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Keep the 'phospho' on MAPK, be happy

Wed, 03/09/2016 - 1:02pm

Depression ruins the lives of millions of people, causing dysphoria and anguish. New findings in rodents and human brain shed light on the mechanisms of this disease, uncovering a phosphatase as a new target to treat depressive behaviors. Comment on: A negative regulator of MAP kinase causes depressive behavior. [Nat Med. 2010]

Hippocampal c-Jun-N-terminal kinases serve as negative regulators of associative learning

Wed, 03/09/2016 - 1:02pm

In the adult mouse, signaling through c-Jun N-terminal kinases (JNKs) links exposure to acute stress to various physiological responses. Inflammatory cytokines, brain injury and ischemic insult, or exposure to psychological acute stressors induce activation of hippocampal JNKs. Here we report that exposure to acute stress caused activation of JNKs in the hippocampal CA1 and CA3 subfields, and impaired contextual fear conditioning. Conversely, intrahippocampal injection of JNKs inhibitors sp600125 (30 mum) or D-JNKI1 (8 mum) reduced activity of hippocampal JNKs and rescued stress-induced deficits in contextual fear. In addition, intrahippocampal administration of anisomycin (100 mug/mul), a potent JNKs activator, mimicked memory-impairing effects of stress on contextual fear. This anisomycin-induced amnesia was abolished after cotreatment with JNKs selective inhibitor sp600125 without affecting anisomycin's ability to effectively inhibit protein synthesis as measured by c-Fos immunoreactivity. We also demonstrated milder and transient activation of the JNKs pathway in the CA1 subfield of the hippocampus during contextual fear conditioning and an enhancement of contextual fear after pharmacological inhibition of JNKs under baseline conditions. Finally, using combined biochemical and transgenic approaches with mutant mice lacking different members of the JNK family (Jnk1, Jnk2, and Jnk3), we provided evidence that JNK2 and JNK3 are critically involved in stress-induced deficit of contextual fear, while JNK1 mainly regulates baseline learning in this behavioral task. Together, these results support the possibility that hippocampal JNKs serve as a critical molecular regulator in the formation of contextual fear.

Requirement of JIP1-mediated c-Jun N-terminal kinase activation for obesity-induced insulin resistance

Wed, 03/09/2016 - 1:01pm

The c-Jun NH(2)-terminal kinase (JNK) interacting protein 1 (JIP1) has been proposed to act as a scaffold protein that mediates JNK activation. However, recent studies have implicated JIP1 in multiple biochemical processes. Physiological roles of JIP1 that are related to the JNK scaffold function of JIP1 are therefore unclear. To test the role of JIP1 in JNK activation, we created mice with a germ line point mutation in the Jip1 gene (Thr(103) replaced with Ala) that selectively blocks JIP1-mediated JNK activation. These mutant mice exhibit a severe defect in JNK activation caused by feeding of a high-fat diet. The loss of JIP1-mediated JNK activation protected the mutant mice against obesity-induced insulin resistance. We conclude that JIP1-mediated JNK activation plays a critical role in metabolic stress regulation of the JNK signaling pathway.

The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice

Wed, 03/09/2016 - 1:01pm

Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member-encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-beta-activated kinase 1 (TAK1; also known as MAP3K7) as the critical activator upstream of p38 in osteoblasts. Osteoblast-specific deletion of Tak1 resulted in clavicular hypoplasia and delayed fontanelle fusion, a phenotype similar to the cleidocranial dysplasia observed in humans haploinsufficient for the transcription factor runt-related transcription factor 2 (Runx2). Mechanistic analysis revealed that the TAK1-MKK3/6-p38 MAPK axis phosphorylated Runx2, promoting its association with the coactivator CREB-binding protein (CBP), which was required to regulate osteoblast genetic programs. These findings reveal an in vivo function for p38beta and establish that MAPK signaling is essential for bone formation in vivo. These results also suggest that selective p38beta agonists may represent attractive therapeutic agents to prevent bone loss associated with osteoporosis and aging.

Distinct roles of c-Jun N-terminal kinase isoforms in neurite initiation and elongation during axonal regeneration

Wed, 03/09/2016 - 1:00pm

c-Jun N-terminal kinases (JNKs) (comprising JNK1-3 isoforms) are members of the MAPK (mitogen-activated protein kinase) family, activated in response to various stimuli including growth factors and inflammatory cytokines. Their activation is facilitated by scaffold proteins, notably JNK-interacting protein-1 (JIP1). Originally considered to be mediators of neuronal degeneration in response to stress and injury, recent studies support a role of JNKs in early stages of neurite outgrowth, including adult axonal regeneration. However, the function of individual JNK isoforms, and their potential effector molecules, remained unknown. Here, we analyzed the role of JNK signaling during axonal regeneration from adult mouse dorsal root ganglion (DRG) neurons, combining pharmacological JNK inhibition and mice deficient for each JNK isoform and for JIP1. We demonstrate that neuritogenesis is delayed by lack of JNK2 and JNK3, but not JNK1. JNK signaling is further required for sustained neurite elongation, as pharmacological JNK inhibition resulted in massive neurite retraction. This function relies on JNK1 and JNK2. Neurite regeneration of jip1(-/-) DRG neurons is affected at both initiation and extension stages. Interestingly, activated JNKs (phospho-JNKs), as well as JIP1, are also present in the cytoplasm of sprouting or regenerating axons, suggesting a local action on cytoskeleton proteins. Indeed, we have shown that JNK1 and JNK2 regulate the phosphorylation state of microtubule-associated protein MAP1B, whose role in axonal regeneration was previously characterized. Moreover, lack of MAP1B prevents neurite retraction induced by JNK inhibition. Thus, signaling by individual JNKs is differentially implicated in the reorganization of the cytoskeleton, and neurite regeneration.

cJun NH2-terminal kinase 1 (JNK1): roles in metabolic regulation of insulin resistance

Wed, 03/09/2016 - 1:00pm

The cJun NH(2)-terminal kinase isoform JNK1 is implicated in the mechanism of obesity-induced insulin resistance. Feeding a high-fat diet causes activation of the JNK1 signaling pathway, insulin resistance, and obesity in mice. Germ-line ablation of Jnk1 prevents both diet-induced obesity and insulin resistance. Genetic analysis indicates that the effects of JNK1 on insulin resistance can be separated from effects of JNK1 on obesity. Emerging research indicates that JNK1 plays multiple roles in the regulation of insulin resistance, including altered gene expression, hormone/cytokine production, and lipid metabolism. Together, these studies establish JNK1 as a potential pharmacological target for the development of drugs that might be useful for the treatment of insulin resistance, metabolic syndrome, and type 2 diabetes.

JNK-mediated phosphorylation of Cdc25C regulates cell cycle entry and G(2)/M DNA damage checkpoint

Wed, 03/09/2016 - 1:00pm

c-Jun NH(2)-terminal Kinases (JNKs) play a central role in the cellular response to a wide variety of stress signals. After their activation, JNKs induce phosphorylation of substrates, which control proliferation, migration, survival, and differentiation. Recent studies suggest that JNKs may also play a role in cell cycle control, although the underlying mechanisms are largely unexplored. Here we show that JNK directly phosphorylates Cdc25C at serine 168 during G(2) phase of the cell cycle. Cdc25C phosphorylation by JNK negatively regulates its phosphatase activity and thereby Cdk1 activation, enabling a timely control of mitosis onset. Unrestrained phosphorylation by JNK, as obtained by a cell cycle-stabilized form of JNK or as seen in some human tumors, results in aberrant cell cycle progression. Additionally, UV irradiation-induced G(2)/M checkpoint requires inactivation of Cdc25C by JNK phosphorylation. JNK phosphorylation of Cdc25C as well as Cdc25A establishes a novel link between stress signaling and unperturbed cell cycle and checkpoint pathways.

Staufen Negatively Modulates microRNA Activity in Caenorhabditis elegans

Wed, 03/09/2016 - 12:01pm

The double-stranded RNA-binding protein Staufen has been implicated in various post-transcriptional gene regulatory processes. Here we demonstrate that the Caenorhabditis elegans homolog of Staufen, STAU-1, functionally interacts with microRNAs. Loss-of-function mutations of stau-1 significantly suppress phenotypes of let-7 family microRNA mutants, a hypomorphic allele of dicer and a lsy-6 microRNA partial loss-of-function mutant. Furthermore, STAU-1 modulates the activity of lin-14, a target of lin-4 and let-7 family microRNAs, and this modulation is abolished when the 3' untranslated region of lin-14 is removed. Deep sequencing of small RNA cDNA libraries reveals no dramatic change in the levels of microRNAs, or other small RNA populations between wild type and stau-1 mutant, with the exception of certain endogenous siRNAs in the WAGO pathway. The modulation of microRNA activity by STAU-1 does not seem to be associated with the previously reported enhanced exogenous RNAi (Eri) phenotype of stau-1 mutants since eri-1 exhibits the opposite effect on microRNA activity. Altogether, our results suggest that STAU-1 negatively modulates microRNA activity downstream of biogenesis, possibly by competing with microRNAs for binding on the 3' untranslated region of target mRNAs.

Development and Psychometric Testing of the EFURMS Scale: An Instrument to Measure Faculty Engagement with Underrepresented Minority Nursing Students: A Dissertation

Tue, 03/08/2016 - 12:31pm

Background: The Institute of Medicine and numerous other healthcare organizations have identified the severe shortage of underrepresented minority healthcare professionals graduating into the workforce, and have called for a radical transformation of healthcare educational programs to make them more welcoming and supportive of underrepresented minority students.

Purpose: The purpose of the study was to develop a reliable and valid measure of faculty response patterns to the needs of underrepresented minority nursing students.

Theory: Yoder’s patterns of faculty interaction formed the conceptual basis for the development of this instrument.

Methods: A mixed-method approach was used to develop this instrument. The first phase (item development phase) consisted of work with underrepresented minority nurse and faculty focus groups, individual interviews, and content experts to develop items. During the second phase of this study, psychometric evaluation of 134 survey responses from nursing faculty in the Northeast was conducted.

Results: A 10-item scale was developed that measured faculty engagement with underrepresented minority nursing students. The Cronbach alpha for the EFURMS scale was .81. Principle component factor analysis with varimax rotation revealed a 3 factor solution that explained 66% of the variance in engagement with underrepresented minority students. The Cronbach alpha for the 3 factors ranged from .72-.78. The EFURM scale did not demonstrate ceiling or floor effects, or social desirability bias. More positive scores (higher EFURMS Scores) were associated with older faculty who had been teaching longer and had more experience teaching underrepresented minority students.

Conclusion and Implications: The results of this study provide preliminary evidence for the reliability (internal consistency) and validity (content, criterion-related, and construct validity) of the 10-item EFURMS Scale. Further testing is needed to test the usefulness of this scale with wider samples of nursing faculty. With further development, the EFURMS Scale could be used to evaluate faculty readiness to engage with underrepresented minority students, and with studies to test the efficacy of interventions designed to improve faculty engagement with underrepresented minority students. A major finding of this study was the significance of age, years teaching, and experience teaching underrepresented minority students with EFURMS Scores suggesting that younger or less experienced faculty could benefit from mentoring by more seasoned faculty who have greater experience teaching underrepresented minority students.

Educating Grandparents of Grandchildren with Type I Diabetes Using Simulation: A Dissertation

Tue, 03/08/2016 - 12:31pm

The purpose of this study was to explore the feasibility of using human patient simulation (HPS) to teach Type 1 diabetes (T1DM) management to grandparents of grandchildren with T1DM. Thirty grandparents (11 male, 19 female) of young grandchildren (aged 12 and under) with T1DM were recruited from an urban medical center. Experimental group (n = 14) grandparents received hands-on visual T1DM management education using an HPS intervention, and control group (n = 16) grandparents received similar education using a non-HPS intervention.

Post-intervention, researchers interviewed twelve grandparents (50% HPS, 50% non-HPS) who scored highest and lowest on the Hypoglycemia Fear Survey. Using a mixed-method design, researchers integrated study instrument data and post-intervention interview data to describe grandparent’s experience learning T1DM management. Post-intervention, grandparent scores for knowledge, confidence, and fear showed no significant difference by group assignment, however, all grandparent scores showed improvement from Time 1 to Time 2. Grandparents described how taking part in T1DM education heightened their awareness of T1DM risks. GP T1DM knowledge gains aided GPs to make sense of T1DM risks. Newfound T1DM knowledge enhanced GP T1DM management confidence. Improved T1DM knowledge and confidence helped to defuse T1DM management fear. Although study instruments did not measure significant difference between grandparents who received the HPS intervention and those who did not, the consistency of larger HPS-taught grandparent score improvement is suggestive of a benefit for HPS.

eMental Health Bridges Project: A Web Site Development Project to Provide Needed Mental and Physical Health Information to People with Serious Mental Illness

Mon, 03/07/2016 - 4:51pm

The eMental Health Bridges project will promote health literacy by developing, testing, and implementing: 1) eMH4me training modules to provide guidance for individuals with SMI on web-based information searching, judging source and site credibility, and interpreting data; and 2) web site prototypes that will serve as a connection to essential physical health information for individuals living with SMI. eMental Health Bridges will embrace user experience and design accommodations required for individuals with SMI to benefit fully from eHealth resources.

Implementation and use of a crisis hotline during the treatment as usual and universal screening phases of a suicide intervention study

Fri, 03/04/2016 - 12:28pm

BACKGROUND: Although research suggests that crisis hotlines are an effective means of mitigating suicide risk, lack of empirical evidence may limit the use of this method as a research safety protocol. PURPOSE: This study describes the use of a crisis hotline to provide clinical backup for research assessments. METHODS: Data were analyzed from participants in the Emergency Department Safety and Follow-up Evaluation (ED-SAFE) study (n=874). Socio-demographics, call completion data, and data available on suicide attempts occurring in relation to the crisis counseling call were analyzed. Pearson chi-squared statistic for differences in proportions were conducted to compare characteristics of patients receiving versus not receiving crisis counseling. P<0.05 was considered statistically significant. RESULTS: Overall, there were 163 counseling calls (6% of total assessment calls) from 135 (16%) of the enrolled subjects who were transferred to the crisis line because of suicide risk identified during the research assessment. For those transferred to the crisis line, the median age was 40 years (interquartile range 27-48) with 67% female, 80% white, and 11% Hispanic. CONCLUSIONS: Increasing demand for suicide interventions in diverse healthcare settings warrants consideration of crisis hotlines as a safety protocol mechanism. Our findings provide background on how a crisis hotline was implemented as a safety measure, as well as the type of patients who may utilize this safety protocol.

The Impact of Sertraline Co-Administration on the Pharmacokinetics of Olanzapine: A Population Pharmacokinetic Analysis of the STOP-PD

Fri, 03/04/2016 - 12:28pm

BACKGROUND AND OBJECTIVE: Clinical evidence and expert opinion support using a combination of an antipsychotic and an antidepressant when treating major depression with psychotic features. We characterized the impact of sertraline co-administration on olanzapine clearance in psychotic depression using population pharmacokinetic methods.

METHODS: The Study of Pharmacotherapy for Psychotic Depression (STOP-PD) randomized 259 participants to olanzapine plus placebo or olanzapine plus sertraline. Olanzapine was started at 2.5-5 mg/day and sertraline at 25-50 mg/day. Doses were increased to a maximum of 20 mg/day for olanzapine and 200 mg/day for sertraline. Up to four olanzapine concentration samples were collected during the 12-week trial and 12-week continuation phase. We used NONMEM (Version VII) for population pharmacokinetic analysis, assessing effects of the covariates sex, African American origin, smoking, age, and sertraline co-administration.

RESULTS: Population pharmacokinetic analysis comprised 336 samples from 175 individuals. The structural model published by Bigos et al. was sufficient to describe the olanzapine data adequately: a one-compartment model with first-order absorption and elimination, using an additive residual error structure with the absorption rate constant fixed to 0.5. Sertraline co-administration significantly increased olanzapine apparent clearance (p < 0.005) by 25-35 % depending on the patient characteristics included. Male sex was associated with a significantly increased clearance. Age and race did not have a significant impact on clearance.

CONCLUSIONS: Contrary to expectations from the knowledge of cytochrome P450 interactions, sertraline increased olanzapine apparent clearance. Plausible explanations include patients treated with sertraline having poorer adherence to olanzapine, or the impact of sertraline inhibition of transporters resulting in increased intracellular concentrations and thus access to metabolizing enzymes.

Comparative Effectiveness of Statin Therapy in Chronic Kidney Disease and Acute Myocardial Infarction: A Retrospective Cohort Study

Fri, 03/04/2016 - 12:27pm

BACKGROUND: Whether there is a kidney function threshold to statin effectiveness in patients with acute myocardial infarction is poorly understood. Our study sought to help fill this gap in clinical knowledge.

METHODS: We undertook a new-user cohort study of the effectiveness of statin therapy by level of estimated glomerular filtration rate (eGFR) in adults who were hospitalized for myocardial infarction between 2000 and 2008. Data came from the Cardiovascular Research Network. The primary clinical outcomes were 1-year all-cause mortality and cardiovascular hospitalizations, with adverse outcomes of myopathy and development of diabetes mellitus. We calculated incidence rates, the number needed to treat, and used Cox proportional hazards regression with propensity score matching and adjustment to control for confounding, with testing for variation of effect by level of kidney function.

RESULTS: Compared with statin non-initiators (n = 5583), statin initiators (n = 5597) had a lower propensity score-adjusted risk for death (hazard ratio 0.79; 95% confidence interval [CI], 0.71-0.88) and cardiovascular hospitalizations (hazard ratio 0.90; 95% CI, 0.82-1.00). We found little evidence of variation in effect by level of eGFR (P = .86 for death; P = .77 for cardiovascular hospitalization). Adverse outcomes were similar for statin initiators and statin non-initiators. The number needed to treat to prevent 1 additional death over 1 year of follow-up ranged from 15 (95% CI, 11-28) for eGFR < 30 mL/min/1.73 m(2) requiring statin treatment over 2 years to prevent 1 additional death, to 67 (95% CI, 49-118) for patients with eGFR > 90 mL/min/1.73 m(2).

CONCLUSIONS: Our findings suggest that there is potential for important public health gains by increasing the routine use of statin therapy for patients with lower levels of kidney function.

Confirmatory factor analysis of the Autonomy over Tobacco Scale (AUTOS) in adults

Fri, 03/04/2016 - 12:27pm

INTRODUCTION: The Autonomy over Tobacco Scale (AUTOS), a 12-item self-administered questionnaire, was designed to measure autonomy in three correlated lower-order symptom domains: withdrawal, psychological dependence, and cue-induced craving. The factor structure of the AUTOS remains an open question; confirmatory analyses in adolescents supported the hierarchical structure, while exploratory analyses in adolescents and adults yield single-factor solutions. Here we seek to determine whether the hypothesized hierarchical structure is valid in adult smokers.

METHODS: The AUTOS was administered to two independent convenience samples of adult current smokers: a calibration sample recruited in the US for online studies, and a confirmation sample drawn from the prospective Nicotine Dependence in Teens study in Montreal. We tested competing hierarchical and single-factor models using the robust weighted least-squares (WLSMV) estimation method.

RESULTS: A single-factor model that allowed correlated error variances between theoretically related items fit well in the calibration sample (n = 434), chi(2)SB(52) = 165.71; chi(2)/df = 3.19; SRMR = 0.03; CFI = 0.96; NNFI = 0.95; RMSEA = 0.07 (95% CI: 0.06, 0.08). Reliability of the single factor was high (omegaB = 0.92) and construct validity was adequate. In the confirmation sample (n = 335), a similar model fit well: chi(2)SB(53) = 126.94; chi(2)/df = 2.44; SRMR = 0.04; CFI = 0.95; NNFI = 0.93; RMSEA = 0.07 (95% CI: 0.05, 0.08). Reliability of the single factor was again high (omegaB = 0.92) and construct validity was adequate.

CONCLUSION: The AUTOS is unidimensional in adult smokers.

The Association Between Midlife Physical Activity and Depressive Symptoms in Late Life: Age Gene/Environment Susceptibility-Reykjavik Study

Fri, 03/04/2016 - 12:27pm

BACKGROUND: There is little evidence on the long-term association between physical activity (PA) and depressive symptoms in old age. We examined the association of midlife PA and depressive symptoms in late life.

METHODS: A large community-based population residing in Reykjavik, Iceland, participated in a longitudinal study with an average of 25 years of follow up. Midlife PA was categorized as active and inactive groups (n = 4,140, Active = 1,292, Inactive = 2,848, mean age 52+/-7 years). The main outcome had six or higher depressive symptoms assessed by the 15-item Geriatric Depression scale. Participants who had a history of depression (n = 226), and were diagnosed with dementia (n = 393), and had incomplete cognitive data (n = 595) and incomplete analytical data (n = 422) were excluded. Level of weekly PA was ascertained by a questionnaire at midlife. Depressive symptoms were assessed on average 25 (+/-4) years later.

RESULTS: After controlling for demographic and health-related risk factors, those who were active at midlife were less likely to have high level of depressive symptomatology (6 or higher Geriatric Depression scale scores, odds ratio = 0.58, 95% confidence interval: 0.41-0.83, p < .005) compared with those who were inactive in midlife. After full adjustment of three domains of late-life cognitive function the results remained significant (odds ratio = 0.61, 95% confidence interval: 0.43-0.86, p = .005).

CONCLUSION: Our study shows that midlife PA is associated with lower depressive symptoms 25 years later. Participating in regular PA in midlife may improve mental health in late life.

MicroRNA Cargo of Extracellular Vesicles from Alcohol-exposed Monocytes Signals Naive Monocytes to Differentiate into M2 Macrophages

Fri, 03/04/2016 - 12:27pm

Membrane-coated extracellular vesicles (EVs) released by cells can serve as vehicles for delivery of biological materials and signals. Recently, we demonstrated that alcohol-treated hepatocytes cross-talk with immune cells via exosomes containing microRNA (miRNAs). Here, we hypothesized that alcohol-exposed monocytes can communicate with naive monocytes via EVs. We observed increased numbers of EVs, mostly exosomes, secreted by primary human monocytes and THP-1 monocytic cells in the presence of alcohol in a concentration- and time-dependent manner. EVs derived from alcohol-treated monocytes stimulated naive monocytes to polarize into M2 macrophages as indicated by increased surface expression of CD68 (macrophage marker), M2 markers (CD206 (mannose receptor) and CD163 (scavenger receptor)), secretion of IL-10, and TGFbeta and increased phagocytic activity. miRNA profiling of the EVs derived from alcohol-treated THP-1 monocytes revealed high expression of the M2-polarizing miRNA, miR-27a. Treatment of naive monocytes with control EVs overexpressing miR-27a reproduced the effect of EVs from alcohol-treated monocytes on naive monocytes and induced M2 polarization, suggesting that the effect of alcohol EVs was mediated by miR-27a. We found that miR-27a modulated the process of phagocytosis by targeting CD206 expression on monocytes. Importantly, analysis of circulating EVs from plasma of alcoholic hepatitis patients revealed increased numbers of EVs that contained high levels of miR-27a as compared with healthy controls. Our results demonstrate the following: first, alcohol increases EV production in monocytes; second, alcohol-exposed monocytes communicate with naive monocytes via EVs; and third, miR-27a cargo in monocyte-derived EVs can program naive monocytes to polarize into M2 macrophages.

Importance of Nucleic Acid Recognition in Inflammation and Autoimmunity

Fri, 03/04/2016 - 12:26pm

An important concept in immunology is the classification of immune responses as either innate or adaptive, based on whether the antigen receptors are encoded in the germline or generated somatically by gene rearrangement. The innate immune system is an ancient mode of immunity, and by being a first layer in our defense against infectious agents, it is essential for our ability to develop rapid and sustained responses to pathogens. We discuss the importance of nucleic acid recognition by the innate immune system to mounting an appropriate immune response to pathogens and also how inflammation driven by uncontrolled recognition of self-nucleic acids can lead to autoimmune diseases. We also summarize current efforts to either harness the immune system using agonists of nucleic acid-specific innate sensors or, on the contrary, by using inhibitors in autoimmune situations.

Prenatal Triptan Exposure and Internalising and Externalising Behaviour Problems in 3-Year-Old Children: Results from the Norwegian Mother and Child Cohort Study

Fri, 03/04/2016 - 12:26pm

BACKGROUND: Triptans are commonly prescribed for migraine, a pain condition that is highly prevalent in women of childbearing age. No prior studies have investigated associations between exposure to triptans during fetal life and risk of externalising and internalising behaviours in children.

METHODS: This study was set in the Norwegian Mother and Child Cohort study, a prospective birth cohort. A total of 41 173 live, singleton births without major malformations present at 36-month post-partum follow-up were included in this study; 396 used a triptan during pregnancy, 798 used a triptan prior to pregnancy only, 3291 reported migraine without triptan use, and 36 688 reported no history of migraine or triptan use. Marginal structural models were used to analyse the association between timing of triptan exposure and neurodevelopmental outcome.

RESULTS: Children exposed to triptans during pregnancy had a 1.39-fold increased risk of externalising behaviours compared with those whose mothers used triptans prior to pregnancy only (95% CI 0.97, 1.97), a 1.36-fold increased risk compared with the unmedicated migraine group (95% CI 1.02, 1.81), and a 1.41-fold increased risk compared with the population comparison group (95% CI 1.08, 1.85). The greatest risk was associated with first trimester exposure (RR 1.77, 95% CI 0.98, 3.14). Risk differences were small, ranging from 3-6%.

CONCLUSIONS: This study found an increased risk of clinically relevant externalising behaviours in children with prenatal exposure to triptans, and this risk was highest for first trimester exposure. Absolute risks were small, and the results may be due to confounding by underlying migraine severity.

Impact of Plasmodium falciparum Coinfection on Longitudinal Epstein-Barr Virus Kinetics in Kenyan Children

Fri, 03/04/2016 - 12:26pm

Endemic Burkitt lymphoma is associated with Epstein-Barr virus (EBV) and Plasmodium falciparum coinfection, although how P. falciparum exposure affects the dynamics of EBV infection is unclear. We have used a modeling approach to study EBV infection kinetics in a longitudinal cohort of children living in regions of high and low malaria transmission in Kenya. Residence in an area of high malaria transmission was associated with a higher rate of EBV expansion during primary EBV infection in infants and during subsequent episodes of EBV DNA detection, as well as with longer episodes of EBV DNA detection and shorter intervals between subsequent episodes of EBV DNA detection. In addition, we found that concurrent P. falciparum parasitemia also increases the likelihood of the first and subsequent peaks of EBV in peripheral blood. This suggests that P. falciparum infection is associated with increased EBV growth and contributes to endemic Burkitt lymphoma pathogenesis.