Determination of milk concentrations and pharmacokinetics of salicylic acid following acetylsalicylic acid (aspirin) administration in postpartum dairy cows.

The objectives of this descriptive study were to (1) describe the pharmacokinetics of salicylic acid (SA) in the milk and plasma of postpartum dairy cattle following oral administration of acetylsalicylic acid (ASA; aspirin), (2) to estimate a recommended milk withdrawal period for dairy cattle treated with ASA, and (3) to determine the effect of ASA administration on plasma prostaglandin E2 metabolite (PGEM) concentrations. Primiparous (n = 3) and multiparous (n = 7) postpartum Holstein dairy cows received 2 oral treatments with ASA at 200 mg/kg of body weight, 24 h apart. Concentrations of SA in plasma and milk from 0 h through 120 h after ASA administration were analyzed using ultra performance liquid chromatography triple quadrupole mass spectrometry and a milk withdrawal period was estimated using the United States Food and Drug Administration Milk Discard App in R. Two withdrawal periods were estimated: (1) a whole-herd treatment scenario with no dilution factor and (2) an individual animal treatment scenario with a bulk tank factor included in analysis. Plasma PGEM concentrations in samples from 0 h to 24 h after ASA administration were determined using a commercially available competitive ELISA. Milk SA concentrations were undetected in all cows by 48 h after the last ASA treatment. Secondary peaks were observed in plasma at 58 and 82 h after the last treatment and in milk at 87 h after the last treatment. In the absence of a tolerance for SA in milk, the estimated milk withdrawal periods were (1) 156 h for the whole-herd treatment scenario and (2) 120 h for the individual animal treatment scenario. Plasma PGEM concentrations were reduced compared with baseline for up to 12 h after ASA administration, with the greatest reduction observed at 2 h. Results from this study suggest that the current milk withhold recommendation for dairy cattle administered ASA may need revision to 120 h (5 d) and that ASA administration may mitigate postpartum inflammation through reduction in prostaglandin production for up to 12 h after treatment. Pharmacokinetic and milk withdrawal data from this study will inform future recommendations for extra-label use of aspirin in postpartum dairy cows. Further research is required to determine the basis for the secondary SA peaks and to elucidate the long-term effects of ASA administration on dairy cow health.

Effects of milk feeding strategies on short- and long-term productivity of Holstein heifers.

Research investigating the effects of feeding raw or pasteurized nonsaleable milk (NSM) on heifers' performance beyond the period of supplementation is limited. This study aimed to examine the effects of type of milk [NSM or milk replacer (MR)] and pasteurization of NSM on preweaning and first-lactation performance of heifers born with low (<36.3 kg) or normal birth weight (≥36.3 kg). Holstein heifers (n = 154) were sequentially assigned to 1 of 3 treatments: MR, pasteurized NSM, or raw NSM. Heifers assigned to raw NSM were fed raw colostrum, whereas heifers assigned to MR and pasteurized NSM were fed pasteurized colostrum. The low birth weight heifers were fed 1.4 L at each feeding until they reached 36.3 kg body weight, whereas normal birth weight heifers were fed 1.9 L at each feeding. A grain mix starter was offered throughout the study. Heifers were weaned ≥42 d old if consuming at least 0.9 kg/d of starter for 3 consecutive days. Data were analyzed with the MIXED procedure of SAS (SAS Institute Inc., Cary, NC), and the basic model included milk treatments, birth weight group, and treatment × birth weight group. The low birth weight heifers fed raw colostrum and NSM versus pasteurized colostrum and NSM had lower serum protein concentrations. Heifers fed MR versus NSM had or tended to have greater concentrations of hematocrit, red blood cells, and eosinophils but lesser concentrations of platelets, although some of those responses were temporary. Pasteurization tended to increase blood lymphocyte concentrations. Heifers with normal birth weight had greater concentrations of blood neutrophils, lymphocytes, and monocytes, compared with low birth weight heifers. For the first 42 d of life, low birth weight heifers fed pasteurized versus raw NSM had greater weight gain, grain intake, and feed efficiency and were weaned earlier (hazard ratio for weaning by 56 d: 2.90). These pasteurization effects for low birth weight heifers tended to be sustained through 24 wk of age, indicated by greater weight gain and hip height growth. In their first lactation, low birth weight heifers produced less mature-equivalent (MEq) protein and tended to produce less MEq milk and fat than normal birth weight heifers. However, the negative effects of low birth weight on MEq milk and fat yield was only evident in heifers fed raw NSM, whereas the performance of low birth weight heifers was similar to that of normal birth weight when fed MR or pasteurized NSM. These findings confirm that calf management practices influence future performance; in this case, failing to pasteurize milk and colostrum for low birth weight heifers had effects that remained apparent for more than 2 years.

Atopic dermatitis, educational attainment and psychological functioning: a national cohort study.

BACKGROUND: Atopic dermatitis (AD) might adversely affect academic performance, possibly through influences on psychological functioning such as stress resilience. OBJECTIVES: To investigate the association of atopic dermatitis with stress resilience, cognitive function and educational attainment. METHODS: We used data from a national cohort of men who underwent a military conscription examination at ages 17-20 years in Sweden between 1969 and 1976. All potential conscripts met a physician who assessed current or previous history of AD. Stress resilience was measured by a psychologist using a semistructured interview. The conscription assessment included a written cognitive function test. The highest level of education achieved was identified through record linkage. RESULTS: The study population included 234 715 men, 1673 (0·7%) of whom had a diagnosis of AD. AD was associated with a greater risk of low stress resilience [adjusted relative risk ratio (RRR) 1·60, 95% confidence interval (CI) 1·38-1·86]. AD was associated with higher cognitive function (ß-coefficient 0·15, 95% CI 0·05-0·24) and higher educational level (RRR 1·29, 95% CI 1·13-1·47). However, adjustment for socioeconomic characteristics of the family of origin attenuated the magnitude of the associations and eliminated the statistical significance (ß-coefficient 0·06, 95% CI -0·03 to 0·15; RRR 1·16, 95% CI 1·00-1·35). CONCLUSIONS: Swedish men with AD had lower stress resilience in late adolescence but did not have lower cognitive function or poorer educational attainment. The lower stress resilience associated with AD is consistent with an increased risk of possible long-term adverse health outcomes.

Clinical factors predicting treatment resistant depression: affirmative results from the European multicenter study.

OBJECTIVES: Clinical variables were investigated in the 'treatment resistant depression (TRD)- III' sample to replicate earlier findings by the European research consortium 'Group for the Study of Resistant Depression' (GSRD) and enable cross-sample prediction of treatment outcome in TRD. EXPERIMENTAL PROCEDURES: TRD was defined by a Montgomery and Åsberg Depression Rating Scale (MADRS) score ≥22 after at least two antidepressive trials. Response was defined by a decline in MADRS score by ≥50% and below a threshold of 22. Logistic regression was applied to replicate predictors for TRD among 16 clinical variables in 916 patients. Elastic net regression was applied for prediction of treatment outcome. RESULTS: Symptom severity (odds ratio (OR) = 3.31), psychotic symptoms (OR = 2.52), suicidal risk (OR = 1.74), generalized anxiety disorder (OR = 1.68), inpatient status (OR = 1.65), higher number of antidepressants administered previously (OR = 1.23), and lifetime depressive episodes (OR = 1.15) as well as longer duration of the current episode (OR = 1.022) increased the risk of TRD. Prediction of TRD reached an accuracy of 0.86 in the independent validation set, TRD-I. CONCLUSION: Symptom severity, suicidal risk, higher number of lifetime depressive episodes, and comorbid anxiety disorder were replicated as the most prominent risk factors for TRD. Significant predictors in TRD-III enabled robust prediction of treatment outcome in TRD-I.

Effects of sodium salicylate on glucose kinetics and insulin signaling in postpartum dairy cows.

Low-grade inflammation has been implicated as a contributor to metabolic disease during the transition to lactation. In previous work, administration of sodium salicylate (SS) for 7 d led to hypoglycemia in mature dairy cows in early lactation. The purpose of this study was to identify the mode of action underlying this response to SS. Twenty mature (parity 3) cows were assigned alternately at time of calving to either control or SS treatments; the control received a molasses placebo in drinking water, whereas SS received 2.3 g/L of SS with the molasses carrier in drinking water for 7 d after parturition. Blood samples were collected daily. A glucose turnover assay was performed on d 7, followed by liver, muscle, and adipose tissue biopsies. There were no treatment effects on intake of dry matter or water. Tumor necrosis factor α mRNA abundance tended to be decreased by SS in adipose tissue but not in muscle or liver, and plasma haptoglobin and adiponectin concentrations were not altered by treatment. Treatment did not significantly alter plasma glucose or insulin concentrations, but plasma glucagon concentration tended to be increased by SS and the insulin:glucagon molar ratio was significantly decreased. Cows on SS had a tendency for a 25% decrease in glucose turnover rate compared with control cows. However, there were no differences in transcript abundance of pyruvate carboxylase (PC) or glucose-6-phosphatase (G6PC) in liver or of glucose transporter 4 (GLUT4) in any of the tissues. Finally, SS did not alter insulin receptor substrate-1 phosphorylation in muscle or adipose, but tended to increase phosphorylation of AMP-activated protein kinase and decrease protein kinase B phosphorylation in adipose tissue. These findings may be explained by enhanced hepatic insulin sensitivity leading to posttranscriptional suppression of gluconeogenesis and adaptive responses to decreased glucose supply in the pancreas and adipose tissue.

Clinical correlates of augmentation/combination treatment strategies in major depressive disorder.

OBJECTIVE: This multicenter, multinational, cross-sectional study aimed to investigate clinical characteristics and treatment outcomes associated with augmentation/combination treatment strategies in major depressive disorder (MDD). METHOD: Sociodemographic, clinical, and treatment features of 1410 adult MDD patients were compared between MDD patients treated with monotherapy and augmentation/combination medication using descriptive statistics, analyses of covariance (ancova), and Spearman's correlation analyses. RESULTS: 60.64% of all participants received augmentation and/or combination strategies with a mean number of 2.18 ± 1.22 simultaneously prescribed psychiatric drugs. We found male gender, older age, Caucasian descent, higher weight, low educational status, absence of occupation, psychotic symptoms, melancholic and atypical features, suicide risk, in-patient treatment, longer duration of hospitalization, some psychiatric comorbidities (panic disorder, agoraphobia, obsessive-compulsive disorder, and bulimia nervosa), comorbid somatic comorbidity in general and concurrent hypertension, thyroid dysfunction, diabetes, and heart disease in particular, higher current and retrospective Montgomery and Åsberg Depression Rating Scale total scores, treatment resistance, and higher antidepressant dosing to be significantly associated with augmentation/combination treatment. These findings were corroborated when examining the number of concurrently administered psychiatric drugs in the statistical analyses. CONCLUSION: Our findings suggest a clear association between augmentation/combination strategies and treatment-resistant/difficult-to-treat MDD conditions characterized by severe symptomatology and high amount of psychiatric and somatic comorbidities.

Divergence in brain composition during the early stages of ecological specialization in Heliconius butterflies.

During speciation across ecological gradients, diverging populations are exposed to contrasting sensory and spatial information that present new behavioural and perceptive challenges. These challenges may be met by heritable or environmentally induced changes in brain function which mediate behaviour. However, few studies have investigated patterns of neural divergence at the early stages of speciation, inhibiting our understanding of the relative importance of these processes. Here, we provide a novel case study. The incipient species pair, Heliconius erato and H. himera, are parapatric across an environmental and altitudinal gradient. Despite ongoing gene flow, these species have divergent ecological, behavioural and physiological traits. We demonstrate that these taxa also differ significantly in brain composition, in particular in the relative levels of investment in structures that process sensory information. These differences are not explained solely by environmentally-induced plasticity, but include heritable, nonallometric shifts in brain structure. We suggest these differences reflect divergence to meet the demands of contrasting sensory ecologies. This conclusion would support the hypothesis that the evolution of brain structure and function play an important role in facilitating the emergence of ecologically distinct species.

Multiple sclerosis and risk of attempted and completed suicide - a cohort study.

BACKGROUND AND PURPOSE: Patients with multiple sclerosis (MS) are known to have an elevated suicide risk, but attempted suicide is incompletely investigated. The relation between education level and suicidality has not been investigated in MS patients. Our objective was to estimate attempted suicide and completed suicide risks amongst MS patients. METHODS: A total of 29 617 Swedish MS patients were identified through the Swedish Patient Register and matched with 296 164 people without MS from the general population. Cox regression analysis estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of MS with attempted and completed suicide, with adjustment for age, sex, education and calendar period. RESULTS: The adjusted HR for attempted suicide amongst MS patients is 2.18 (95% CI 1.97-2.43) compared with the general population cohort. For completed suicide the HR is 1.87 (95% CI 1.53-2.30). In both groups women are at higher risk of attempting suicide, whilst men are at higher risk of completing suicide. Education level is inversely associated with completed suicide amongst the non-MS cohort (0.68, 0.51-0.91), but not amongst MS patients (1.10, 0.60-2.04). CONCLUSION: Multiple sclerosis patients are at higher risk of both attempted and completed suicide. No evidence was found of an inverse association between educational level and risk of completed suicide amongst MS patients.

Evaluation of TLR4 Inhibitor, T5342126, in Modulation of Ethanol-Drinking Behavior in Alcohol-Dependent Mice.

AIMS: Several lines of evidence support a critical role of TLR4 in the neuroimmune responses associated with alcohol disorders and propose inhibitors of TLR4 signaling as potential treatments for alcoholism. In this work, we investigated the effect of T5342126 compound, a selective TLR4 inhibitor, on excessive drinking and microglial activation associated with ethanol dependence. METHODS: We used 2BC-CIE (two-bottle choice-chronic ethanol intermittent vapor exposure) paradigm to induce ethanol dependence in mice. After induction of the ethanol dependence, we injected T5342126 (i.p., 57 mg/kg) for 14 days while monitoring ethanol intake by 2BC (limited access to ethanol) method. RESULTS: T5342126 decreased ethanol drinking in both ethanol-dependent and non-dependent mice but T5342126 showed also dose-dependent non-specific effects represented by decreased animal locomotor activity, saccharine intake, and body core temperature. Six days after the last ethanol-drinking session, we examined the immunohistochemical staining of Iba-1 (ionized calcium-binding adapter molecule 1), a microglial activation marker, in the central nucleus of the amygdala (CeA) and dentate gyrus (DG) of the hippocampus. Notably, T5342126 reduced Iba-1 density in the CeA of both ethanol-dependent and non-dependent mice injected with T5342126. There were no significant differences in the DG Iba-1 density among the treatment groups. CONCLUSIONS: Collectively, our data suggest that T5342126, via blocking TLR4 activation, contributes to the reduction of ethanol drinking and ethanol-induced neuroimmune responses. However, the non-specific effects of T5342126 may play a significant role in the T5342126 effects on ethanol drinking and thus, may limit its therapeutic potential for treatment of alcohol dependence. SHORT SUMMARY: T5342126, an experimental TLR4 inhibitor, is effective in reducing ethanol drinking and inhibiting the activation and proliferation of microglia in both ethanol-dependent and non-dependent mice. However, T5342126's use as a potential candidate for the treatment of alcohol addiction may be limited due to its non-specific effects.

Long-term pattern of opioid prescriptions after femoral shaft fractures.

BACKGROUND: The use of opioids in non-cancer-related pain following skeletal trauma is controversial due to the presumed risk of dose escalation and dependence. We therefore examined the pattern of opioid prescriptions, that is, those actually dispensed, in patients with femoral shaft fractures. METHODS: We analysed data from the Swedish National Hospital Discharge Register and the Swedish Prescribed Drug Register between 2005 and 2008. RESULTS: We identified 1471 patients with isolated femoral shaft fractures. The median age was 75 (16-102) years and 56% were female. In this cohort, 891 patients (61%) received dispensed opioid prescriptions during a median follow-up of 20 months (interquartile range 11-32). In the age- and sex-matched comparison cohort (7339 individuals) without fracture, 25% had opioid prescriptions dispensed during the same period. The proportions of patients receiving opioid analgesics at 6 and 12 months after the fracture were 45% (95% CI 42-49) and 36% (32-39), respectively. The median daily morphine equivalent dose (MED) was between 15 and 17 mg 1-12 months post-fracture. After 3 months, less than 5% used prescription doses higher than 20 mg MED per day. Older age (≥ 70 compared with < 70 years) was a significant predictor of earlier discontinuation of opioid use (Hazard ratio [HR] 1.9). CONCLUSION: A notable proportion of patients continued to receive dispensed prescriptions for opioids for over 6 months (45%) and more than a third of them (36%) continued treatment for at least 12 months. However, the risk of dose escalation seems to be small in opioid-naïve patients.

Donor-derived Strongyloides stercoralis infection in solid organ transplant recipients in the United States, 2009-2013.

Infection with Strongyloides stercoralis is typically asymptomatic in immunocompetent hosts, despite chronic infection. In contrast, immunocompromised hosts such as solid organ transplant recipients are at risk for hyperinfection syndrome and/or disseminated disease, frequently resulting in fatal outcomes. Infection in these recipients may result from reactivation of latent infection or infection through transmission from an infected donor. We describe the Centers for Disease Control and Prevention's experience with seven clusters of donor-derived infection from 2009 to 2013. Six of the seven (86%) donors were born in Latin America; donor screening was not performed prior to organ transplantation in any of these investigations. Eleven of the 20 (55%) organ recipients were symptomatic, two of whom died from complications of strongyloidiasis. We also describe the New York Organ Donor Network (NYODN) experience with targeted donor screening from 2010 to 2013. Of the 233 consented potential donors tested, 10 tested positive for Strongyloides antibody; and 18 organs were transplanted. The majority (86%) of the donors were born in Central or South America. Fourteen recipients received prophylaxis after transplantation; no recipients developed strongyloidiasis. The NYODN experience provides evidence that when targeted donor screening is performed prior to transplantation, donor-derived infection can be averted in recipients.

Neuronal cell adhesion genes and antidepressant response in three independent samples.

Drug-effect phenotypes in human lymphoblastoid cell lines recently allowed to identify CHL1 (cell adhesion molecule with homology to L1CAM), GAP43 (growth-associated protein 43) and ITGB3 (integrin beta 3) as new candidates for involvement in the antidepressant effect. CHL1 and ITGB3 code for adhesion molecules, while GAP43 codes for a neuron-specific cytosolic protein expressed in neuronal growth cones; all the three gene products are involved in synaptic plasticity. Sixteen polymorphisms in these genes were genotyped in two samples (n=369 and 90) with diagnosis of major depressive episode who were treated with antidepressants in a naturalistic setting. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) genome-wide study (n=1861) as both individual genes and through a pathway analysis (Reactome and String databases). Gene-based analysis suggested CHL1 rs4003413, GAP43 rs283393 and rs9860828, ITGB3 rs3809865 as the top candidates due to their replication across the largest original sample and the STAR*D cohort. GAP43 molecular pathway was associated with both response and remission in the STAR*D, with ELAVL4 representing the gene with the highest percentage of single nucleotide polymorphisms (SNPs) associated with outcomes. Other promising genes emerging from the pathway analysis were ITGB1 and NRP1. The present study was the first to analyze cell adhesion genes and their molecular pathways in antidepressant response. Genes and biomarkers involved in neuronal adhesion should be considered by further studies aimed to identify predictors of antidepressant response.

The diversification of Heliconius butterflies: what have we learned in 150 years?

Research into Heliconius butterflies has made a significant contribution to evolutionary biology. Here, we review our understanding of the diversification of these butterflies, covering recent advances and a vast foundation of earlier work. Whereas no single group of organisms can be sufficient for understanding life's diversity, after years of intensive study, research into Heliconius has addressed a wide variety of evolutionary questions. We first discuss evidence for widespread gene flow between Heliconius species and what this reveals about the nature of species. We then address the evolution and diversity of warning patterns, both as the target of selection and with respect to their underlying genetic basis. The identification of major genes involved in mimetic shifts, and homology at these loci between distantly related taxa, has revealed a surprising predictability in the genetic basis of evolution. In the final sections, we consider the evolution of warning patterns, and Heliconius diversity more generally, within a broader context of ecological and sexual selection. We consider how different traits and modes of selection can interact and influence the evolution of reproductive isolation.

Type I interferon signaling genes in recurrent major depression: increased expression detected by whole-blood RNA sequencing.

A study of genome-wide gene expression in major depressive disorder (MDD) was undertaken in a large population-based sample to determine whether altered expression levels of genes and pathways could provide insights into biological mechanisms that are relevant to this disorder. Gene expression studies have the potential to detect changes that may be because of differences in common or rare genomic sequence variation, environmental factors or their interaction. We recruited a European ancestry sample of 463 individuals with recurrent MDD and 459 controls, obtained self-report and semi-structured interview data about psychiatric and medical history and other environmental variables, sequenced RNA from whole blood and genotyped a genome-wide panel of common single-nucleotide polymorphisms. We used analytical methods to identify MDD-related genes and pathways using all of these sources of information. In analyses of association between MDD and expression levels of 13 857 single autosomal genes, accounting for multiple technical, physiological and environmental covariates, a significant excess of low P-values was observed, but there was no significant single-gene association after genome-wide correction. Pathway-based analyses of expression data detected significant association of MDD with increased expression of genes in the interferon α/ß signaling pathway. This finding could not be explained by potentially confounding diseases and medications (including antidepressants) or by computationally estimated proportions of white blood cell types. Although cause-effect relationships cannot be determined from these data, the results support the hypothesis that altered immune signaling has a role in the pathogenesis, manifestation, and/or the persistence and progression of MDD.

All-cause mortality following a cancer diagnosis amongst multiple sclerosis patients: a Swedish population-based cohort study.

BACKGROUND AND PURPOSE: A reduced cancer risk amongst patients with multiple sclerosis (MS) has been reported. Theoretically, this could represent a genuine reduction in risk or, alternatively, 'diagnostic neglect', where cancer is undiagnosed when symptoms are misattributed to MS. OBJECTIVE: Assess all-cause mortality risk following a cancer diagnosis in patients with MS compared with a cohort without MS. PATIENTS: A cohort of MS patients (n = 19,364) and a cohort of the general population (n = 192,519) were extracted from national Swedish registers from 1969 to 2005. All-cause mortality after cancer in MS was compared with the general population. Poisson regression analysis was conducted in the MS and non-MS cohorts separately. The models were adjusted for follow-up duration, year at entry, sex, region and socioeconomic index. The two cohorts were combined and differences in mortality risk were assessed using interaction testing. RESULTS: The adjusted relative risk (and 95% confidence interval) for all-cause mortality following a cancer diagnosis in MS patients (compared with MS patients without cancer) is 3.06 (2.86-3.27; n = 1768) and amongst those without MS 5.73 (5.62-5.85; n = 24,965). This lower magnitude mortality risk in the MS patients was confirmed by multiplicative interaction testing (P < 0.001). CONCLUSIONS: A consistent pattern of lower magnitude of all-cause mortality risk following cancer in MS patients for a range of organ-specific cancer types was found. It suggests that cancer diagnoses tend not to be delayed in MS and diagnostic neglect is unlikely to account for the reduced cancer risk associated with MS. The lower magnitude cancer risk in MS may be due to disease-associated characteristics or exposures.

Characteristics in childhood and adolescence associated with future multiple sclerosis risk in men: cohort study.

BACKGROUND AND PURPOSE: Associations with multiple sclerosis (MS) of living conditions in childhood and characteristics in adolescence including physical fitness, cognitive function and psychological stress resilience were investigated. METHODS: A cohort of male Swedish residents born 1952-1956 who were included in the Swedish Military Conscription Register was used to create a nested case-control study comprising 628 MS cases and 6187 controls matched on birth year, county of residence and vital status at time of diagnosis. Conscription examination records were linked with other national register data. Conditional logistic regression was used to evaluate associations with MS subsequent to the conscription examination. RESULTS AND CONCLUSIONS: Men with MS were less likely to be from more crowded households in childhood (>two persons per room) with an adjusted odds ratio of 0.67 (95% confidence interval 0.51-0.86, P = 0.023). They had lower physical working capacity in adolescence with adjusted odds ratio of 0.94 (95% confidence interval 0.89-0.99, P = 0.026). Cognitive function and stress resilience scores displayed no significant differences between cases and controls. Parental occupation in childhood and body mass index in adolescence were not associated with future MS risk. The inverse association of MS risk with higher levels of household crowding may reflect environmental factors such as the pattern of exposure to microorganisms. Lower physical fitness in men at MS risk may indicate a protective effect of exercise or could be due to prodromal disease activity, although there was no association with cognitive function. Poor psychological stress resilience (and thus risk of chronic stress arousal) was not associated with MS.

Single donor-derived strongyloidiasis in three solid organ transplant recipients: case series and review of the literature.

Donor-derived Strongyloides stercoralis infections in transplant recipients are a rare but recognized complication. In this case series, we report donor-derived allograft transmission of Strongyloides in three solid organ transplant recipients. Following detection of infection in heart and kidney-pancreas recipients at two different transplant centers, a third recipient from the same donor was identified and diagnosed. S. stercoralis larvae were detected in duodenal aspirates, bronchial washings, cerebrospinal fluid, urine and stool specimens. Treatment with ivermectin and albendazole was successful in two of the three patients identified. The Centers for Disease Control and Prevention was contacted and performed an epidemiologic investigation. Donor serology was strongly positive for S. stercoralis antibodies on retrospective testing while all pretransplant recipient serum was negative. There should be a high index of suspicion for parasitic infection in transplant recipients and donors from endemic regions of the world. This case series underscores the need for expanded transplant screening protocols for Strongyloides. Positive serologic or stool tests should prompt early treatment or prophylaxis in donors and recipients as well as timely notification of organ procurement organizations and transplant centers.

Determining causality and consequence of expression quantitative trait loci.

Expression quantitative trait loci (eQTLs) are currently the most abundant and systematically-surveyed class of functional consequence for genetic variation. Recent genetic studies of gene expression have identified thousands of eQTLs in diverse tissue types for the majority of human genes. Application of this large eQTL catalog provides an important resource for understanding the molecular basis of common genetic diseases. However, only now has both the availability of individuals with full genomes and corresponding advances in functional genomics provided the opportunity to dissect eQTLs to identify causal regulatory variants. Resolving the properties of such causal regulatory variants is improving understanding of the molecular mechanisms that influence traits and guiding the development of new genome-scale approaches to variant interpretation. In this review, we provide an overview of current computational and experimental methods for identifying causal regulatory variants and predicting their phenotypic consequences.

PPP3CC gene: a putative modulator of antidepressant response through the B-cell receptor signaling pathway.

Antidepressant pharmacogenetics represents a stimulating, but often discouraging field. The present study proposes a combination of several methodologies across three independent samples. Genes belonging to monoamine, neuroplasticity, circadian rhythm and transcription factor pathways were investigated in two samples (n=369 and 88) with diagnosis of major depression who were treated with antidepressants. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) genome-wide study (n=1861). Top genes were further studied through a pathway analysis. In both original samples, markers associated with outcomes were concentrated in the PPP3CC gene. Other interesting findings were particularly in the HTR2A gene in one original sample and the STAR*D. The B-cell receptor signaling pathway proved to be the putative mediator of PPP3CC's effect on antidepressant response (P=0.03). Among innovative candidates, PPP3CC, involved in the regulation of immune system and synaptic plasticity, seems promising for further investigation.

Multiple sclerosis clinical course and cardiovascular disease risk - Swedish cohort study.

BACKGROUND AND PURPOSE: Cardiovascular disease (CVD) risk amongst multiple sclerosis (MS) patients appears raised, but few studies have examined CVD risk amongst an unselected MS patient group. MS course may be relevant for CVD risk. Our aim was to assess CVD risk and variation by course in MS patients. METHODS: The Multiple Sclerosis Register identified 7667 patients who received an MS diagnosis between 1964 and 2005. They were matched by age, period, region and sex with 76 045 members of the general population without MS using Swedish registers. Poisson regression compared the two cohorts to estimate the relative risk for CVD, overall, as well as grouped and individual CVD diagnoses. RESULTS: MS patients had an increased adjusted relative risk (with 95% confidence intervals; number of MS cohort events) for CVD of 1.31 (1.22-1.41; n = 847), with some variation by course: relapsing-remitting 1.38 (1.17-1.62; n = 168); secondary progressive 1.30 (1.18-1.53; n = 405) and primary progressive 1.15 (0.93-1.41; n = 108). The association for the relapsing-remitting course was not significant after excluding the first year of follow-up. Overall incidence rates per 1000 person-years for CVD are 11.8 (11.06-12.66) for the MS cohort and 8.8 (8.60-9.05) for the non-MS cohort. The most pronounced association was for deep vein thrombosis: relapsing-remitting 2.16 (1.21-3.87; n = 14), secondary progressive 3.41 (2.45-4.75; n = 52) and primary progressive 3.57 (1.95-6.56; n = 15). MS was associated with ischaemic stroke but largely during the first year of follow-up. MS was associated with a decreased relative risk for angina pectoris and atrial fibrillation. CONCLUSIONS: There is a significantly increased relative risk for CVD in MS, particularly for venous thromboembolic disorders in progressive MS, suggesting immobility as a possible factor. An increased frequency of ischaemic stroke in MS is most probably due to surveillance bias resulting from diagnostic investigations for MS. There is no increased relative risk for ischaemic heart disease in MS and atrial fibrillation appears to be less common than amongst the general population.