Effect of suppression of postpartum ovulation on endometrial inflammation in dairy cows.
The objective of this study was to investigate the effect of time of first postpartum ovulation on endometrial inflammation in dairy cows with and without uterine disease during the early puerperal period. Transvaginal follicular puncture (FP) was carried out to suppress postpartum ovulation and formation of a CL until Day 42. Fifty-three lactating Holstein Friesian cows were divided into four groups on the basis of presence (UD+) or absence (UD-) of uterine disease, which was defined as retained fetal membranes and/or metritis, and whether FP had (FP+) or had not been (FP-) carried out. This resulted in the following groups: UD-FP- (n = 15), UD-FP+ (n = 13), UD+FP- (n = 13), and UD+FP+ (n = 12). Cloprostenol was given on Days 55 to 60 postpartum, and GnRH was administered 2 days later for synchronization of ovulation. In the FP- groups, endometrial swab and biopsy samples were collected during the second estrus (approximately Day 40) and during the estrus after synchronization. In the FP+ groups, the same samples were collected during the first estrus (approximately Day 49) and during the estrus after synchronization. The prevalence of positive bacteriologic cultures of the endometrium was not affected by FP (P > 0.05). Histologic signs of endometritis were more severe in UD+FP- cows at second sampling than in UD+FP+ cows (P ≤ 0.05). Endometrial expression of IL1α (in UD- after first sampling and in UD+ after second sampling) and IL1β (in UD- and UD+ after first sampling) was higher (P ≤ 0.05) in FP- cows than in FP+ cows. Regardless of group, cows with histopathologic evidence of endometritis had higher expression (P ≤ 0.05) of IL1α, IL1β, IL6, and TNFα than cows without endometritis. In conclusion, suppression of early ovulation by transvaginal FP enhances clearance of uterine inflammation in postpartum cows.


Genetic Architecture of Flowering Time and Sex Determination in Hemp (Cannabis sativa L.): A Genome-Wide Association Study.
Flowering time and sex determination in hemp (Cannabis sativa L.) strongly influence fiber quality and seed production of this crop. The control of these traits is paramount for the breeding of new cultivars. Yet, little is known about the genetics underlying such complex traits and a better understanding requires in depth knowledge of the molecular mechanisms responsible for these traits. In this report, the genetic architecture of flowering time and sex determination in hemp was studied using a Genome-Wide Association Studies (GWAS) approach. Association studies were performed on a panel of 123 hemp accessions, tested in three contrasting environments, using a set of 600 K SNP markers. Altogether, eight QTLs were identified across environments; six for flowering time traits and two for sex determination. These QTLs covered genomic regions with 33 transcripts predicted to be involved in flowering and sex determination as well as a microRNA, miR156. Genes related to perception and transduction of light and transcription factors well-known to regulate flowering were identified in QTLs for flowering time traits. Transcription factors and genes involved in regulating the balance of phytohormones, specially auxins and gibberellic acid, were identified in QTLs for sex determination. Sex determination QTLs were associated with the development of male flowers in female plants and thus with the stability of sex determination in monecious plants. The present study elucidates relevant knowledge on the genetic mechanisms of flowering and sex determination traits in hemp, and provides new tools for hemp breeding.


Effect of a retinoid X receptor partial agonist on airway inflammation and hyperresponsiveness in a murine model of asthma.
Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signaling by 9-cis retinoic acid, a vitamin A (retinol) derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners-e.g., retinoic acid receptors (RARs), vitamin D receptors (VDRs), liver X receptors (LXRs), and peroxisome proliferator-activated receptors (PPARs). The NR family was recently associated with allergic diseases, but the role of RXRs in allergen-induced airway responses is not well defined. The goal of this study is to elucidate the role of RXRs in asthma pathogenesis and the potency of RXR partial agonist in the treatment of allergic airway inflammation and airway hyperresponsiveness using a murine model of asthma. We investigated the effect of a novel RXR partial agonist (NEt-4IB) on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in a murine model of asthma. Balb/c mice were sensitized (days 0 and 14) and challenged (days 28-30) with ovalbumin (OVA), and airway inflammation and airway responses were monitored 48 h after the last OVA challenge. NEt-4IB was administered orally on days 25 to 32. Oral administration of NEt-4IB significantly suppressed AHR and inflammatory cell accumulation in the airways and attenuated the levels of TNF-α in the lung and IL-5, IL-13 and NO levels in bronchoalveolar lavage (BAL) fluid and the number of periodic acid Schiff (PAS)-positive goblet cells in lung tissue. Treatment with NEt-4IB also significantly suppressed NF-κB expression. These data suggest that RXRs may be of crucial importance in the mechanism of allergic asthma and that the novel RXR partial agonist NEt-4IB may be a promising candidate for the treatment of allergic airway inflammation and airway hyperresponsiveness in a model of allergic asthma.


The national drug abuse treatment clinical trials network data share project: website design, usage, challenges, and future directions.
There are many benefits of data sharing, including the promotion of new research from effective use of existing data, replication of findings through re-analysis of pooled data files, meta-analysis using individual patient data, and reinforcement of open scientific inquiry. A randomized controlled trial is considered as the 'gold standard' for establishing treatment effectiveness, but clinical trial research is very costly, and sharing data is an opportunity to expand the investment of the clinical trial beyond its original goals at minimal costs. We describe the goals, developments, and usage of the Data Share website (http://www.ctndatashare.org) for the National Drug Abuse Treatment Clinical Trials Network (CTN) in the United States, including lessons learned, limitations, and major revisions, and considerations for future directions to improve data sharing. Data management and programming procedures were conducted to produce uniform and Health Insurance Portability and Accountability Act (HIPAA)-compliant de-identified research data files from the completed trials of the CTN for archiving, managing, and sharing on the Data Share website. Since its inception in 2006 and through October 2012, nearly 1700 downloads from 27 clinical trials have been accessed from the Data Share website, with the use increasing over the years. Individuals from 31 countries have downloaded data from the website, and there have been at least 13 publications derived from analyzing data through the public Data Share website. Minimal control over data requests and usage has resulted in little information and lack of control regarding how the data from the website are used. Lack of uniformity in data elements collected across CTN trials has limited cross-study analyses. The Data Share website offers researchers easy access to de-identified data files with the goal to promote additional research and identify new findings from completed CTN studies. To maximize the utility of the website, ongoing collaborative efforts are needed to standardize the core measures used for data collection in the CTN studies with the goal to increase their comparability and to facilitate the ability to pool data files for cross-study analyses.


Sleep and circadian rhythm function and trait impulsivity: An actigraphy study.
We report the relationship between daily rest-activity patterns and trait impulsivity in healthy young adults. The Barratt Impulsiveness Scale was used to identify high and low impulsive individuals among a group of 51 volunteers. Participants' sleep behaviour and circadian rhythm function was assessed using week-long actigraphy. High impulsive individuals displayed phase-delayed patterns of sleep, a decreased total sleep time and sleep efficiency, and disrupted circadian function. Such outcomes were also associated with greater self-reported attention deficit hyperactivity disorder symptoms. The results highlight that sleep and circadian rhythm disturbances may be associated with impulsive traits replicating relationships described in psychiatric illnesses in which impulsivity is a core feature.


Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines.
While the role of nuclear transcription factor activator protein-1 (AP-1) in cell proliferation, and of nuclear factor-kappaB (NF-kappaB) in the suppression of apoptosis are known, their role in survival of prostate cancer cells is not well understood. We investigated the role of NF-kappaB and AP-1 in the survival of human androgen-independent (DU145) and -dependent (LNCaP) prostate cancer cell lines. Our results show that the faster rate of proliferation of DU145 cells when compared to LNCaP cells correlated with the constitutive expression of activated NF-kappaB and AP-1 in DU-145 cells. The lack of constitutive expression of NF-kappaB and AP-1 in LNCaP cells also correlated with their sensitivity to the antiproliferative effects of tumor necrosis factor (TNF). TNF induced NF-kappaB activation but not AP-1 activation in LNCaP cells. In DU145 cells both c-Fos and c-Jun were expressed and treatment with TNF activated c-Jun NH2-terminal kinase (JNK), needed for AP-1 activation. In LNCaP cells, however, only low levels of c-Jun was expressed and treatment with TNF minimally activated JNK. Treatment of cells with curcumin, a chemopreventive agent, suppressed both constitutive (DU145) and inducible (LNCaP) NF-kappaB activation, and potentiated TNF-induced apoptosis. Curcumin alone induced apoptosis in both cell types, which correlated with the downregulation of the expression of Bcl-2 and Bcl-xL and the activation of procaspase-3 and procaspase-8. Overall, our results suggest that NF-kappaB and AP-1 may play a role in the survival of prostate cancer cells, and curcumin abrogates their survival mechanisms.


Rhamnolipid surfactant production affects biofilm architecture in Pseudomonas aeruginosa PAO1.
In response to certain environmental signals, bacteria will differentiate from an independent free-living mode of growth and take up an interdependent surface-attached existence. These surface-attached microbial communities are known as biofilms. In flowing systems where nutrients are available, biofilms can develop into elaborate three-dimensional structures. The development of biofilm architecture, particularly the spatial arrangement of colonies within the matrix and the open areas surrounding the colonies, is thought to be fundamental to the function of these complex communities. Here we report a new role for rhamnolipid surfactants produced by the opportunistic pathogen Pseudomonas aeruginosa in the maintenance of biofilm architecture. Biofilms produced by mutants deficient in rhamnolipid synthesis do not maintain the noncolonized channels surrounding macrocolonies. We provide evidence that surfactants may be able to maintain open channels by affecting cell-cell interactions and the attachment of bacterial cells to surfaces. The induced synthesis of rhamnolipids during the later stages of biofilm development (when cell density is high) implies an active mechanism whereby the bacteria exploit intercellular interaction and communication to actively maintain these channels. We propose that the maintenance of biofilm architecture represents a previously unrecognized step in the development of these microbial communities.


Polyphosphate modifies the fibrin network and down-regulates fibrinolysis by attenuating binding of tPA and plasminogen to fibrin.
Activated platelets secrete a negatively charged polymer, polyphosphate (polyP). Here, we explore the interactions of polyP with fibrin(ogen) and its effect on fibrin structure and fibrinolysis. Electrophoretic mobility and binding assays indicate that polyP interacts with fibrinogen and soluble fibrin. Clots formed in the presence of polyP exhibited reduced turbidity and permeability indicative of a tighter fibrin network, but these changes were not related to cross-linking or fibrinopeptide release. Microscopy showed a change in fibrin distribution in clots formed with polyP; with formation of tight aggregates of fibrin fibers interspaced with large pores in contrast to homogenous fiber distribution in control clots. Lysis by tissue plasminogen activator (tPA) and plasminogen or plasmin was delayed in clots formed with polyP and depended on both the activator and polyP concentration. Adding polyP to the clot after fibrin formation or to repolymerizing soluble fibrin did not affect lysis, indicating changes induced by polyP occur at the level of conversion of fibrinogen to fibrin. Surface plasmon resonance showed that the presence of polyP reduced the binding of both plasminogen and tPA to partially lysed fibrin surfaces. These data show that polyP directly influences fibrin architecture and attenuates fibrinolysis through reduced binding of fibrinolytic proteins.


Stability of the human faecal microbiome in a cohort of adult men.
Characterizing the stability of the gut microbiome is important to exploit it as a therapeutic target and diagnostic biomarker. We metagenomically and metatranscriptomically sequenced the faecal microbiomes of 308 participants in the Health Professionals Follow-Up Study. Participants provided four stool samples-one pair collected 24-72 h apart and a second pair ~6 months later. Within-person taxonomic and functional variation was consistently lower than between-person variation over time. In contrast, metatranscriptomic profiles were comparably variable within and between subjects due to higher within-subject longitudinal variation. Metagenomic instability accounted for ~74% of corresponding metatranscriptomic instability. The rest was probably attributable to sources such as regulation. Among the pathways that were differentially regulated, most were consistently over- or under-transcribed at each time point. Together, these results suggest that a single measurement of the faecal microbiome can provide long-term information regarding organismal composition and functional potential, but repeated or short-term measures may be necessary for dynamic features identified by metatranscriptomics.


Chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms.
Patients with unexplained chronic pain and/or fatigue have been described for centuries in the medical literature, although the terms used to describe these symptom complexes have changed frequently. The currently preferred terms for these syndromes are fibromyalgia and chronic fatigue syndrome, names which describe the prominent clinical features of the illness without any attempt to identify the cause. This review delineates the definitions of these syndromes, and the overlapping clinical features. A hypothesis is presented to demonstrate how genetic and environmental factors may interact to cause the development of these syndromes, which we postulate are caused by central nervous system dysfunction. Various components of the central nervous system appear to be involved, including the hypothalamic pituitary axes, pain-processing pathways, and autonomic nervous system. These central nervous system changes lead to corresponding changes in immune function, which we postulate are epiphenomena rather than the cause of the illnesses.


ARHGAP10 is necessary for alpha-catenin recruitment at adherens junctions and for Listeria invasion.
E-cadherin mediates the formation of adherens junctions between epithelial cells. It serves as a receptor for Listeria monocytogenes, a bacterial pathogen that enters epithelial cells. The L. monocytogenes surface protein, InlA, interacts with the extracellular domain of E-cadherin. In adherens junctions, this ectodomain is involved in homophilic interactions whereas the cytoplasmic domain binds beta-catenin, which then recruits alpha-catenin. alpha-catenin binds to actin directly, or indirectly, thus linking E-cadherin to the actin cytoskeleton. Entry of L. monocytogenes into cells and adherens junction formation are dynamic events that involve actin and membrane rearrangements. To understand these processes better, we searched for new ligands of alpha-catenin. Using a two-hybrid screen, we identified a new partner of alpha-catenin: ARHGAP10. This protein colocalized with alpha-catenin at cell-cell junctions and was recruited at L. monocytogenes entry sites. In ARHGAP10-knockdown cells, L. monocytogenes entry and alpha-catenin recruitment at cell-cell contacts were impaired. The GAP domain of ARHGAP10 has GAP activity for RhoA and Cdc42. Its overexpression disrupted actin cables, enhanced alpha-catenin and cortical actin levels at cell-cell junctions and inhibited L. monocytogenes entry. Altogether, our results show that ARHGAP10 is a new component of cell-cell junctions that controls alpha-catenin recruitment and has a key role during L. monocytogenes uptake.


Fully nonlinear dynamics of stochastic thin-film dewetting.
The spontaneous formation of droplets via dewetting of a thin fluid film from a solid substrate allows materials nanostructuring. Often, it is crucial to be able to control the evolution, and to produce patterns characterized by regularly spaced droplets. While thermal fluctuations are expected to play a role in the dewetting process, their relevance has remained poorly understood, particularly during the nonlinear stages of evolution that involve droplet formation. Within a stochastic lubrication framework, we show that thermal noise substantially influences the process of droplets formation. Stochastic systems feature a smaller number of droplets with a larger variability in size and space distribution, when compared to their deterministic counterparts. Finally, we discuss the influence of stochasticity on droplet coarsening for asymptotically long times.


Comparison of the global gene expression of choroid plexus and meninges and associated vasculature under control conditions and after pronounced hyperthermia or amphetamine toxicity.
The meninges (arachnoid and pial membranes) and associated vasculature (MAV) and choroid plexus are important in maintaining cerebrospinal fluid (CSF) generation and flow. MAV vasculature was previously observed to be adversely affected by environmentally-induced hyperthermia (EIH) and more so by a neurotoxic amphetamine (AMPH) exposure. Herein, microarray and RT-PCR analysis was used to compare the gene expression profiles between choroid plexus and MAV under control conditions and at 3 hours and 1 day after EIH or AMPH exposure. Since AMPH and EIH are so disruptive to vasculature, genes related to vasculature integrity and function were of interest. Our data shows that, under control conditions, many of the genes with relatively high expression in both the MAV and choroid plexus are also abundant in many epithelial tissues. These genes function in transport of water, ions, and solutes, and likely play a role in CSF regulation. Most genes that help form the blood-brain barrier (BBB) and tight junctions were also highly expressed in MAV but not in choroid plexus. In MAV, exposure to EIH and more so to AMPH decreased the expression of BBB-related genes such as Sox18, Ocln, and Cldn5, but they were much less affected in the choroid plexus. There was a correlation between the genes related to reactive oxidative stress and damage that were significantly altered in the MAV and choroid plexus after either EIH or AMPH. However, AMPH (at 3 hr) significantly affected about 5 times as many genes as EIH in the MAV, while in the choroid plexus EIH affected more genes than AMPH. Several unique genes that are not specifically related to vascular damage increased to a much greater extent after AMPH compared to EIH in the MAV (Lbp, Reg3a, Reg3b, Slc15a1, Sct and Fst) and choroid plexus (Bmp4, Dio2 and Lbp). Our study indicates that the disruption of choroid plexus function and damage produced by AMPH and EIH is significant, but the changes may not be as pronounced as they are in the MAV, particularly for AMPH. Expression profiles in the MAV and choroid plexus differed to some extent and differences were not restricted to vascular related genes.


Fast Exact Search in Hamming Space With Multi-Index Hashing.
There is growing interest in representing image data and feature descriptors using compact binary codes for fast near neighbor search. Although binary codes are motivated by their use as direct indices (addresses) into a hash table, codes longer than 32 bits are not being used as such, as it was thought to be ineffective. We introduce a rigorous way to build multiple hash tables on binary code substrings that enables exact k-nearest neighbor search in Hamming space. The approach is storage efficient and straight-forward to implement. Theoretical analysis shows that the algorithm exhibits sub-linear run-time behavior for uniformly distributed codes. Empirical results show dramatic speedups over a linear scan baseline for datasets of up to one billion codes of 64, 128, or 256 bits.


Effect of rituximab on pulmonary function in patients with rheumatoid arthritis.
Rituximab (RTX), a B-cell depleting monoclonal antibody is increasingly used in several antibody-mediated diseases. It has been reported to cause pulmonary toxicity, though mainly during polychemotherapy of malignant lymphoma. Prospective data on RTX-induced pulmonary complications in patients with rheumatoid arthritis (RA) are lacking. Serial spirometries and measurements of diffusion capacity of the lung for carbon monoxide (DLCO) in patients with RA before and 2, 4, 8, and 26 weeks after treatment with RTX were performed. A reduction from baseline of forced vital capacity (FVC) of ≥10%, or ≥15% of DLCO was defined as indicative for pulmonary toxicity. Thirty-three patients (mean (SD) age 59 (12) years, 27% males) were included. Mean (SD) FVC predicted and DLCO predicted at baseline were 108% (18%) and 88% (18%), respectively. In contrast to FVC, DLCO showed a progressive decline during follow-up with a maximum reduction of 6.1% (95%CI 2.5%, 9.7%; p = 0.001) at 26 weeks compared with baseline. After 26 weeks, 22% of the patients had a ≥15% DLCO decline. None of the patients reported increased dyspnea during follow-up. Risk factors for pulmonary function changes after treatment with RTX were cigarette smoking, repeated administration of the drug, and co-medication with Prednisone. Although no cases of symptomatic lung injury were observed, the progressive DLCO decline seems to indicate the presence of subclinical RTX-induced pulmonary toxicity.


History of Lung Transplantation.
History of lung transplantation in the world can be traced back to the early years of the 20th century when experimental vascular anastomotic techniques were developed by Carrel and Guthrie, followed by transplantation of thoracic organs on animal models by Demikhov and finally it was James Hardy who did the first lung transplantation attempt on human. But it was not until the discovery of cyclosporine and development of better surgical techniques that success could be achieved in that field by the Toronto Lung Transplant Group led by Joel Cooper. Up to the present day, over 51.000 lung transplants were performed in the world at different centers. The start of lung transplantation in Turkey has been delayed for various reasons. From 1998 on, there were several attempts but the first successful lung transplant was performed at Sureyyapasa Hospital in 2009. Today there are four lung transplant centers in Turkey; two in Istanbul, one in Ankara and another one in Izmir. Three lung transplant centers from Istanbul which belong to private sector have newly applied for licence from the Ministry of Health.


Assessment of a novel screening score for nutritional risk in predicting complications in gastro-intestinal surgery.
Malnutrition is a recognized risk factor for perioperative morbidity, but there is currently no standardized definition of malnutrition. The Nutrition Risk Screening 2002 score was recently proposed to identify patients at nutritional risk who may benefit from nutritional support therapy, and has been officially adopted by the European Society of Parenteral and Enteral Nutrition. The aim of this study was to assess the value of the Nutrition Risk Screening 2002 score in predicting the incidence and severity of postoperative complications in gastrointestinal surgery. We prospectively evaluated 608 patients admitted for elective gastrointestinal surgery. Nutritional risk was defined by the Nutrition Risk Screening 2002 score and correlated to the incidence and severity of postoperative complications. Complications were classified using an established surgical complication classification. The overall incidence of nutritional risk was 14%. We observed a significantly higher complication rate of 40% (35 out of 87) in patients at nutritional risk, compared to 15% (81 out of 521) in patients with a normal score (p<0.001). The incidence of severe complications was significantly higher in patients at nutritional risk (54% versus 15%; p<0.001). The odds ratio to develop a complication was 2.8 in patients at risk (p=0.001), and 3.0 in patients with malignant disease (p<0.001). The median length of stay in nutritional risk patients was significantly longer (10 versus 4 days, p<0.001). The prevalence of nutritional risk patients in gastrointestinal surgery is high. We showed that nutritional risk screening using the NRS 2002 strongly predicts the incidence and severity of complications.


Altered sphingoid base profiles in type 1 compared to type 2 diabetes.
Sphingolipids are increasingly recognized to play a role in insulin resistance and diabetes. Recently we reported significant elevations of 1-deoxysphingolipids (1-deoxySL) - an atypical class of sphingolipids in patients with metabolic syndrome (MetS) and diabetes type 2 (T2DM). It is unknown whether 1-deoxySL in patients with diabetes type 1 (T1DM) are similarly elevated. We analyzed the long chain base profile by LC-MS after hydrolyzing the N-acyl and O-linked headgroups in plasma from individuals with T1DM (N = 27), T2DM (N = 30) and healthy controls (N = 23). 1-deoxySLs were significantly higher in the groups with T2DM but not different between T1DM and controls. In contrast to patients with T2DM, 1-deoxSL levels are not elevated in T1DM. Our study indicates that the 1-deoxySL formation is not per-se caused by hyperglycemia but rather specifically associated with metabolic changes in T2DM, such as elevated triglyceride levels.


Release from cross-orientation suppression facilitates 3D shape perception.
Cross-orientation suppression (COS) in striate cortex has been implicated in the efficient encoding of visual stimuli. We show that release from COS facilitates the decoding of 3-D shape. In planar surfaces overlaid with textures, slanting the surface can increase the visibility of the component parallel to the slant. Since this component provides the orientation flows that signify 3-D shape, the enhancement of visibility facilitates 3-D slant perception. Contrast thresholds reveal that this enhancement results from a decrease in COS when 3-D slant creates a frequency mismatch between texture components. We show that coupling compressive nonlinearities in LGN neurons with expansive nonlinearities in cortical neurons can model the frequency-specific component of suppression.


SCA8 repeat expansion: large CTA/CTG repeat alleles in neurological disorders and functional implications.
Spinocerebellar ataxia type 8 (SCA8) involves bidirectional expression of CUG (ATXN8OS) and CAG (ATXN8) expansion transcripts. The pathogenesis of SCA8 is complex and the spectrum of clinical presentations is broad. In the present study, we assessed the SCA8 repeat size ranges in Taiwanese Parkinson's disease, Alzheimer's disease and atypical parkinsonism and investigated the genetic variation modulating ATXN8 expression. Thirteen large SCA8 alleles and a novel ATXN8 -62 G/A promoter SNP were found. There is a significant difference in the proportion of the individuals carrying SCA8 larger alleles in atypical parkinsonism (P = 0.044) as compared to that in the control subjects. In lymphoblastoid cells carrying SCA8 large alleles, treatment of MG-132 or staurosporine significantly increases the cell death or caspase 3 activity. Although expressed at low steady-state, ATXN8 expression level is significantly higher (P = 0.012) in cells with SCA8 large alleles than that of the control cells. The ATXN8 transcriptional activity was significantly higher in the luciferase reporter construct containing the -62G allele than that containing the -62A allele in both neuroblastoma and embryonic kidney cells. Therefore, our preliminary results suggest that ATXN8 gene -62 G/A polymorphism may be functional in modulating ATXN8 expression.


Histopathology of Red Stripe of Rice.
A histological study of red stripe of rice was conducted to elucidate the mode of infection of the causal bacterium Microbacterium sp. When pin-point-sized spots first appeared at 3 days after inoculation, the bacterial cells had entered through stomata and multiplied in the intercellular spaces of substomatal parenchymatous tissues. With the early appearance of small yellow spots at 4 to 5 days after inoculation, the bacterium was detected in some xylem vessels as well as in parenchymatous tissues, and it had apparently translocated directly from parenchymatous tissues to transverse vascular systems through spiral vessel walls. With the appearance of typical red stripe symptoms comprised of orange lesions and halos at 8 days after inoculation, bacterial masses were present in transverse and longitudinal vascular bundles in areas with orange lesions. In the areas with orange to light brown spots, granules that stained dark blue using Stoughton's method appeared in the protoplasm of the host parenchymatous cells, which later became necrotic. In halo areas, bacterial masses were observed only in some cases, and chloroplasts were disorganized. Bacterial infection was also confirmed by observing sections of naturally infected samples, and the distribution of bacteria was much more extensive than in artificially inoculated samples.


Reversal of experimental autoimmune encephalomyelitis by a soluble peptide variant of a myelin basic protein epitope: T cell receptor antagonism and reduction of interferon gamma and tumor necrosis factor alpha production.
An immunodominant epitope of myelin basic protein (MBP), VHFFKNIVTPRTP (p87-99), is a major target of T cells in lesions of multiple sclerosis (MS) and in experimental allergic encephalomyelitis (EAE). T cells found in EAE lesions bear the same amino acids in the third complementary determining region of the T cell receptor (TCR) as those found in MS lesions. We analyzed the trimolecular interactions between MBP p87-99, class II major histocompatibility complex (MHC), and TCR, and designed soluble inhibitors for therapy. F, N, I, and V at positions 90, 92, 93, and 94 interact with MHC, whereas K, T, and P at positions 91, 95, and 96 interact with TCR. The peptides, p87-99[95T > A] and p87-99[96P > A] could compete more effectively with p87-99 for binding to MHC and could antagonize the in vitro response to T cells to p87-99 more effectively than p87-99[91K > A]. However, only p87-99[91K > A] prevented and reversed EAE, indicating that the extent of MHC or TCR competition does not predict success in treating EAE. To elucidate the mechanism of inhibition of EAE, draining lymph node cells from rats immunized with the native peptide alone or together with each of the three TCR antagonists were challenged in vitro with p87-99. Administration of p87-99[91K > A], but not p87-99 [95T > A] or p87-99[96P > A], reduced the production of tumor necrosis factor (TNF)- alpha and interferon (IFN) gamma. IFN-gamma and TNF-alpha are two cytokines that are critical in the pathogenesis of EAE and MS.


Detailed exploration of face-related processing in congenital prosopagnosia: 2. Functional neuroimaging findings.
Specific regions of the human occipito-temporal cortex are consistently activated in functional imaging studies of face processing. To understand the contribution of these regions to face processing, we examined the pattern of fMRI activation in four congenital prosopagnosic (CP) individuals who are markedly impaired at face processing despite normal vision and intelligence, and with no evidence of brain damage. These individuals evinced a normal pattern of fMRI activation in the fusiform gyrus (FFA) and in other ventral occipito-temporal areas, in response to faces, buildings, and other objects, shown both as line drawings in detection and discrimination tasks and under more naturalistic testing conditions when no task was required. CP individuals also showed normal adaptation levels in a block-design adaptation experiment and, like control subjects, exhibited evidence of global face representation in the FFA. The absence of a BOLD-behavioral correlation (profound behavioral deficit, normal face-related activation in the ventral occipito-temporal cortex) challenges existing accounts of face representation, and suggests that activation in these cortical regions per se is not sufficient to ensure intact face processing.


Unique inbred strain MSM/Ms established from the Japanese wild mouse.
Most laboratory mice belong to a species of house mouse, Mus musculus. So far, at least three subspecies groups have been recognized; domesticus subspecies group (DOM) distributed in western Europe, musculus subspecies group (MUS) distributed in eastern Europe and northeast Asia, and castaneus subspecies group (CAS) found in southwest and southeast Asia including southern China. These subspecies are estimated to have branched off roughly one million years ago. Genetic comparison between subspecies' groups and common inbred strains (CIS) have revealed that the genetic background of CIS is derived mainly from DOM. This shows the importance of non-DOM wild mice as valuable genetic resources. We started to establish our unique strain, MSM/Ms, from MUS in Japan in 1978. In the beginning, we kept wild mice trapped in Mishima in large plastic buckets. In 1979, breeding by sister-brother mating started. The MSM/Ms inbred strain was established in 1986 and 21 years later it reached F(100). During breeding, no significant fluctuations in litter size and sex ratios have been observed. Extensive genetic analyses of chromosome C-banding pattern, biochemical markers and microsatellite DNA (MIT) markers of this strain have demonstrated the characteristics of MUS. A phylogenetic tree constructed from MIT markers has confirmed the MUS nature of MSM strain. Taken together with its genetic remoteness from CIS, MSM appears to maintain many valuable alleles for investigation of biological functions and diseases. Some of these alleles have avoided selection during breeding as either fancy mice or laboratory mice. The MSM-specific genetic traits discovered to date are discussed.


The experience of living with a traumatic hand injury in a rural and remote location: an interpretive phenomenological study.
The aim of this research study was to gain an understanding of how rural and remote residents in North Queensland, Australia, engaged in work, activities of daily living tasks and social activities following a traumatic hand injury. Findings from a previous retrospective survey with these participants revealed that patients experienced difficulties such as pain for many years after their injury; however, because of the survey methodology, the voices of participants were not heard. This study contributes to a larger project that seeks to propose a model of service delivery to rural and remote residents who have sustained a traumatic injury. Utilising an interpretive phenomenological research design, data were gathered through in-depth, semistructured interviews. Fifteen participants were recruited into this study and questions were designed to explore the experience of having a traumatic hand injury in rural and remote areas of North Queensland. The thematic analysis indicated five major themes: injury and impairment, pain, occupation and activity, and resilience. Participants reported that having a hand injury often caused further injury due to the impairment. The pain experienced could be 'all consuming' yet participants reported 'pushing through' this pain to complete daily tasks. Participants reported that they would 'go mad' if they did not work and highlighted the importance of activity in their recovery. Participants felt grateful at having their hand and thought towards the future. Being self-reliant was important but they were willing to accept support from others when needed. Incorporating activity and occupation in rehabilitation programs as opposed to focusing on strict protocols is an important consideration in the recovery process of rural and remote residents. In particular, engaging in activity and occupation was an important part of managing the pain associated with the hand trauma. This research also found that participants demonstrated resilient qualities while recovering from a traumatic hand injury. Health professionals who work with people from a rural and remote location with a traumatic hand injury should consider a treatment model that encourages active patient participation, identifying collaborative treatment goals that align with the values of people living in rural and remote locations. Education regarding the high risk of further injury due to the nature of, and exposure to, the type of work and activity in rural and remote locations is also recommended.


Proximity and cooperativity effects in binuclear d(0) olefin polymerization catalysis. theoretical analysis of structure and reaction mechanism.
This contribution focuses on the distinctive center-to-center cooperative catalytic properties exhibited by bimetallic "constrained geometry catalysts" (CGCs), and analyzes metal-metal proximity effects on ethylene polymerization processes mediated by (mu-CH(2)-3,3'){(eta(5)-indenyl)[1-H(2)Si((t)BuN)](ZrMe(2))}(2) (Zr(2))-derived catalysts using density functional theory. Precatalyst geometries are first discussed, and then ion-pair formation/heterolytic dissociation processes involving the binuclear bis(borane) cocatalyst 1,4-(C(6)F(5))(2)BC(6)F(4)B(C(6)F(5))(2) (BN(2)), are analyzed and compared with those in the parent mononuclear analogue. It is found that, on proceeding from the mononuclear to binuclear catalyst system, ion-pair dissociation energies increase due to the stronger catalyst center-counterdianion interactions. Moreover, in the binuclear case, the interaction energies are markedly sensitive to geometrical matching between the binuclear bis(borane) and the precatalyst Zr-methyl positions. Binuclear catalytic effects between the metal centers are then explored, with the specific contribution from the proximity of the second metal center. Possible agostic interactions of alpha-alkenes pi-coordinated to one Zr center with the second Zr center of the binuclear catalyst are scrutinized for the case of 1-octene. It is argued that these agostic interactions are at least partly responsible for the unusual enchainment properties of the bimetallic catalysts. In particular, the greater polyethylene product branch densities found experimentally for the bimetallic catalysts can be correlated with an intramolecular reinsertion process, assisted by agostic interactions. Moreover, these same agostic interactions involving a chain growing at one metal site with the second metal site of the binuclear catalyst modify the environment to increase propagation/termination rate ratios, in turn favoring increased product molecular weight (M(n)). These effects are observed experimentally at closer Zr...Zr proximities in olefin polymerizations mediated by binuclear CGC catalysts.


Neonatal Morbidity After Maternal Use of Antidepressant Drugs During Pregnancy.
To estimate the rate of admissions to NICUs, as well as infants' morbidity and neonatal interventions, after exposure to antidepressant drugs in utero. Data on pregnancies, deliveries, prescription drug use, and health status of the newborn infants were obtained from the Swedish Medical Birth Register, the Prescribed Drug Register, and the Swedish Neonatal Quality Register. We included 741 040 singletons, born between July 1, 2006, and December 31, 2012. Of the infants, 17 736 (2.4%) had mothers who used selective serotonin reuptake inhibitors (SSRIs) during pregnancy. Infants exposed to an SSRI were compared with nonexposed infants, and infants exposed during late pregnancy were compared with those exposed during early pregnancy only. The results were analyzed with logistic regression analysis. After maternal use of an SSRI, 13.7% of the infants were admitted to the NICU compared with 8.2% in the population (adjusted odds ratio: 1.5 [95% confidence interval: 1.4-1.5]). The admission rate to the NICU after treatment during late pregnancy was 16.5% compared with 10.8% after treatment during early pregnancy only (adjusted odds ratio: 1.6 [95% confidence interval: 1.5-1.8]). Respiratory and central nervous system disorders and hypoglycemia were more common after maternal use of an SSRI. Infants exposed to SSRIs in late pregnancy compared with early pregnancy had a higher risk of persistent pulmonary hypertension (number needed to harm: 285). Maternal use of antidepressants during pregnancy was associated with increased neonatal morbidity and a higher rate of admissions to the NICU. The absolute risk for severe disease was low, however.


Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans.
Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat. Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear. To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, we studied seven BAT-positive (BAT(+)) men and five BAT-negative (BAT(-)) men under thermoneutral conditions and after prolonged (5-8 h) cold exposure (CE). The two groups were similar in age, BMI, and adiposity. CE significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation, and insulin sensitivity in the BAT(+) group only. These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans, and support the notion that BAT may function as an antidiabetic tissue in humans.


Neoliberal Health Restructuring, Neoconservatism and the Limits of Law: Erosion of Reproductive Rights in Turkey.
Through focusing on the neoliberal "Health Transformation Programme" launched in 2003 in Turkey, I show how reproductive law can be modified by neoliberal mechanisms that are implemented with neoconservative policies and pressures. The paper builds on original data collected in 2014 and 2015 through focus groups and interviews with health practitioners in family health centers and women receiving reproductive care in Izmir, Diyarbakir, Van, and Gaziantep. The data analysis informed by writings on the debt economy by Maurizio Lazzarato and Bifo Berardi and transnational feminist theory demonstrate that neoliberal mechanisms of "dismantling the public" interact with pronatalist policies and pressures to erode women's reproductive rights in Turkey. This has resulted in (1) indebtedness of women through out-of-pocket payments for contraception and abortion, (2) indebtedness of providers through performance measures, (3) reduction in the quality of reproductive care, and (4) reduction in access to reproductive care itself (contraception, counseling, and abortion). There is a need to pay attention to neoliberal mechanisms and the legal framings of reproductive rights to fully understand the limitations of law and counter the neoliberal and conservative assaults on women's sexual and reproductive rights.


Renin-angiotensin system polymorphisms in Taiwanese primary vesicoureteral reflux.
We studied the angiotensin-converting enzyme (ACE), angiotensinogen (AGT), and angiotensin II type 1 receptor (AT1R) gene polymorphisms for association with susceptibility to primary vesicoureteral reflux (VUR) and disease progression in 74 Taiwanese children, including 16 with end-stage renal disease (ESRD), and 117 normal controls. Polymerase chain reaction-amplified products containing the ACE gene T-5491C, A-5466C, T-3892C, A-3692C, A-240T, Alu I/D, the AGT gene C-532T, G-217A, G-152A, A-20C, A-6G, T174M, T235M, and the AT1R gene A-1138T, T-810A, T-713G, C-521T, AG-214CC, A-153G, A1166C polymorphisms were analyzed by restriction enzyme digestion, gel electrophoresis, or single-strand conformation polymorphism analysis. All the polymorphisms examined were in Hardy-Weinberg equilibrium. The strong non-random association within the ACE, AGT, and AT1R genes suggests low levels of intragenic recombination. None of these polymorphisms showed association with VUR susceptibility. However, the allele frequency distribution of the six ACE polymorphisms among primary VUR patients with or without ESRD was statistically different. The linked ACE T-A-T-A-A-I allele was observed significantly more frequently in VUR children with ESRD (P<0.001). A significant increase of left ventricular mass index was also found in the linked ACE T-A-T-A-A-I allele group compared with the non-ACE T-A-T-A-A-I allele group of patients aged 18 years with renal progression. The AGT A-6G genotype frequencies were significantly different when the analysis was stratified by genotype of the ACE polymorphisms. The data showed that ACE gene polymorphisms were associated with progressive renal deterioration in Taiwanese children with VUR and might act synergistically with the -6 G allele of the AGT gene.


Use of an impedance threshold device in spontaneously breathing patients with hypotension secondary to trauma: an observational cohort feasibility study.
An impedance threshold device (ITD) intended for use in the spontaneously breathing patient has been shown to raise blood pressure in hypotensive patients. This device has not been evaluated in patients with hypotension secondary to trauma. This study focused on changes in key vital signs when the ITD was added to the paramedic treatment protocol for hypotensive patients with prehospital traumatic injury. A 6-month prospective nonrandomized observational cohort study was conducted of 200 spontaneously breathing symptomatic adult patients with prehospital hypotension due to multiple causes; the patients of primary interest experienced a traumatic injury. Upon determination of hypotension (systolic blood pressure of approximately ≤90 mm Hg), standard therapy was initiated by application of the mask-style ITD. Vital signs were documented every 2 minutes to 5 minutes after intervention. A change in mean arterial pressure (MAP) with ITD use was the primary study endpoint. Of the 200 hypotensive subjects treated, 29 (3 were excluded because of incomplete data sets and 3 patients treated with the ITD were excluded because their blood pressure did not meet inclusion criterion) were hypotensive secondary to trauma. Their MAP increased from 60 mm Hg (SD, 11 mm Hg; 95% confidence interval [CI], 8.17-15.432) to 78 mm Hg (16 mm Hg; 95% CI, 12.43-23.46) (p = 0.001), without significant change in mean heart rate. Approximately 75% of the patients reported moderate to easy tolerance. Similar increases in MAP were observed in the nontraumatic patients, from 60 mm Hg (10 mm Hg; 95% CI, 9.4-11.5) to 70 (15; 95% CI, 13.4-16.7) (p = 0.0001). In this observational cohort study of patients with hypotension secondary to trauma, the ITD was well tolerated, and MAP as well as systolic and diastolic blood pressure were improved. The patients were not overresuscitated with this intervention. On the basis of these findings, additional studies in patients with hypotension secondary to traumatic injury should be performed to better define the need and benefit of additional fluid resuscitation when the ITD is used. Therapeutic study, level IV.


Soluble CD14 acts as a shuttle in the neutralization of lipopolysaccharide (LPS) by LPS-binding protein and reconstituted high density lipoprotein.
We have recently shown that lipopolysaccharide (LPS)-binding protein (LBP) is a lipid transfer protein that catalyzes two distinct reactions: movement of bacterial LPS (endotoxin) from LPS micelles to soluble CD14 (sCD14) and movement of LPS from micelles to reconstituted high density lipoprotein (R-HDL) particles. Here we show that LBP facilitates a third lipid transfer reaction: movement of LPS from LPS-sCD14 complexes to R-HDL particles. This action of LBP is catalytic, with one molecule of LBP enabling the movement of multiple LPS molecules into R-HDL. LBP-catalyzed movement of LPS from LPS-sCD14 complexes to R-HDL neutralizes the capacity of LPS to stimulate polymorphonuclear leukocytes. Our findings show that LPS may be transferred to R-HDL either by the direct action of LBP or by a two-step reaction in which LPS is first transferred to sCD14 and subsequently to R-HDL. We have observed that the two-step pathway of LPS transfer to R-HDL is strongly favored over direct transfer. Neutralization of LPS by LBP and R-HDL was accelerated more than 30-fold by addition of sCD14. Several observations suggest that sCD14 accelerates this reaction by serving as a shuttle for LPS: addition of LBP and sCD14 to LPS micelles resulted in LPS-sCD14 complexes that could diffuse through a 100-kD cutoff filter; LPS-sCD14 complexes appeared transiently during movement of LPS to R-HDL facilitated by purified LBP; and sCD14 could facilitate transfer of LPS to R-HDL without becoming part of the final LPS-R-HDL complex. Complexes of LPS and sCD14 were formed transiently when LPS was incubated in plasma, suggesting that these complexes may play a role as intermediates in the neutralization of LPS under physiological conditions. These findings detail a new activity for sCD14 and suggest a novel mechanism for lipid transfer by LBP.


A flexible model-free prediction-based framework for feature ranking.
Despite the availability of numerous statistical and machine learning tools for joint feature modeling, many scientists investigate features marginally, i.e., one feature at a time. This is partly due to training and convention but also roots in scientists' strong interests in simple visualization and interpretability. As such, marginal feature ranking for some predictive tasks, e.g., prediction of cancer driver genes, is widely practiced in the process of scientific discoveries. In this work, we focus on marginal ranking for binary classification, one of the most common predictive tasks. We argue that the most widely used marginal ranking criteria, including the Pearson correlation, the two-sample t test, and two-sample Wilcoxon rank-sum test, do not fully take feature distributions and prediction objectives into account. To address this gap in practice, we propose two ranking criteria corresponding to two prediction objectives: the classical criterion (CC) and the Neyman-Pearson criterion (NPC), both of which use model-free nonparametric implementations to accommodate diverse feature distributions. Theoretically, we show that under regularity conditions, both criteria achieve sample-level ranking that is consistent with their population-level counterpart with high probability. Moreover, NPC is robust to sampling bias when the two class proportions in a sample deviate from those in the population. This property endows NPC good potential in biomedical research where sampling biases are ubiquitous. We demonstrate the use and relative advantages of CC and NPC in simulation and real data studies. Our model-free objective-based ranking idea is extendable to ranking feature subsets and generalizable to other prediction tasks and learning objectives.


The bone response to non-weight-bearing exercise is sport-, site-, and sex-specific.
To examine whether skeletal adaptations to chronic non-weight-bearing exercise depend on the type of aquatic exercise (swimming or water polo) as well as on sex (men or women). This was a cross-sectional study at the Laboratory of Nutrition and Clinical Dietetics, Department of Nutrition and Dietetics, Harokopio University, Athens, Greece. A total of 43 water polo players, 26 swimmers, and 30 sedentary individuals, aged 17 to 34 years, were recruited (52 men, 47 women). Bone mineral content (BMC) and areal bone mineral density (aBMD) of the total body and of various subregions. : Compared with controls, swimmers had lower leg and total aBMD (P < 0.05), whereas water polo players had lower leg but higher arm and trunk aBMD (all P < 0.05). Swimmers and water polo athletes differed at the arms (men only), trunk, and total body (all higher in water polo players, at P < 0.05). Bone adaptations to water polo playing were unaffected by sex. Female swimmers, but not male swimmers, had 13% higher arm BMC than controls (P < 0.05), whereas male swimmers, but not female swimmers, had 12% lower leg BMC than controls (P < 0.05). Athletes participating in long-term water polo playing and swimming have substantially different total and regional aBMD. The effect is not mediated by sex in water polo players; however, sex may mediate the differences between swimmers and controls. Whether the observed differences between athlete groups and sexes arise from different bone adaptations to activity or from other factors cannot be answered by the current data. Water polo playing may be preferable over swimming for maintaining bone health; both types of aquatic exercise at the elite level of participation, however, have unfavorable effects on the lower limb bones.


Surface fouling as a mechanism for chemotaxis in isotropic catalytic swimmers.
We present microscopic models for surface fouling of an isotropic spherical catalytic microswimmer at and away from equilibrium and show how a foulant gradient can induce chemotactic behavior. Our simulations establish that the presence of foulant manifests itself in two ways: as a braking effect on propulsive particle motion, and as a drift term which probes the foulant concentration gradient. Our results suggest that, while foulant gradients are unlikely to be directly useful for chemotactically directed particles, they nevertheless exert a non-negligible influence on particle motion under a wide range of conditions.


Y-chromosome genetic variation in Rio de Janeiro population.
The present-day Brazilian gene pool is known to be the outcome of an admixture process of populations from different origins, mainly Amerindians, Europeans, and Africans. It is also known that in Brazil, a wide variation in the admixture process occurred in different regions of the country or even in different subpopulations from the same region. In the present study, we aimed to characterize the male lineages present in the Rio de Janeiro population, the second most populated of the 26 Brazilian states. A random sample of 127 unrelated males from Rio de Janeiro was typed for 28 Y-chromosome-specific biallelic markers. In total, 17 different haplogroups were defined within our sample, most of them of European ancestry (88.1%). Those of sub-Saharan African origin (E3a) amounted to 7.9%, while only 2 males carried Amerindian lineages (characterized by the presence of an M3 mutation: haplogroup Q3). Using both Y-STR haplotype and Y-SNP haplogroup information, genetic distances were calculated between the subgroup of Rio de Janeiro males carrying European haplogroups and the Portuguese population. Low, nonsignificant, values were obtained. Thus, in contrast with what is observed in their female counterparts, the vast majority of the present Rio de Janeiro male gene pool is of European extraction, while the original Amerindian lineages are residual and much less frequent than the sub-Saharan component resulting from the slave trade. These observations can be interpreted as the signature of the strong gender asymmetry of the admixture processes in colonial systems.


Time pressure and sleep problems due to thoughts about work as risk factors for future sickness absence.
This study investigated whether time pressure or sleep problems due to thoughts about work are associated with future sickness absence (SA) among women and men employed in different sectors, also when adjusting for confounders including familial factors (genetics and shared environment). The study sample included 16,127 twin individuals (52% women), aged 19-47 years who in 2005 participated in an online survey including questions regarding time pressure, sleep, work and health. Register data on SA (> 14 days) were obtained from the National Social Insurance Agency and individuals were followed from date of survey response until 12/31/2013. Associations between time pressure, sleep problems due to thoughts about work and future SA were investigated using logistic regression analyses to assess odds ratios (OR) with 95% confidence intervals (CI). In total 5723 (35%) individuals had an incident SA spell during follow-up. Sleep problems due to thoughts about work were associated with SA in the fully adjusted model (OR 1.22, CI 1.10-1.36). Stratified by sector, the highest estimate was found for state employees (OR 1.54, CI 1.11-2.13). Familial factors did not seem to influence the associations. We found no statistically significant associations between time pressure and SA. No sex differences were found. Results indicated that sleep problems due to thoughts about work is a risk factor for future SA. This follows previous research showing that sleep length and sleep disturbances, regardless of reason, are associated with SA. But, experiences of work-related time pressure seem to have no effect on SA.


Effect of different surface treatments and bonding modalities on the shear bond strength between metallic orthodontic brackets and glazed monolithic zirconia crowns.
To evaluate the effect of different surface treatments and bonding modalities on the shear bond strength (SBS) between metallic orthodontic brackets and zirconia crowns. Sixty zirconia specimens were computer-aided design/computer-aided manufacturing milled, sintered, glazed, and embedded in acrylic resin. The specimens were divided into three groups according to the surface treatment applied: C: no surface treatment (control), S: sandblasted with 50 μm Al2O3, and D: Sof-Lex disc roughening. Each group was further subdivided into two subgroups according to the resin cement used: P: Clearfil Ceramic Primer + Panavia F2.0 (Kuraray) and R: RelyX U200 (3M/ESPE). Metallic orthodontic brackets were bonded to the labial surface of the specimens. All specimens underwent thermocycling. SBS test was applied using a universal test machine at a cross head speed of 1 mm/min. Data were analyzed using Mann-Whitney test (α = 0.05). Subgroup SP showed the highest SBS (20.8 ± 4.8 MPa), followed by subgroups SR (16.7 ± 4.6 MPa), DP (12.3 ± 2.8 MPa), and DR (11.6 ± 3 MPa). However, all specimens in the control group underwent debonding during thermocycling. The different surface treatment groups showed highly significant differences (P < 0.05), whereas the resin cement subgroups showed no significant differences (P > 0.05). SBS between glazed zirconia crowns and metallic brackets strongly depended on the surface treatment applied. Sandblasting achieved the highest SBS. Roughening with Sof-Lex disc proved to be a reliable surface treatment modality for glazed zirconia. Bonding to untreated glazed zirconia surfaces led to bond failure. Both resin cements yielded strong SBS results.


Sleep outcomes following sleep-hygiene-related interventions for individuals with traumatic brain injury: A systematic review.
Sleep disturbance is commonly reported following traumatic brain injury (TBI) and can adversely impact health and wellbeing and interfere with the rehabilitation process. As such, effective treatment of sleep disturbance is critical for overall recovery. Sleep hygiene, which is non-invasive, low cost, and low risk, could serve as a suitable first line of treatment for individuals experiencing sleep disturbance post-TBI. To assess the efficacy of sleep hygiene on sleep outcomes post-TBI. PsycINFO, Medline and EMBASE databases were systematically searched using mesh terms and keywords related to 'traumatic brain injury', 'sleep' and 'treatment'. Studies that met inclusion criteria were assessed on their methodological quality using validated assessment tools. Ten studies met inclusion criteria, none of which contained a child or adolescent population. Their methodological quality varied. The following interventions were shown to improve sleep outcomes amongst adults with TBI: Cognitive Behaviour Therapy for Insomnia, blue light therapy, Problem Solving Treatment and combined sleep hygiene and Prazosin. There was mixed evidence for the efficacy of exercise on sleep outcomes. Preliminary findings suggest that some sleep-hygiene-related interventions, either in isolation or in combination with other treatments, may reduce sleep difficulties post-TBI.


Insights into molecular plasticity in protein complexes from Trm9-Trm112 tRNA modifying enzyme crystal structure.
Most of the factors involved in translation (tRNA, rRNA and proteins) are subject to post-transcriptional and post-translational modifications, which participate in the fine-tuning and tight control of ribosome and protein synthesis processes. In eukaryotes, Trm112 acts as an obligate activating platform for at least four methyltransferases (MTase) involved in the modification of 18S rRNA (Bud23), tRNA (Trm9 and Trm11) and translation termination factor eRF1 (Mtq2). Trm112 is then at a nexus between ribosome synthesis and function. Here, we present a structure-function analysis of the Trm9-Trm112 complex, which is involved in the 5-methoxycarbonylmethyluridine (mcm(5)U) modification of the tRNA anticodon wobble position and hence promotes translational fidelity. We also compare the known crystal structures of various Trm112-MTase complexes, highlighting the structural plasticity allowing Trm112 to interact through a very similar mode with its MTase partners, although those share less than 20% sequence identity.


Sub-terahertz spectroscopy reveals that proteins influence the properties of water at greater distances than previously detected.
The initial purpose of the study is to systematically investigate the solvation properties of different proteins in water solution by terahertz (THz) radiation absorption. Transmission measurements of protein water solutions have been performed using a vector network analyser-driven quasi-optical bench covering the WR-3 waveguide band (0.220-0.325 THz). The following proteins, ranging from low to high molecular weight, were chosen for this study: lysozyme, myoglobin, and bovine serum albumin (BSA). Absorption properties of solutions were studied at different concentrations of proteins ranging from 2 to 100 mg/ml. The concentration-dependent absorption of protein molecules was determined by treating the solution as a two-component model first; then, based on protein absorptivity, the extent of the hydration shell is estimated. Protein molecules are shown to possess a concentration-dependent absorptivity in water solutions. Absorption curves of all three proteins sharply peak towards a dilution-limit that is attributed to the enhanced flexibility of protein and amino acid side chains. An alternative approach to the determination of hydration shell thickness is thereby suggested, based on protein absorptivity. The proposed approach is independent of the absorption of the hydration shell. The derived estimate of hydration shell thickness for each protein supports previous findings that protein-water interaction dynamics extends beyond 2-3 water solvation-layers as predicted by molecular dynamics simulations and other techniques such as NMR, X-ray scattering, and neutron scattering. According to our estimations, the radius of the dynamic hydration shell is 16, 19, and 25 Å, respectively, for lysozyme, myoglobin, and BSA proteins and correlates with the dipole moment of the protein. It is also seen that THz radiation can serve as an initial estimate of the protein hydrophobicity.


Analytical characterization of NOTA-modified somatropins.
Chemical modification of biomolecules like the introduction of metal-chelators into proteins can lead to heterogeneous product formation. The nature and extend of the modification is important in interpreting the biological properties of the bioconjugate, given their possible influence on the pharmacokinetics as well as on the binding affinity to the target. The present study describes the synthesis and analytical characterization of somatropin modified on its lysine's ɛ-amino groups with the acylating chelator S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA). Direct separation and identification techniques (i.e. RP-MS and CE-MS) and peptide mapping after trypsin and chymotrypsin digestion demonstrated that the use of higher amounts of p-SCN-Bn-NOTA during synthesis leads to a complex product composition with higher order substitution degrees (i.e. multiple NOTA-moieties per somatropin molecule), as well as the presence of different position isomers. From the nine lysine (Lys) residues in somatropin, Lys-70 was experimentally found to be the modification hotspot under our synthesis conditions (pH=9.0). This was supported by the in silico calculated lowest pKa value of 8.3 for Lys-70. Based on the crystal structure of somatropin in complex with the extracellular parts of the growth hormone receptor, the Lys-70 residue is positioned outside the binding pockets and will therefore not directly interfere with receptor binding. Gallium chelation by NOTA-somatropin resulted in a 100% complexation. The synthesis of NOTA-somatropin using p-SCN-Bn-NOTA and somatropin under our operational conditions is therefore a suitable synthesis procedure for the production of a target-specific radiopharmaceutical for further investigation toward treatment and visualization of growth hormone-specific cancers.


The Outcome and Implications of Public Precautionary Measures in Taiwan-Declining Respiratory Disease Cases in the COVID-19 Pandemic.
With the rapid development of the COVID-19 pandemic, countries are trying to cope with increasing medical demands, and, at the same time, to reduce the increase of infected numbers by implementing a number of public health measures, namely non-pharmaceutical interventions (NPIs). These public health measures can include social distancing, frequent handwashing, and personal protective equipment (PPE) at the personal level; at the community and the government level, these measures can range from canceling activities, avoiding mass gatherings, closing facilities, and, at the extreme, enacting national or provincial lockdowns. Rather than completely stopping the infectious disease, the major purpose of these NPIs in facing an emerging infectious disease is to reduce the contact rate within the population, and reduce the spread of the virus until the time a vaccine or reliable medications become available. The idea is to avoid a surge of patients with severe symptoms beyond the capacity of the hospitals' medical resources, which would lead to more mortality and morbidity. While many countries have experienced steep curves in new cases, some, including Hong Kong, Vietnam, South Korea, New Zealand, and Taiwan, seem to have controlled or even eliminated the infection locally. From its first case of COVID-19 on the 21 January until the 12 May, Taiwan had 440 cases, including just 55 local infections, and seven deaths in total, representing 1.85 cases per 100,000 population and a 1.5% death rate (based on the Worldometer 2020 statistics of Taiwan's population of 23.8 million). This paper presents evidence that spread prevention involving mass masking and universal hygiene at the early stage of the COVID-19 pandemic resulted in a 50% decline of infectious respiratory diseases, based on historical data during the influenza season in Taiwan. These outcomes provide potential support for the effectiveness of widely implementing public health precaution measures in controlling COVID-19 without a lockdown policy.


Desktop NMR for structure elucidation and identification of strychnine adulteration.
Elucidating the structure of complex molecules is difficult at low magnetic fields due to the overlap of different peak multiplets and second-order coupling effects. This is even more challenging for rigid molecules with small chemical shift differences and with prochiral centers. Since low-field NMR spectroscopy is sometimes presumed as restricted to the analysis of only small and simple molecules, this paper aims at countering this misconception: it demonstrates the use of low-field NMR spectroscopy in chemical forensics for identifying strychnine and its counterions by exploring the chemical shift as a signature in different 1D 1H and 13C experiments. Hereby the applied methodologies combine various 1D and 2D experiments such as 1D 1H, 13C, DEPT, and 2D COSY, HETCOR, HSQC, HMBC and J-resolved spectroscopy to elucidate the molecular structure and skeleton of strychnine at 1 Tesla. Strychnine is exemplified here, because it is a basic precursor in the chemistry of natural products and is employed as a chemical weapon and as a doping agent in sports including the Olympics. In our study, the molecular structure of the compound could be identified either with a 1D experiment at high magnetic field or with HMBC and HSQC experiments at 1 T. In conclusion, low-field NMR spectroscopy enables the chemical elucidation of the strychnine structure through a simple click with a computer mouse. In situations where a high-field NMR spectrometer is unavailable, compact NMR spectrometers can nevertheless generate knowledge of the structure, important for identifying the different chemical reaction mechanisms associated with the molecule. Desktop NMR is a cost-effective viable option in chemical forensics. It can prove adulteration and identify the origin of different strychnine salts, in particular, the strychnine free base, strychnine hemisulphate and strychnine hydrochloride. The chemical shift signatures report the chemical structure of the molecules due to the impact of the counterions on the chemical shift of the protons adjacent to the heteroatoms. This can serve as a methodology for the structure elucidation of complex molecules at lower-magnetic fields.


N6-methyldeoxyadenosine 5'-triphosphate as a probe of the fidelity mechanisms of bacteriophage T4 DNA polymerase.
The incorporation of m6dATP by T4 DNA polymerase has been investigated. Unlike Escherichia coli DNA polymerase I (Engel, J.D., and von Hippel, P.H. (1978) J. Biol. Chem, 253, 935-939), the T4 enzyme discriminates at the insertion step against the methylated triphosphate as compared to the normal substrate (dATP). The apparent Km values measured in two ways agree with the overall 7-fold discrimination measured in double label experiments. The apparent Vmax values measured for net DNA synthesis are the same, while those measured for nucleotide turnover show that the rate for m6dATP is 2-fold greater than for dATP itself. The T4 enzyme results are consistent with the generally held theory that fidelity at the insertion step of DNA polymerization is determined by the relative free energies of primer-enzyme-triphosphate ternary complexes formed by competing, alternative substrate dNTPs. These results are also consistent with the view that these free energies chiefly depend on formation of satisfactory hydrogen bonds between the bases of the template and triphosphate.


Childhood-onset epilepsy with and without preceding febrile seizures.
To identify characteristics in children with epilepsy that differ between those who did versus did not have a history of preceding febrile seizures. Febrile seizures precede epilepsy in 10 to 15% of children. Little is known about the specific types of epilepsy associated with febrile seizures. In a community-based, prospectively identified cohort of children, the association between prior febrile seizures and characteristics of the children's epilepsy (seizure type, epilepsy syndrome, age at onset, underlying etiology, family history) were examined for 524 of the children who were aged > or =1 year at onset of epilepsy. Seventy-three (13.9%) had febrile seizures. Children with febrile seizures were more likely to have a first-degree or a second-higher-degree relative with febrile seizures and less likely to have childhood absence epilepsy and absence seizures compared with children without febrile seizures. This was especially true for simple febrile seizures. There was no specific association with localization-related forms of epilepsy. Complex, but not simple, febrile seizures were associated with younger age at onset of epilepsy. There was no evidence that focal or prolonged febrile seizures were associated with localization-related epilepsy or temporal lobe epilepsy per se. Of the three children whose initial MRIs demonstrated hippocampal atrophy, none had a history of febrile seizures. At the time of diagnosis, febrile seizures are not specifically related to temporal lobe epilepsy or localization-related epilepsy in general. A genetic component for febrile seizures is suggested by its positive associations with family history, especially for simple febrile seizures. Complex febrile seizures represent an underlying age-dependent susceptibility.


[Impact of malaria during pregnancy in the Amazon region].
To estimate the impact of malaria on the course of pregnancy in women from the Amazon region and to investigate possible risk factors in this population. This cross-sectional study is part of a larger project to study malaria and pregnancy in the Amazon region. Pregnant women with malaria receiving care at the Amazon Tropical Medicine Foundation (Fundação de Medicina Tropical do Amazonas) who answered a structured interview were included in the study. Socioeconomic, behavioral and clinical data were collected in the first consultation relating to each new malaria attack. All the women were followed-up throughout their pregnancy. The following risk factors for impact of malaria on the course of pregnancy were considered: being younger than 20 years of age, first pregnancy, first malaria infection, and type of infecting plasmodium species. Five hundred and thirty-five malaria episodes were evaluated in 417 pregnant women, with 20.56% being caused by P. falciparum, 78.69% by P. vivax and 0.75% by the association of both parasites. Changes in the course of pregnancy were very frequent (26.2%). Threat of abortion was observed in 49 cases (25.5%), abortion in two (1.0%), threat of premature birth in 74 (25.1%), and premature birth in three (1.0%). First pregnancy and age < 20 years were significantly associated with threat of premature birth and abortion. Changes in the course of pregnancy were very frequent during acute malaria attacks, despite the low frequency of abortion. The present results do not highlight specific risk factors, suggesting that any pregnant woman may be at risk for the threat of abortion or for abortion during acute malaria attacks.


Magnesium supplement promotes sciatic nerve regeneration and down-regulates inflammatory response.
Magnesium (Mg) supplements have been shown to significantly improve functional recovery in various neurological disorders. The essential benefits of Mg supplementation in peripheral nerve disorders have not been elucidated yet. The effect and mechanism of Mg supplementation on a sciatic nerve crush injury model was investigated. Sciatic nerve injury was induced in mice by crushing the left sciatic nerve. Mice were randomly divided into three groups with low-, basal- or high-Mg diets (corresponding to 10, 100 or 200% Mg of the basal diet). Neurobehavioral, electrophysiological and regeneration marker studies were conducted to explore nerve regeneration. First, a high Mg diet significantly increased plasma and nerve tissue Mg concentrations. In addition, Mg supplementation improved neurobehavioral, electrophysiological functions, enhanced regeneration marker, and reduced deposits of inflammatory cells as well as expression of inflammatory cytokines. Furthermore, reduced Schwann cell apoptosis was in line with the significant expression of bcl-2, bcl-X(L) and down-regulated expression of active caspase-3 and cytochrome C. In summary, improved neurological function recovery and enhanced nerve regeneration were found in mice with a sciatic nerve injury that were fed a high- Mg diet, and Schwann cells may have been rescued from apoptosis by the suppression of inflammatory responses.


Senior pathology resident in-service examination scores correlate with outcomes of the American Board of Pathology certifying examinations.
The Resident In-Service Examination (RISE) addresses 1 area of the Accreditation Council for Graduate Medical Education Outcome Project; RISE results demonstrate progressive attainment of pathology knowledge during training. We compared RISE scores with primary pathology board certification success for residents graduating in 2008 and 2009. Overall RISE and nearly all sectional scores in anatomic and clinical pathology were significantly higher for residents passing all certifying examinations at the first attempt vs residents who failed any examination. The risk of failing increased with each lower quartile of overall RISE score, such that 34% (2009) and 54% (2008) of residents in the lowest quartile failed at least 1 certifying examination. Two thirds of graduating residents with lowest quartile scores had a similar quartile ranking in the previous RISE, identifying them as at risk. Residents passing the American Board of Pathology certifying examinations have a higher level of medical knowledge in general and specific pathology disciplines as assessed by senior RISE scores.


The effects of rate variation on ancestral inference in the coalescent.
We describe a Markov chain Monte Carlo approach for assessing the role of site-to-site rate variation in the analysis of within-population samples of DNA sequences using the coalescent. Our framework is a Bayesian one. We discuss methods for assessing the goodness-of-fit of these models, as well as problems concerning the separate estimation of effective population size and mutation rate. Using a mitochondrial data set for illustration, we show that ancestral inference concerning coalescence times can be dramatically affected if rate variation is ignored.


Biomechanical comparison of parallel versus 90-90 plating of bicolumn distal humerus fractures with intra-articular comminution.
To compare the biomechanical properties of 90-90 versus mediolateral parallel plating of C-3 bicolumn distal humerus fractures. We created intra-articular AO/Orthopaedic Trauma Association C-3 bicolumn fractures in 10 fresh-frozen matched pairs of cadaveric elbows. We determined bone mineral density of the metaphyseal region with dual-energy x-ray absorptiometry. The matched pairs of elbows were randomly assigned to either 90-90 or parallel plate fixation. We tested anteroposterior displacement at a rate of 0.5 mm/s to a maximum load of ± 100 N for both the articular and entire distal humerus segments. We tested torsional stability at a displacement rate of 0.1 Hz to a maximum torque of ± 2.5 Nm. After cyclical testing, we loaded the specimens in torsion to failure. There was no significant difference in the bone density of the paired specimens. Compared with parallel fixation, 90-90 plate fixation had significantly greater torque to failure load. Both plating constructs were equally sensitive to bone density. Both techniques had the same mode of failure in torsion, a spiral fracture extending from the medial plate at the metaphyseal-diaphyseal junction. There was no significant difference in the stiffness of fixation of the articular fragment or the entire distal segment in anteroposterior loading. This study demonstrated that 90-90 and parallel plating had comparable biomechanical properties for fixation of comminuted intra-articular distal humerus fractures, and that 90-90 plating had greater resistance to torsional loading.


Clinical review: Is lack of recombinant growth hormone (GH)-releasing hormone in the United States a setback or time to consider glucagon testing for adult GH deficiency?
The use of the combined GHRH and arginine (GHRH-ARG) test has gained increasing acceptance in the United States as a reliable alternative test to the insulin tolerance test (ITT) for diagnosing adult GH deficiency (GHD). In July 2008, the only manufacturer of recombinant GHRH in the United States, EMD Serono, Inc., announced the discontinuation of Geref, thus raising the question of which reliable alternative GH stimulation test should practicing endocrinologists be considering in place of the GHRH-ARG test. In this article, we review the existing published data and consensus guidelines and provide recommendations for alternative stimulation tests to the GHRH-ARG test. The major source of data acquisition included PubMed search strategies and personal experience of the authors from clinical experience. Previous consensus guidelines and previous data assessing the reliability and discriminatory value of the GHRH-ARG, glucagon, ARG, and GH secretagogues on assessing GH reserve are discussed. Our recommendations for performing the glucagon stimulation test, potential drawbacks in conducting this test, and caveats in interpreting this test are also discussed. The ITT should remain the test of choice in diagnosing adult GHD. However, when the ITT is not desirable and recombinant GHRH remains unavailable in the United States, we recommend the alternative to the GHRH-ARG test to be the glucagon stimulation test, based on its reliability and availability. Nevertheless, further studies into alternative GH stimulation tests that are available in the United States, comparable, and simpler to perform than the ITT in diagnosing adult GHD are still needed.


Supplementation of saturated long-chain fatty acids maintains intestinal eubiosis and reduces ethanol-induced liver injury in mice.
Alcoholic liver disease is a leading cause of mortality. Chronic alcohol consumption is accompanied by intestinal dysbiosis, and development of alcoholic liver disease requires gut-derived bacterial products. However, little is known about how alterations to the microbiome contribute to pathogenesis of alcoholic liver disease. We used the Tsukamoto-French mouse model, which involves continuous intragastric feeding of isocaloric diet or alcohol for 3 weeks. Bacterial DNA from the cecum was extracted for deep metagenomic sequencing. Targeted metabolomics assessed concentrations of saturated fatty acids in cecal contents. To maintain intestinal metabolic homeostasis, diets of ethanol-fed and control mice were supplemented with saturated long-chain fatty acids (LCFA). Bacterial genes involved in fatty acid biosynthesis, amounts of lactobacilli, and saturated LCFA were measured in fecal samples of nonalcoholic individuals and patients with active alcohol abuse. Analyses of intestinal contents from mice revealed alcohol-associated changes to the intestinal metagenome and metabolome, characterized by reduced synthesis of saturated LCFA. Maintaining intestinal levels of saturated fatty acids in mice resulted in eubiosis, stabilized the intestinal gut barrier, and reduced ethanol-induced liver injury. Saturated LCFA are metabolized by commensal Lactobacillus and promote their growth. Proportions of bacterial genes involved in fatty acid biosynthesis were lower in feces from patients with active alcohol abuse than controls. Total levels of LCFA correlated with those of lactobacilli in fecal samples from patients with active alcohol abuse but not in controls. In humans and mice, alcohol causes intestinal dysbiosis, reducing the capacity of the microbiome to synthesize saturated LCFA and the proportion of Lactobacillus species. Dietary approaches to restore levels of saturated fatty acids in the intestine might reduce ethanol-induced liver injury in patients with alcoholic liver disease.


Genotyping complex structural variation at the malaria-associated human glycophorin locus using a PCR-based strategy.
Structural variation in the human genome can affect risk of disease. An example is a complex structural variant of the human glycophorin gene cluster, called DUP4, which is associated with a clinically significant level of protection against severe malaria. The human glycophorin gene cluster harbours at least 23 distinct structural variants, and accurate genotyping of this complex structural variation remains a challenge. Here, we use a polymerase chain reaction-based strategy to genotype structural variation at the human glycophorin gene cluster, including the alleles responsible for the U- blood group. We validate our approach, based on a triplex paralogue ratio test, on publically available samples from the 1000 Genomes project. We then genotype 574 individuals from a longitudinal birth cohort (Tori-Bossito cohort) using small amounts of DNA at low cost. Our approach readily identifies known deletions and duplications, and can potentially identify novel variants for further analysis. It will allow exploration of genetic variation at the glycophorin locus, and investigation of its relationship with malaria, in large sample sets at minimal cost, using standard molecular biology equipment.


A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma.
Glioblastoma, the most common primary malignant brain tumor among adults, is a highly angiogenic and deadly tumor. Angiogenesis in glioblastoma, driven by hypoxia-dependent and independent mechanisms, is primarily mediated by vascular endothelial growth factor (VEGF), and generates blood vessels with distinctive features. The outcome for patients with recurrent glioblastoma is poor because of ineffective therapies. However, recent encouraging rates of radiographic response and progression-free survival, and adequate safety, led the FDA to grant accelerated approval of bevacizumab, a humanized monoclonal antibody against VEGF, for the treatment of recurrent glioblastoma in May 2009. These results have triggered significant interest in additional antiangiogenic agents and therapeutic strategies for patients with both recurrent and newly diagnosed glioblastoma. Given the potent antipermeability effect of VEGF inhibitors, the Radiologic Assessment in Neuro-Oncology (RANO) criteria were recently implemented to better assess response among patients with glioblastoma. Although bevacizumab improves survival and quality of life, eventual tumor progression is the norm. Better understanding of resistance mechanisms to VEGF inhibitors and identification of effective therapy after bevacizumab progression are currently a critical need for patients with glioblastoma.


Outcomes in Patients With Severe West Nile Neuroinvasive Disease.
To assess the long-term outcomes of patients hospitalized with severe West Nile neuroinvasive disease. Retrospective cohort. Patients admitted to a referral center (Saint Mary's Hospital, Mayo Clinic). Twenty-six patients with West Nile neuroinvasive disease were identified by retrospective search of electronic database of Saint Mary's Hospital from January 1999 to November 2016. Retrospective electronic medical records review and prospective telephone follow-up. Functional disability and cognitive outcomes were evaluated with the modified Rankin Scale and the Telephone Interview for Cognitive Status scores. Data on the time that the patient returned home after the hospitalization for West Nile neuroinvasive disease and the time of return to work were also collected. We identified 26 patients (81% males), 59 ± 17 years old. After a median hospital stay of 14.5 days (3-126), four patients died and 90% of survivors had a modified Rankin Scale of 3-5. Two additional patients died, and 80% of survivors had a modified Rankin Scale of 0-2 after a median follow-up of 73 months (1-144). Seven patients had cognitive impairment, which was severe in two of them. The combination of encephalitis and acute flaccid paralysis at presentation was associated with lower likelihood of returning home within 1 month after discharge (p < 0.01). Patients who required mechanical ventilation were more likely to have a modified Rankin Scale of 3-5 at last follow-up (p = 0.03), less likely to return home within 1 month of discharge (p < 0.01), less likely to return to their jobs (p < 0.01), and showed a trend toward having cognitive impairment (p = 0.05). Despite having poor outcomes at discharge, most West Nile neuroinvasive disease survivors with severe early disability can recover functional independence in the long term, justifying aggressive support during the acute phase and extensive rehabilitation efforts.


Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Antiretrovirals in HIV-Associated Neurocognitive Disorders.
Despite effective viral suppression through combined antiretroviral therapy (cART), approximately half of HIV-positive individuals have HIV-associated neurocognitive disorders (HAND). Studies of antiretroviral-treated patients have revealed persistent white matter abnormalities including diffuse myelin pallor, diminished white matter tracts, and decreased myelin protein mRNAs. Loss of myelin can contribute to neurocognitive dysfunction because the myelin membrane generated by oligodendrocytes is essential for rapid signal transduction and axonal maintenance. We hypothesized that myelin changes in HAND are partly due to effects of antiretroviral drugs on oligodendrocyte survival and/or maturation. We showed that primary mouse oligodendrocyte precursor cell cultures treated with therapeutic concentrations of HIV protease inhibitors ritonavir or lopinavir displayed dose-dependent decreases in oligodendrocyte maturation; however, this effect was rapidly reversed after drug removal. Conversely, nucleoside reverse transcriptase inhibitor zidovudine had no effect. Furthermore, in vivo ritonavir administration to adult mice reduced frontal cortex myelin protein levels. Finally, prefrontal cortex tissue from HIV-positive individuals with HAND on cART showed a significant decrease in myelin basic protein compared with untreated HIV-positive individuals with HAND or HIV-negative controls. These findings demonstrate that antiretrovirals can impact myelin integrity and have implications for myelination in juvenile HIV patients and myelin maintenance in adults on lifelong therapy.


Empirical evidence reveals seasonally dependent reduction in nitrification in coastal sediments subjected to near future ocean acidification.
Research so far has provided little evidence that benthic biogeochemical cycling is affected by ocean acidification under realistic climate change scenarios. We measured nutrient exchange and sediment community oxygen consumption (SCOC) rates to estimate nitrification in natural coastal permeable and fine sandy sediments under pre-phytoplankton bloom and bloom conditions. Ocean acidification, as mimicked in the laboratory by a realistic pH decrease of 0.3, significantly reduced SCOC on average by 60% and benthic nitrification rates on average by 94% in both sediment types in February (pre-bloom period), but not in April (bloom period). No changes in macrofauna functional community (density, structural and functional diversity) were observed between ambient and acidified conditions, suggesting that changes in benthic biogeochemical cycling were predominantly mediated by changes in the activity of the microbial community during the short-term incubations (14 days), rather than by changes in engineering effects of bioturbating and bio-irrigating macrofauna. As benthic nitrification makes up the gross of ocean nitrification, a slowdown of this nitrogen cycling pathway in both permeable and fine sediments in winter, could therefore have global impacts on coupled nitrification-denitrification and hence eventually on pelagic nutrient availability.


Functional constraint and small insertions and deletions in the ENCODE regions of the human genome.
We describe the distribution of indels in the 44 Encyclopedia of DNA Elements (ENCODE) regions (about 1% of the human genome) and evaluate the potential contributions of small insertion and deletion polymorphisms (indels) to human genetic variation. We relate indels to known genomic annotation features and measures of evolutionary constraint. Indel rates are observed to be reduced approximately 20-fold to 60-fold in exonic regions, 5-fold to 10-fold in sequence that exhibits high evolutionary constraint in mammals, and up to 2-fold in some classes of regulatory elements (for instance, formaldehyde assisted isolation of regulatory elements [FAIRE] and hypersensitive sites). In addition, some noncoding transcription and other chromatin mediated regulatory sites also have reduced indel rates. Overall indel rates for these data are estimated to be smaller than single nucleotide polymorphism (SNP) rates by a factor of approximately 2, with both rates measured as base pairs per 100 kilobases to facilitate comparison. Indel rates exhibit a broadly similar distribution across genomic features compared with SNP density rates, with a reduction in rates in coding transcription and evolutionarily constrained sequence. However, unlike indels, SNP rates do not appear to be reduced in some noncoding functional sequences, such as pseudo-exons, and FAIRE and hypersensitive sites. We conclude that indel rates are greatly reduced in transcribed and evolutionarily constrained DNA, and discuss why indel (but not SNP) rates appear to be constrained at some regulatory sites.


Closing the quality gap: revisiting the state of the science (vol. 2: the patient-centered medical home).
As part of the Closing the Quality Gap: Revisiting the State of the Science series of the Agency for Healthcare Research and Quality (AHRQ), this systematic review sought to identify completed and ongoing evaluations of the comprehensive patient-centered medical home (PCMH), summarize current evidence for this model, and identify evidence gaps. We searched PubMed®, CINAHL®, and the Cochrane Database of Systematic Reviews for published English-language studies, and a wide variety of databases and Web resources to identify ongoing or recently completed studies. Two investigators per study screened abstracts and full-text articles for inclusion, abstracted data, and performed quality ratings and evidence grading. Our functional definition of PCMH was based on the definition used by AHRQ. We included studies that explicitly claimed to be evaluating PCMH and those that did not but which met our functional definition. Seventeen studies with comparison groups evaluated the effects of PCMH (Key Question [KQ] 1). Older adults in the United States were the most commonly studied population (8 of 17 studies). PCMH interventions had a small positive impact on patient experiences (including patient-perceived care coordination) and small to moderate positive effects on preventive care services (moderate strength of evidence [SOE]). Staff experiences were also improved by a small to moderate degree (low SOE). There were too few studies to estimate effects on clinical or most economic outcomes. Twenty-one of 27 studies reported approaches that addressed all 7 major PCMH components (KQ 2), including team-based care, sustained partnership, reorganized care or structural changes to care, enhanced access, coordinated care, comprehensive care, and a systems-based approach to quality. A total of 51 strategies were used to address the 7 major PCMH components. Twenty-two of 27 studies reported information on financial systems used to implement PCMH, implementation strategies, and/or organizational learning strategies for implementing PCMH (KQ 3). The 31 studies identified in the horizon scan of ongoing PCMH studies (KQ 4) were broadly representative of the U.S. health care system, both in geography and in the complexity of private and public health care payers and delivery networks. Published studies of PCMH interventions often have similar broad elements, but precise components of care varied widely. The PCMH holds promise for improving the experiences of patients and staff, and potentially for improving care processes. However, current evidence is insufficient to determine effects on clinical and most economic outcomes. Ongoing studies identified through the horizon scan have potential to greatly expand the evidence base relating to PCMH.