to co-morbidity of HIV infection, cytomegalovirus has the propensity to cause multiorgan involvement. We report the case of a 34-year-old seropositive man who presented with bilateral lower limb weakness and symptomatic pallor. He was already on antiretroviral drugs for a month prior to presentation. Detailed clinical examination and laboratory investigations revealed cytomegalovirus polyradiculoneuropathy associated with bone marrow dysplasia. Dysplasia of haematopoeitic cell lines occurs in 30% to 70% of HIV infected patients, and is often indistinguishable from myelodysplastic syndrome. However, in our case, the bone marrow picture reverted back to normal with treatment of the CMV infection, pointing to a possible role of CMV as the causative agent of bone marrow dysplasia. Moreover, CMV has been incriminated as a pathogen producing the immune reconstitution inflammatory syndrome. The onset of the disease in our case one month after initiation of HAART strongly raises the possibility of this being a case of CMV related IRIS. This is the first reported case where IRIS has presented with CMV polyradiculoneuropathy and bone marrow dysplasia. We would like to highlight that in today's era of HIV care, clinicians should be aware of the possibility of multiorgan involvement by CMV, for appropriate management of this disease in the background of AIDS.


Prediction of Cervical Spinal Joint Loading and Secondary Motion Using a Musculoskeletal Multibody Dynamics Model Via Force-Dependent Kinematics Approach.
A cervical spine biomechanical investigation using multibody dynamics. To develop a comprehensive cervical spine multibody dynamics model incorporated with the force-dependent kinematics (FDK) approach, and to study the influence of soft tissue deformation on the joint loading prediction. Musculoskeletal multibody dynamics models have been widely used to analyze joint loading. Current cervical spine musculoskeletal models, however, neglect the joint internal motion caused by soft tissue deformation. A novel FDK approach is introduced, which can predict joint internal motion and spinal joint loading simultaneously. A comprehensive cervical spine musculoskeletal model with the posterior facet joints and essential ligaments was developed. To quantify the influence of soft tissue structures on joint loading prediction, four different models with different features were created. These newly developed models were validated, under flexion-extension movement. The predicted intervertebral disc loads (from C3-C4 to C5-C6) were compared with the published cadaveric experimental results. Moreover, the predicted facet joint forces, ligament forces, and anterior-posterior translations of instantaneous centers of rotation were also studied. The obtained intervertebral disc loads were varied among different models. Model 3 provided the closest prediction of joint loading to the experimental results. Moreover, the facet joint and ligament forces were in similar range of magnitude as literature findings. The predicted instantaneous centers of rotation translational changes were in accordance with the in vivo kinematics observation. In the present study, a validated cervical spine musculoskeletal model was developed, using multibody dynamics and FDK approach. It can simulate the function of musculature and consider joint internal motion, and thus provides more reliable joint loading prediction. This newly developed cervical model can be used as an efficient tool to study the biomechanical behaviors of human cervical spine, and to understand the fundamental pathologies of spinal pains. N /A.


Normal production of erythrocytes by mouse marrow continuous for 73 months.
Marrow cell transplants from old and young control donors were carried in genetically anemic W/W(v) recipients whose anemias were cured by successful transplants. After maximum of 36 months and four serial transplants, marrow cell lines from both old and younger control donors continued to produce erythrocytes normally. The oldest marrow cell lines had produced erythrocytes normally for 73 months. NORMAL ERYTHROCYTE PRODUCTION WAS DEMONSTRATED BY: (1) cure of the anemia in W/W(v) recipients, (2) normal rather than delayed recovery rate of cured recipients after severe bleeding, and (3) normal rather than ineffective response of cured recipients to erythropoietin. Hemoglobin patterns, tested in cured W/W(v) recipients after the first transplantation, showed that at least 90% of the circulating erythrocytes were of the donor type even in donor lines that had produced erythrocytes continuously for 45 months and were recovering from severe bleeding. Concentrations of cells capable of forming macroscopic spleen colonies were more than two orders of magnitude higher in W/W(v) mice cured by old or younger marrow than in uncured W/W(v) mice. Nevertheless, colony-forming unit concentrations declined slowly with successive transplants, and the decline seemed more pronounced at the fourth transplant in old than in younger cell lines.The hypothesis is suggested that senescence is caused by declines in function of only a few vital cell types. The system for comparing old and younger marrow cell lines offers a model for experiments to test this hypothesis and to identify the cell types whose decline causes aging.


Unraveling the Role of Microalgae in Mitigating Antibiotics and Antibiotic Resistance Genes in Photogranules Treating Antibiotic Wastewater.
Harnessing the potential of specific antibiotic-degrading microalgal strains to optimize microalgal-bacterial granular sludge (MBGS) technology for sustainable antibiotic wastewater treatment and antibiotic resistance genes (ARGs) mitigation is currently limited. This article examined the performance of bacterial granular sludge (BGS) and MBGS (of Haematococcus pluvialis, an antibiotic-degrading microalga) systems in terms of stability, nutrient and antibiotic removal, and fate of ARGs and mobile genetic elements (MGEs) under multiclass antibiotic loads. The systems exhibited excellent performance under none and 50 μg/L mixed antibiotics and a decrease in performance at a higher concentration. The MBGS showed superior potential, higher nutrient removal, 53.9 mg/L/day higher chemical oxygen demand (COD) removal, and 5.2-8.2% improved antibiotic removal, notably for refractory antibiotics, and the system removal capacity was predicted. Metagenomic analysis revealed lower levels of ARGs and MGEs in effluent and biomass of MBGS compared to the BGS bioreactor. Particle association niche and projection pursuit regression models indicated that microalgae in MBGS may limit gene transfers among biomass and effluent, impeding ARG dissemination. Moreover, a discrepancy was found in the bacterial antibiotic-degrading biomarkers of BGS and MBGS systems due to the microalgal effect on the microcommunity. Altogether, these findings deepened our understanding of the microalgae's value in the MBGS system for antibiotic remediation and ARG propagation control.


Genome-wide scan for quantitative trait loci influencing LDL size and plasma triglyceride in familial hypertriglyceridemia.
Small, dense LDLs and hypertriglyceridemia, two highly correlated and genetically influenced risk factors, are known to predict for risk of coronary heart disease. The objective of this study was to perform a whole-genome scan for linkage to LDL size and triglyceride (TG) levels in 26 kindreds with familial hypertriglyceridemia (FHTG). LDL size was estimated using gradient gel electrophoresis, and genotyping was performed for 355 autosomal markers with an average heterozygosity of 76% and an average spacing of 10.2 centimorgans (cMs). Using variance components linkage analysis, one possible linkage was found for LDL size [logarithm of odds (LOD) = 2.1] on chromosome 6, peak at 140 cM distal to marker F13A1 (closest marker D6S2436). With adjustment for TG and/or HDL cholesterol, the LOD scores were reduced, but remained in exactly the same location. For TG, LOD scores of 2.56 and 2.44 were observed at two locations on chromosome 15, with peaks at 29 and 61 cM distal to marker D15S822 (closest markers D15S643 and D15S211, respectively). These peaks were retained with adjustment for LDL size and/or HDL cholesterol. These findings, if confirmed, suggest that LDL particle size and plasma TG levels could be caused by two different genetic loci in FHTG.


Unimodal statistical learning produces multimodal object-like representations.
The concept of objects is fundamental to cognition and is defined by a consistent set of sensory properties and physical affordances. Although it is unknown how the abstract concept of an object emerges, most accounts assume that visual or haptic boundaries are crucial in this process. Here, we tested an alternative hypothesis that boundaries are not essential but simply reflect a more fundamental principle: consistent visual or haptic statistical properties. Using a novel visuo-haptic statistical learning paradigm, we familiarised participants with objects defined solely by across-scene statistics provided either visually or through physical interactions. We then tested them on both a visual familiarity and a haptic pulling task, thus measuring both within-modality learning and across-modality generalisation. Participants showed strong within-modality learning and 'zero-shot' across-modality generalisation which were highly correlated. Our results demonstrate that humans can segment scenes into objects, without any explicit boundary cues, using purely statistical information.


Diagnostic Tools for Bluetongue and Epizootic Hemorrhagic Disease Viruses Applicable to North American Veterinary Diagnosticians.
This review provides an overview of current and potential new diagnostic tests for bluetongue (BT) and epizootic hemorrhagic disease (EHD) viruses compiled from international participants of the Orbivirus Gap Analysis Workshop, Diagnostic Group. The emphasis of this review is on diagnostic tools available to North American veterinary diagnosticians. Standard diagnostic tests are readily available for BT/EHD viruses, and there are described tests that are published in the World Organization for Animal Health (OIE) Terrestrial Manual. There is however considerable variation in the diagnostic approach to these viruses. Serological assays are well established, and many laboratories are experienced in running these assays. Numerous nucleic acid amplification assays are also available for BT virus (BTV) and EHD virus (EHDV). Although there is considerable experience with BTV reverse-transcriptase PCR (RT-PCR), there are no standards or comparisons of the protocols used by various state and federal veterinary diagnostic laboratories. Methods for genotyping BTV and EHDV isolates are available and are valuable tools for monitoring and analyzing circulating viruses. These methods include RT-PCR panels or arrays, RT-PCR and sequencing of specific genome segments, or the use of next-generation sequencing. In addition to enabling virus characterization, use of advanced molecular detection methods, including DNA microarrays and next-generation sequencing, significantly enhance the ability to detect unique virus strains that may arise through genetic drift, recombination, or viral genome segment reassortment, as well as incursions of new virus strains from other geographical areas.


External validation of the ACUTE HF score in patients hospitalized for acute decompensated heart failure.
Recently, the ACUTE HF score has been developed as a new tool for predicting short and long term mortality in patients with acute heart failure (AHF). However, this. score has not yet been validated externally. The present study aimed to investigate the prognostic value of ACUTE HF score in a different patient cohort. We retrospectively enrolled all consecutive adult patients hospitalized due to AHF between January 2016 and January 2019. The ACUTE HF score is calculated by 7 different variables including age, creatinine, non-invasive ventilation, history of stroke or transient ischemic attack, left ventricular systolic function, mitral regurgitation and history of hospitalization.The primary endpoint of the study was in-hospital mortality. A total of 418 AHF patients (mean age 70.2 ± 11.3 years, 52% male) were included, and 26 (6.2%) patients died during the in-hospital course. Patients in the study were divided into three groups according to ACUTE HF score: low-risk (<1.5, n = 210), intermediate-risk (1.5-3, n = 50), and high-risk groups (>3, n = 158). The multivariate analysis showed that the ACUTE HF score was an independent predictor of in-hospital mortality(OR: 2.15; 95% CI, 0.94-4.34; p < 0.001). The ACUTE HF score was a useful prognostic score for the prediction of in-hospital mortality in patients with AHF. Further validation studies in different regions of the world and with different AHF populations are needed to determine its generalisability.


Redescription of 'Polyzonium' malagassum, a new synonym of Rhinotus purpureus (Pocock, 1894), with notes about the occurrence of the order Polyzoniida on Madagascar (Diplopoda).
Polyzonium malagassum de Saussure & Zehntner, 1902, the only indigenous record of the order Polyzoniida from Madagascar, is redescribed after a study of the type specimens. The only male specimen is selected as the lectotype and illustrated. P. malagassum is discovered to be a synonym of the widespread tropical tramp species Rhinotus purpureus (Pocock, 1894). A mapping of additional locality data of R. pupureus shows that the species is widespread in Malagasy rainforests and montane rainforests, and occurs locally in high densities. Seven potentially indigenous Polyzoniida morphospecies also occur on Madagascar, but these undescribed species are more localized and show a lower abundance than R. purpureus. Brief notes, locality data, and Museum acronyms are given for the undescribed Polyzoniida species, which will hopefully assist future studies on Malagasy representatives of this little-known but biogeographically interesting order. With the discovery of the ubiquitous presence of R. purpureus on Madagascar, the similarity of the defense secretions of South American and of endemic Malagasy poison dart frogs (family Mantellidae) might derive from the fact that both groups prey on and sequester alkaloids from the same species of millipede.


Two Lineages of Oribatid Mites Morphologically Correspond to the Circumpolar Species Ameronothrus nigrofemoratus (Acari, Oribatida) but Differ Genetically as Distinct Species Are Revealed on the Kolguev Island.
Data reported from Northern Canada were until recently the only available data on the genetic characteristics of the oribatid mite Ameronothrus nigrofemoratus, which has a circumpolar distribution on the coasts of Arctic seas. A partial cytochrome oxidase I gene (COI) mtDNA sequence was examined in mites morphologically assigned to this species from the Kolguev Island. Two highly divergent phylogenetic lineages of A. nigrofemoratus (7% divergence) were revealed, neither of which was found on the Canadian coast. Four COI amino acid substitutions distinguished one of the lineages from North American A. nigrofemoratus, corresponding to the degree of difference between A. nigrofemoratus and its sister species A. lineatus.


Depression in feed intake by a highly fermentable diet is related to plasma insulin concentration and insulin response to glucose infusion.
The effects of dietary starch fermentability on feed intake and nutrient digestibility were evaluated in a crossover study, which was also designed to find factors that predict individual variation in feed intake response to starch fermentability. Thirty-two multiparous Holstein cows (121 +/- 48 d in milk, 44 +/- 7 kg/d of milk yield; mean +/- SD) were randomly assigned to treatment sequence and were fed a diet intermediate to the treatments during a preliminary 28-d period. Treatments were dry ground corn grain and high-moisture corn harvested from the same field. Treatment periods were 14 d, with the final 4 d used for data and sample collection. Diets included corn silage and alfalfa haylage at a 2:1 ratio and were 26% neutral detergent fiber, 17% crude protein, 32% starch, and 3.5% fatty acids. High-moisture corn decreased dry matter intake (DMI) by 8%, but did not significantly alter digestible DMI. Individual DMI responses were highly variable, and variables from preliminary plasma analyses, propionate challenge tests, glucose tolerance tests, and hepatic mRNA analysis were assessed as potential predictors of DMI response to increased dietary starch fermentability. Of the covariates tested, only preliminary plasma insulin concentration and insulin response to glucose infusion were significant predictors of DMI response. High preliminary plasma insulin concentration was correlated with greater depression in DMI with increased fermentability; conversely, greater insulin secretion in response to glucose infusion was associated with minimal depression in DMI. These insulin variables were not significantly correlated. Consistent with past results, increased dietary starch fermentability decreased DMI. Significant correlations between insulin variables and individual DMI responses may warrant further investigation.


Optomotor Swimming in Larval Zebrafish Is Driven by Global Whole-Field Visual Motion and Local Light-Dark Transitions.
Stabilizing gaze and position within an environment constitutes an important task for the nervous system of many animals. The optomotor response (OMR) is a reflexive behavior, present across many species, in which animals move in the direction of perceived whole-field visual motion, therefore stabilizing themselves with respect to the visual environment. Although the OMR has been extensively used to probe visuomotor neuronal circuitry, the exact visual cues that elicit the behavior remain unidentified. In this study, we use larval zebrafish to identify spatiotemporal visual features that robustly elicit forward OMR swimming. These cues consist of a local, forward-moving, off edge together with on/off symmetric, similarly directed, global motion. Imaging experiments reveal neural units specifically activated by the forward-moving light-dark transition. We conclude that the OMR is driven not just by whole-field motion but by the interplay between global and local visual stimuli, where the latter exhibits a strong light-dark asymmetry.


Pan-Inhibition of Protein Disulfide Isomerase Caused Cell Death through Disrupting Cellular Proteostasis in Pancreatic Ductal Adenocarcinoma Cells.
The protein disulfide isomerase (PDI) family is a group of thioredoxin endoplasmic reticulum (ER)-resident enzymes and molecular chaperones that play crucial roles in the correct folding of proteins. PDIs are upregulated in multiple cancer types and are considered a novel target for cancer therapy. In this study, we found that a potent pan-PDI inhibitor, E64FC26, significantly decreased the proliferation of pancreatic ductal adenocarcinoma (PDAC) cells. As expected, E64FC26 treatment increased ER stress and the unfolded protein response (UPR), as evidenced by upregulation of glucose-regulated protein, 78-kDa (GRP78), phosphorylated (p)-PKR-like ER kinase (PERK), and p-eukaryotic initiation factor 2α (eIF2α). Persistent ER stress was found to lead to apoptosis, ferroptosis, and autophagy, all of which are dependent on lysosomal functions. First, there was little cleaved caspase-3 in E64FC26-treated cells according to Western blotting, but a higher dose of E64FC26 was needed to induce caspase activity. Then, E64FC26-induced cell death could be reversed by adding the iron chelator, deferoxamine, and the reactive oxygen species scavengers, ferrostatin-1 and N-acetylcysteine. Furthermore, the autophagosome-specific marker, light chain 3B (LC3B)-II, increased, but the autolysosome marker, sequestosome 1 (SQSTM1)/p62, was not degraded in E64FC26-treated cells. Using the FUW mCherry-LC3 plasmid and acridine orange staining, we also discovered a lower number of acidic vesicles, such as autolysosomes and mature lysosomes, in E64FC26-treated cells. Finally, E64FC26 treatment increased the cathepsin L precursor (pre-CTSL) but decreased mature CTSL expression according to Western blotting, indicating a defective lysosome. These results suggested that the PDI inhibitor, E64FC26, might initially impede proper folding of proteins, and then induce ER stress and disrupt proteostasis, subsequently leading to lysosomal defects. Due to defective lysosomes, the extents of apoptosis and ferroptosis were limited, and fusion with autophagosomes was blocked in E64FC26-treated cells. Blockade of autolysosomal formation further led to the autophagic cell death of PDAC cells.


High-Quality Draft Genome Sequences of Eight Bacteria Isolated from Fungus Gardens Grown by Trachymyrmex septentrionalis Ants.
For their food source, Trachymyrmex septentrionalis ants raise symbiotic fungus gardens that contain bacteria whose functions are poorly understood. Here, we report the genome sequences of eight bacteria isolated from these fungus gardens to better describe the ecology of these strains and their potential to produce secondary metabolites in this niche.


Clomiphene-induced mood swings.
A study of couples' perceptions of infertility treatment with clomiphene (clomiphene citrate) revealed mood swings in 9 out of 14 women using the drug. This paper describes the mood swings and the responses of women and their spouses. Three phases of mood swing response emerged from the data: lacking awareness of the relation of the mood swings to the drug; gaining awareness of that relation; and managing the mood swings. The results of the study provide important information for nurses counseling couples who are experiencing clomiphene-induced mood swings.


Fossils and the mosaic nature of human evolution.
These new fossils, dates, analyses, and interpretations lead to confirmation and refinement of the mosaic scheme of human evolution as proposed by early evolutionists such as Lamarck, Haeckel, and Darwin. Evolutionary changes in the body adapting our ancestors to bipedalism occurred before 3 million years ago, judging by the completeness of the adaptation in the late Pliocene-early Pleistocene hominids. The skeletons of these early hominids were not identical to those of modern humans, but locomotor behavior was probably human. At about 3 million years ago their brains were relatively small, although internal reorganization may have been taking place. By 2 million years ago a wider range of variation in brain size appears in the fossil record, with an average size somewhat larger than that in earlier hominids. Concomitant with this beginning of brain size increase was the reshaping of the pelvic region, perhaps related to an increase in birth canal size to accommodate larger-brained fetuses. Evidence for tool manufacturing, meat eating, shelter building, and probably food sharing also occurs at about this time, which signals the coming of a new adaptive strategy.


'Captivity bias' in animal tool use and its implications for the evolution of hominin technology.
Animals in captive or laboratory settings may outperform wild animals of the same species in both frequency and diversity of tool use, a phenomenon here termed 'captivity bias'. Although speculative at this stage, a logical conclusion from this concept is that animals whose tool-use behaviour is observed solely under natural conditions may be judged cognitively or physically inferior than if they had also been tested or observed under controlled captive conditions. In turn, this situation creates a potential problem for studies of the behaviour of extinct members of the human family tree-the hominins-as hominin cognitive abilities are often judged on material evidence of tool-use behaviour left in the archaeological record. In this review, potential factors contributing to captivity bias in primates (including increased contact between individuals engaged in tool use, guidance or shaping of tool-use behaviour by other tool-users and increased free time and energy) are identified and assessed for their possible effects on the behaviour of the Late Pleistocene hominin Homo floresiensis. The captivity bias concept provides one way to uncouple hominin tool use from cognition, by considering hominins as subject to the same adaptive influences as other tool-using animals.


Does chronomodulated radiotherapy improve pathological response in locally advanced rectal cancer?
The predominant mode of radiation-induced cell death for solid tumours is mitotic catastrophe, which is in part dependent on sublethal damage repair being complete at around 6 h. Circadian variation appears to play a role in normal cellular division, and this could influence tumour response of radiation treatment depending on the time of treatment delivery. We tested the hypothesis that radiation treatment later in the day may improve tumour response and nodal downstaging in rectal cancer patients treated neoadjuvantly with radiation therapy. Recruitment was by retrospective review of 267 rectal cancer patients treated neoadjuvantly in the Department of Radiation Oncology at the Canberra Hospital between January 2010 and November 2015. One hundred and fifty-five patients met the inclusion criteria for which demographic, pathological and imaging data were collected, as well as the time of day patients received treatment with each fraction of radiotherapy. Data analysis was performed using the Statistical Package R with nonparametric methods of significance for all tests set at p < 0.05. Of the 45 female and 110 male patients, the median age was 64. Seventy-three percent had cT3 disease and there was a mean tumour distance from the anal verge of 7 cm. Time to surgical resection following radiotherapy ranged from 4 to 162 days with a median of 50 days, with a complete pathological response seen in 21% of patients. Patients exhibiting a favourable pathological response had smaller median pre- and postradiotherapy tumour size and had a greater change in tumour size following treatment (p < 0.01). Patients who received the majority of their radiotherapy fractions after 12:00 pm were more likely to show a complete or moderate pathological response (p = 0.035) and improved nodal downstaging. There were also more favourable responses amongst patients with longer time to surgical resection postradiotherapy (p < 0.004), although no relationship was seen between response and tumour distance from the anal verge. Females were less likely to exhibit several of the above responses. Neoadjuvant radiotherapy for locally advanced rectal cancer performed later in the day coupled with a longer time period to surgical resection may improve pathological tumour response rates and nodal downstaging. A prospective study in chronomodulated radiotherapy in this disease is warranted.


Gene mapping of the putative structural region of the hepatitis C virus genome by in vitro processing analysis.
Processing of the putative structural proteins of hepatitis C virus was examined by using an in vitro expression system. An RNA transcript for cell-free translation was prepared from a cDNA construct that encompasses the region encoding the 980 amino-terminal residues of the viral polyprotein precursor. Processing of the in vitro translation product proceeded cotranslationally in the presence of microsomal membranes and generated four major membrane-associated products. Two of these four major products, named gp35 and gp70, were shown to be transported into microsomes and heavily glycosylated, suggesting that the processing events are partly mediated by the signal peptidase of the endoplasmic reticulum. The other two products, p19 and p21, were probably associated with the outer surface of the microsomal membrane. Analysis of processed proteins translated from a series of truncated forms of the cDNA construct as well as determination of amino-terminal amino acid sequences of gp35 and gp70 indicated that these four products are arranged from the amino-terminal end of the polyprotein precursor in the order: NH2-p22-gp35-gp70-p19. Both gp35 and gp70 could be candidates of initially processed forms of envelope proteins of the hepatitis C virus.


Structural neuroanatomy of tinnitus and hyperacusis in semantic dementia.
Tinnitus and hyperacusis are common symptoms of excessive auditory perception in the general population; however, their anatomical substrates and disease associations continue to be defined. with semantic dementia (SemD) frequently report tinnitus and hyperacusis but the significance and basis for these symptoms have not been elucidated. 43 patients with a diagnosis of SemD attending a specialist cognitive disorders clinic were retrospectively studied. 14 patients (32% of the cohort) reported at least moderately severe chronic auditory symptoms: seven had tinnitus and a further seven had hyperacusis, and all had brain MRI while symptomatic. MRI data from SemD patients with and without auditory symptoms were compared using voxel based morphometry in order to identify neuroanatomical associations of tinnitus and hyperacusis. Compared with SemD patients with no history of auditory symptoms, patients with tinnitus or hyperacusis had relative preservation of grey matter in the posterior superior temporal lobe and reduced grey matter in the orbitofrontal cortex and medial geniculate nucleus. Tinnitus and hyperacusis may be a significant issue in SemD. Neuroanatomical evidence in SemD supports previous work implicating a distributed cortico-subcortical auditory and limbic network in the pathogenesis of these abnormal auditory percepts.


Medical and pharmacy students' attitudes towards physician-pharmacist collaboration in Kuwait.
To assess and compare the attitudes of medical and pharmacy students towards physician-pharmacist collaboration and explore their opinions about the barriers to collaborative practice in Kuwait. A cross-sectional survey of pharmacy and medical students (n=467) was conducted in Faculties of Medicine and Pharmacy, Kuwait University. Data were collected via self-administered questionnaire from first-year pharmacy and medical students and students in the last two professional years of the pharmacy and medical programs. Descriptive and comparative analyses were performed using SPSS, version 22. Statistical significance was accepted at p<0.05. The response rate was 82.4%. Respondents had overall positive attitudes towards physician-pharmacist collaboration. Pharmacy students expressed significantly more positive attitudes than medical students (p< 0.001). Medical students rated the three most significant barriers to collaboration to be: pharmacists' separation from patient care areas (n=100, 70.0%), lack of pharmacists' access to patients' medical record (n=90, 63.0%) and physicians assuming total responsibility for clinical decision-making (n=87, 60.8%). Pharmacy students' top three perceived barriers were: lack of pharmacists' access to patients' medical record (n=80, 84.2%), organizational obstacles (n=79, 83.2%), and pharmacists' separation from patient care areas (n=77, 81.1%). Lack of interprofessional education was rated the fourth-largest barrier by both medical (n=79, 55.2%) and pharmacy (n=76, 80.0%) students. Medical and pharmacy students in Kuwait advocate physician-pharmacist collaborative practice, but both groups identified substantial barriers to implementation. Efforts are needed to enhance undergraduate/postgraduate training in interprofessional collaboration, and to overcome barriers to physician-pharmacist collaboration to advance a team approach to patient care.


[To see oneself in a context--medicine and historia--the two cultures].
Historians and physicians have different social vantage points and have developed widely different professional cultures. This diversity is a distinct feature of their research, their theoretical approaches, and their scholarly methods. The historian's and the physician's points of view both seem to be necessary parts of medical history. The subject itself as well as the scholars involved may profit from teamwork. The author also asks whether historical knowledge in the field of medicine is useful for today's practitioners. Her answer is yes. Historical insight might contribute to a better understanding of day-to-day problems and the complex structures of which physicians are part. Furthermore, it is suggested that physicians will benefit from insights into why their discipline and their professional position have developed in the ways they have. At its best, historical knowledge can contribute to a deeper understanding of the limitations of medicine, and so may add to physicians' ability to adjust their role in line with the present time. Historical knowledge might even contribute to increased respect for other branches of knowledge and for other people's skills and professional problems.


ML2Motif-Reliable extraction of discriminative sequence motifs from learning machines.
High prediction accuracies are not the only objective to consider when solving problems using machine learning. Instead, particular scientific applications require some explanation of the learned prediction function. For computational biology, positional oligomer importance matrices (POIMs) have been successfully applied to explain the decision of support vector machines (SVMs) using weighted-degree (WD) kernels. To extract relevant biological motifs from POIMs, the motifPOIM method has been devised and showed promising results on real-world data. Our contribution in this paper is twofold: as an extension to POIMs, we propose gPOIM, a general measure of feature importance for arbitrary learning machines and feature sets (including, but not limited to, SVMs and CNNs) and devise a sampling strategy for efficient computation. As a second contribution, we derive a convex formulation of motifPOIMs that leads to more reliable motif extraction from gPOIMs. Empirical evaluations confirm the usefulness of our approach on artificially generated data as well as on real-world datasets.


Acute myeloid leukemia and acute promyelocytic leukemia.
The therapeutic approach to the patient with acute myeloid leukemia (AML) currently evolves toward new frontiers. This is particularly apparent from the entree of high-throughput diagnostic technologies and the identification of prognostic and therapeutic targets, the introduction of therapies in genetically defined subgroups of AML, as well as the influx of investigational approaches and novel drugs into the pipeline of clinical trials that target pathogenetic mechanisms of the disease. In Section I, Dr. Bob Löwenberg reviews current issues in the clinical practice of the management of adults with AML, including those of older age. Dr. Löwenberg describes upcoming possibilities for predicting prognosis in defined subsets by molecular markers and reviews experimental strategies to improve remission induction and postinduction treatment. In Section II, Dr. James Griffin reviews the mechanisms that lead to activation of tyrosine kinases by mutations in AML, the consequences of that activation for the cell, and the opportunities for targeted therapy and discusses some examples of developing novel drugs (tyrosine kinase inhibitors) and their effectiveness in AML (FLT3). In Section III, Dr. Martin Tallman describes the evaluation and management of patients with acute promyelocytic leukemia, a notable example of therapeutic progress in a molecularly defined entity of leukemia. Dr. Tallman focuses on the molecular genetics of APL, current curative treatment strategies and approaches for patients with relapsed and refractory disease. In addition, areas of controversy regarding treatment are addressed.


Recent Clinical Trials Insights into the Treatment of Primary Membranous Nephropathy.
Immunosuppressive therapy is mandatory for primary membranous nephropathy with persistent nephrotic proteinuria or anti-phospholipase A2 receptor antibodies, reduced kidney function, or another risk factor for progression. Rituximab has demonstrated efficacy for proteinuria remission compared with renin-angiotensin system blockade or cyclosporine in two well-powered randomized controlled trials. More recently, STARMEN showed that alternating glucocorticoid-cyclophosphamide is superior to sequential tacrolimus-rituximab for proteinuria remission, although it was associated with a higher risk of non-serious adverse events. However, sequential tacrolimus-rituximab involved delayed lower dose rituximab and was the worst-performing rituximab regimen among those tested in randomized clinical trials. The RI-CYCLO pilot study did not demonstrate superiority of glucocorticoid-cyclophosphamide over rituximab and found no difference in adverse events. Overall, STARMEN and RI-CYCLO confirmed the efficacy of glucocorticoid-cyclophosphamide in patients with high-risk membranous nephropathy and the role of rituximab as a valid alternative. However, none of the trials tested an optimized rituximab protocol involving a second rituximab cycle before declaring treatment failure. Calcineurin inhibitors should be considered third-line drugs and sequential use of calcineurin inhibitor rituximab did not add over rituximab-only regimens. We critically review recent randomized controlled trials, propose a research agenda, and call for multinational pragmatic trials that enroll patients at referral centers to address unmet research needs.


Early animal evolution and highly oxygenated seafloor niches hosted by microbial mats.
The earliest unambiguous evidence for animals is represented by various trace fossils in the latest Ediacaran Period (550-541 Ma), suggesting that the earliest animals lived on or even penetrated into the seafloor. Yet, the O2 fugacity at the sediment-water interface (SWI) for the earliest animal proliferation is poorly defined. The preferential colonization of seafloor as a first step in animal evolution is also unusual. In order to understand the environmental background, we employed a new proxy, carbonate associated ferrous iron (Fecarb), to quantify the seafloor oxygenation. Fecarb of the latest Ediacaran Shibantan limestone in South China, which yields abundant animal traces, ranges from 2.27 to 85.43 ppm, corresponding to the seafloor O2 fugacity of 162 μmol/L to 297 μmol/L. These values are significantly higher than the oxygen saturation in seawater at the contemporary atmospheric pO2 levels. The highly oxygenated seafloor might be attributed to O2 production of the microbial mats. Despite the moderate atmospheric pO2 level, microbial mats possibly provided highly oxygenated niches for the evolution of benthic metazoans. Our model suggests that the O2 barrier could be locally overcome in the mat ground, questioning the long-held belief that atmospheric oxygenation was the key control of animal evolution.