DRD4 polymorphism moderates the effect of alcohol consumption on social bonding

Development of interpersonal relationships is a fundamental human motivation, and behaviors facilitating social bonding are prized. Some individuals experience enhanced reward from alcohol in social contexts and may be at heightened risk for developing and maintaining problematic drinking. We employed a 3 (group beverage condition) ×2 (genotype) design (N = 422) to test the moderating influence of the dopamine D4 receptor gene (DRD4 VNTR) polymorphism on the effects of alcohol on social bonding. A significant gene x environment interaction showed that carriers of at least one copy of the 7-repeat allele reported higher social bonding in the alcohol, relative to placebo or control conditions, whereas alcohol did not affect ratings of 7-absent allele carriers. Carriers of the 7-repeat allele were especially sensitive to alcohol's effects on social bonding. These data converge with other recent gene-environment interaction findings implicating the DRD4 polymorphism in the development of alcohol use disorders, and results suggest a specific pathway by which social factors may increase risk for problematic drinking among 7-repeat carriers. More generally, our findings highlight the potential utility of employing transdisciplinary methods that integrate genetic methodologies, social psychology, and addiction theory to improve theories of alcohol use and abuse. © 2012 Creswell et al

Detailed characterization of a long-term rodent model of critical illness and recovery

Objective: To characterize a long-term model of recovery from critical illness, with particular emphasis on cardiorespiratory, metabolic, and muscle function. Design: Randomized controlled animal study. Setting: University research laboratory. Subjects: Male Wistar rats. Interventions: Intraperitoneal injection of the fungal cell wall constituent, zymosan or n-saline. Measurements and Main Results: Following intervention, rats were followed for up to 2 weeks. Animals with zymosan peritonitis reached a clinical and biochemical nadir on day 2. Initial reductions were seen in body weight, total body protein and fat, and muscle mass. Leg muscle fiber diameter remained subnormal at 14 days with evidence of persisting myonecrosis, even though gene expression of regulators of muscle mass (e.g., MAFbx, MURF1, and myostatin) had peaked on days 2–4 but normalized by day 7. Treadmill exercise capacity, forelimb grip strength, and in vivo maximum tetanic force were also reduced. Food intake was minimal until day 4 but increased thereafter. This did not relate to appetite hormone levels with early (6 hr) rises in plasma insulin and leptin followed by persisting subnormal levels; ghrelin levels did not change. Serum interleukin-6 level peaked at 6 hours but had normalized by day 2, whereas interleukin-10 remained persistently elevated and high-density lipoprotein cholesterol persistently depressed. There was an early myocardial depression and rise in core temperature, yet reduced oxygen consumption and respiratory exchange ratio with a loss of diurnal rhythmicity that showed a gradual but incomplete recovery by day 7. Conclusions: This detailed physiological, metabolic, hormonal, functional, and histological muscle characterization of a model of critical illness and recovery reproduces many of the findings reported in human critical illness. It can be used to assess putative therapies that may attenuate loss, or enhance recovery, of muscle mass and function

A danger of low copy numbers for inferring incorrect cooperativity degree

Background: A dose-response curve depicts fraction of bound proteins as a function of unbound ligands. Dose-response curves are used to measure the cooperativity degree of a ligand binding process. Frequently, the Hill function is used to fit the experimental data. The Hill function is parameterized by the value of the dissociation constant, and the Hill coefficient which describes the cooperativity degree. The use of Hill's model and the Hill function have been heavily criticised in this context, predominantly the assumption that all ligands bind at once, which lead to further refinements of the model. In this work, the validity of the Hill function has been studied from an entirely different point of view. In the limit of low copy numbers the dynamics of the system becomes noisy. The goal was to asses the validity of the Hill function in this limit, and to see in which ways the effects of the fluctuations change the form of the dose-response curves. Results: Dose-response curves were computed taking into account effects of fluctuations. The effects of fluctuations were described at the lowest order (the second moment of the particle number distribution) by using previously developed Pair Approach Reaction Noise EStimator (PARNES) method. The stationary state of the system is described by nine equations with nine unknowns. To obtain fluctuation corrected dose-response curves the equations have been investigated numerically. Conclusions: The Hill function cannot describe dose-response curves in a low particle limit. First, dose-response curves are not solely parameterized by the dissociation constant and the Hill coefficient. In general, the shape of a dose-response curve depends on the variables that describe how an experiment (ensemble) is designed. Second, dose-response curves are multi valued in a rather non-trivial way

Toxoplasma, Toxocara and Tuberculosis co-infection in a four year old child

<p>Abstract</p> <p>Background</p> <p>Tuberculosis. toxocariasis and toxoplasmosis are among the common infectious causes of lymphadenitis in children. Cases of <it>Toxoplasma gondii </it>and <it>Toxocara spp </it>co-infection have been reported.</p> <p>Case Presentation</p> <p>This case report describes a co-infection of <it>Toxoplasma gondii</it>, <it>Toxocara </it>spp and tuberculosis in a child with chronic lymphadenopathy and eosinophilia.</p> <p>Conclusion</p> <p>The case report highlights two important points. First is the diagnostic challenges that are encountered by clinicians in tropical countries such as Sri Lanka, where lymphadenopathy and eosinophilia with a positive serology commonly point towards a parasitic infection. Secondly the importance of proper history taking and performing the Mantoux test as a first line investigation in a country where the incidence of tuberculosis is low, even in the absence of a positive contact history.</p

Effects of Antiepileptic Drugs on GABA Responses and on Reduction of GABA Responses by PTZ and DMCM on Mouse Neurons in Cell Culture

The mechanisms of action of antiepileptic drugs effective against generalized absence seizures (antiabsence AEDs) remain uncertain. Antiabsence AEDs are generally effective against seizures induced in experimental animals by pentylenÉtÉtrazol (PTZ) and methyl-6,7-dimethoxy-4-ethyl-Β-carboline-3-carboxylate (DMCM), drugs which reduce GABAergic inhibition. Thus, antiabsence AEDs have been suggested to enhance GABAergic inhibition. We studied the effects of several AEDs on GABA responses recorded from mouse spinal cord neurons grown in primary dissociated cell culture. Four antiabsence AEDs were included: ethosuximide (ESM), dimethadione (DMO), sodium valproate (VPA), and diazepam (DZP). Two experimental AEDs, CGS 9896 and ZK 91296, with anticonvulsant action against PTZ- or DMCM-induced seizures were also included. Possible effects of the antiabsence and experimental AEDS on PTZ- and DMCM-induced inhibition of GABA responses were also evaluated. PTZ and DMCM revers-ibly reduced GABA responses in a concentration-dependent manner. PTZ complÉtÉly inhibited GABA responses at 10 mM (IC 50 of 1.1 mM), whereas DMCM-induced inhibition of GABA responses reached a plateau level of 39% of control values at 1 p.M (IC 50 of 33 nM). ESM (1,200 ΜM), DMO (6 mM), VPA (200 u.M), CGS 9896 (2 ΜM), and ZK 98% (2 Μ M ) did not alter GABA responses. DZP enhanced GABA responses in a concentration-dependent manner. The inhibition of GABA responses produced by PTZ 1 mM was unaltered by ESM (600 Μ M ), DMO (6 mM), CGS 9896 (1 Μ M), or ZK 9896 (1 ΜM)- Coapplication of VPA (200 ΜM) and PTZ (1 mM) slightly enhanced the PTZ effect. DZP (> 10 nM), however, reversed the PTZ-induced reduction of GABA responses. The DMCM (250 nM) inhibition of GABA-responses was unaltered by ESM (600 Μ.M), DMO (2 mM), or VPA (200 ΜM). CGS 9896 (2 Μ M ) and ZK 91296 (2 ΜM), however, antagonized the DMCM effect. DZP (> 10 nM) significantly reversed the DMCM-induced inhibition of GABA responses. The lack of effect of VPA, ESM, and DMO on postsynaptic GABA responses suggests that direct enhancement of postsynaptic GABA action is not a common mechanism of action of antiabsence AEDs. The AEDs DZP, CGS 98%, and ZK 912% all reversed DMCM, but not PTZ, reduction of GABA responses, suggesting that these AEDs blocked DMCM seizures by acting at benzodiazepine receptors. However, since only DZP enhanced GABA responses, it is unclear how CGS 98% and ZK 912% blocked PTZ seizures. Key Words: Anticonvulsants–GABA–Neuron culture–Cell culture–Spinal cord neurons–Convulsants. RESUMEN Los mecanismos de accidn de las medicaciones antiepilÉpticas eficaces contra los ataques generalizados de ausencia (AEDs antiausencia) permanecen inciertos. Los AEDs antiausencia son, generalmente, eficaces contra ataques experimentales inducidos por el pentilentetrazol (PTZ) y el metil-6,7-dimetoxy-4-etil-Pcarbolina-3-carboxilato (DMCM) en animates, medicaciones que reducen la inhibiciÓn GABAÉrgica. Hemos estudiado los efectos de varios AEDs sobre respuestas-GABA registradas en las neuronas de la mÉdula espinal de ratones que habian crecido en cultivos de cÉlulas primarieas disociadas. Cuatro AEDs antiausencia fueron incluidos: etoxusimida (ESM), dimetadiona (DMO), valproato sÓdico (VPA) y diazepan (DZP). TambtÉn se incluyeron dos AEDs experimentales, CGS 9896 y ZK 912%, con acciÓn anticonvulsiva contra los ataques inducidos por PTZ o DMCM. TambiÓn se valoraron los posibles efectos de los AEDs antiausencia y experimentales sobre el PTZ y la inhibiciÓn de las respuestas-GABA inducidas por el DMCM. El PTZ y el DMCM redujeron las respuestas-GABA de modo reversible y dependiendo de sus concentraciones. El PTZ inhibiÓ cmpleta-mente las respuestas-GABA a 10 mM (IC 50 de 1.1 mM) mientras que la inhibitiÓn de las respuestas GABA inducida por el DMCM alcanzÓ un nivel estable del 39% de los valores control con 1 Μ. M (IC 50 de 33 mM). La ESM (1200 Μ.M), la DMO (6 mM), el VPA (200 Μ M ), el CGS 98% (2 Μ M) y el ZK 98% (2 Μ M) no alteraron las respuestas-GABA. El DZP aumentÓ las respuestas GABA de una manera concentraciÓn-dependiente. La inhibition de las respuestas-GABA producidas por el PTZ (1 mM), no se altero con las ESM (600 Μ M), la DMO (6 mM), el CGS 98% (1 Μ M) o el ZK 98% (1 Μ .M). La co-aplicacion de VPA (200 Μ M) y el PTZ (1 mM) aument6 ligeramente los efectos del PTZ. Sin embargo el DZP (10 nM) revirtiÓ significativamente la inhibition de las respuestas GABA inducidas por el DMCM. La falta de efectos de CPA, ESM y DMO sobre las respuestas GABA post-sinÁpticas sugiere que el incremento de la acciÓn GABA post-sinÁptica no es un mecanismo comÚn de actuatiÓn de las AEDs antiausencia. Todas las AEDs DZP, CGS 98% y ZK 912% revirtieron la reduction de las respuestas GABA producidas por el DMCM pero no las inducidas por el PTZ lo que sugiere que estos AEDs bloquean los ataques DMCM actuando sobre los receptores de la benzodiazepina. Sin embargo, puesto que el incremento de las respuestas GABA sÓlÓ se produce por el DZP, permanece todavia sin aclarar el por quÉ el CGS 98% y el ZK 912% bloquean los ataques producidos por el PTZ. ZUSAMMENFASSUNG Der Wirkmechansimus von Antiepileptika gegen generalisierte Absencen ist unklar. Antiabsencemittel sind generell wirkungs-voll gegen PTZ- und Methyl-6,7-Dimethoxy-4-Äthyl-P-Carbolin-Β-Carboxylat (DMCM) induzierte tierexperimentelle AnfÄlle, also von Medikamenten, die die GABA-erge Inhibition reduzieren. Es wurde vermutet, daß Antiabsencemittel die GABA-erge Inhibition verstÄrken. Wir untersuchten die Wirkung von verschiedenen Antiepileptika auf GABA-Antworten in spinalen MÄuseneuronen, die in Zellkulturen gew-achsen waren. Es wurden 4 Absencemittel untersucht: Ethosux-imid (ESM), Dimethadion (DMD), Sodium Valproat (VPA) und Diazepam (DZP). ZusÄtzlich wurden 2 experimentelle Antiepileptika, CGS 98% und ZK 912%, die gegen PTZ0 oder DMCM-induzierte AnfÄlle wirkungsvoll sind, eingeschlossen. Mogliche Wirkungen der Antiabsence- und experimentellen Antiepileptika auf PTZ- und DMCM-induzierte Hemmung der GABA-Antworten wurden ebenfalls ausgewertet. PTZ und DMCM zeigten eine konzentrationsabhÄngige reversible Reduktion der GABA-Antworten. PTZ zeigte eine komplette Hemmung der GABA-Antworten bei 10 mM (IC 50 1,1 mM), DMCM-Hemmung der GABA-Antworten zeigte ein Plateau von 39% der Kontroll-werte bei 1 uJtf (ICJO von 33 mAfl. ESM (1200 uJtf), DMD (6 mM), VPA (200 Μ M), CGS 98% (2 Μ M) und ZK 98% (2 Μ M) anderten nicht die GABA-Antworten. DZP verstarkte die GABA-Antworten konzentrationsabhangig. Die durch PTZ (1 mM) hervorgerufene Hemmung der GABA-Antworten war bei ESM (600 Μ M), DMD (6 mM), CGS 98% (1 mAO und ZK 3836 (1 mM) unverÄndert. ZusÄtliche Anwendung von VPA (200 mM) und PTZ (1 mM) verstÄrkten geringfÜgig den PTZ-Effekt. DZP (10 nM) kehrte die durch PTZ hervorgerufene Reduktion der GABA-Antworten um. Die durch DMCM (250 nM) hervorgerufene Hemmung der GABA-Antworten war durch ESM (600 Μ .M), DMD (2 mM) und VPA (200 Μ M ) unbeeinflusst. CGS 98% (2 Μ M) und ZK 912% (2 Μ M ) antagonisierten die DMCM-Wirkung. DZP (>10 nM) kehrte die durch DMCM-induzierte Hemmung der GABA-Antworten um. Das Fehlen einer Wirkung von VPA. ESM und DMD auf die postsynaptischen GABA-Antworten legen nahe, daß eine direkte VerstÄrkung der postsynaptischen GABA-Aktion kein gemeinsamer Mechanis-mus der Antiabsencemittel darstellt. Die Antiepileptika DZP, CGS 98% und ZK 912% kehrten die DMCM-Wirkung auf die GABA-Antworten um, jedoch nicht die von PTZ, was vermuten lapt, daß diese Antiepileptika die DMCM-AnfÄlle Über die Wirkung an den Benzodiazipin-Rezeptoren verhinderte. Da jedoch nur DZP GABA-Antworten verstarkte, ist unklar, in welcher Weise CGS 98% und ZK 912% die PTZ-AnfaUe ver-hinderten.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65188/1/j.1528-1157.1989.tb05275.x.pd

Flavor Physics in an SO(10) Grand Unified Model

In supersymmetric grand-unified models, the lepton mixing matrix can possibly affect flavor-changing transitions in the quark sector. We present a detailed analysis of a model proposed by Chang, Masiero and Murayama, in which the near-maximal atmospheric neutrino mixing angle governs large new b -> s transitions. Relating the supersymmetric low-energy parameters to seven new parameters of this SO(10) GUT model, we perform a correlated study of several flavor-changing neutral current (FCNC) processes. We find the current bound on B(tau -> mu gamma) more constraining than B(B -> X_s gamma). The LEP limit on the lightest Higgs boson mass implies an important lower bound on tan beta, which in turn limits the size of the new FCNC transitions. Remarkably, the combined analysis does not rule out large effects in B_s-B_s-bar mixing and we can easily accomodate the large CP phase in the B_s-B_s-bar system which has recently been inferred from a global analysis of CDF and DO data. The model predicts a particle spectrum which is different from the popular Constrained Minimal Supersymmetric Standard Model (CMSSM). B(tau -> mu gamma) enforces heavy masses, typically above 1 TeV, for the sfermions of the degenerate first two generations. However, the ratio of the third-generation and first-generation sfermion masses is smaller than in the CMSSM and a (dominantly right-handed) stop with mass below 500 GeV is possible.Comment: 44 pages, 5 figures. Footnote and references added, minor changes, Fig. 2 corrected; journal versio

Investigating the association between obesity and asthma in 6- to 8-year-old Saudi children:a matched case-control study

Background: Previous studies have demonstrated an association between obesity and asthma, but there remains considerable uncertainty about whether this reflects an underlying causal relationship. Aims: To investigate the association between obesity and asthma in pre-pubertal children and to investigate the roles of airway obstruction and atopy as possible causal mechanisms. Methods: We conducted an age- and sex-matched case–control study of 1,264 6- to 8-year-old schoolchildren with and without asthma recruited from 37 randomly selected schools in Madinah, Saudi Arabia. The body mass index (BMI), waist circumference and skin fold thickness of the 632 children with asthma were compared with those of the 632 control children without asthma. Associations between obesity and asthma, adjusted for other potential risk factors, were assessed separately in boys and girls using conditional logistic regression analysis. The possible mediating roles of atopy and airway obstruction were studied by investigating the impact of incorporating data on sensitisation to common aeroallergens and measurements of lung function. Results: BMI was associated with asthma in boys (odds ratio (OR)=1.14, 95% confidence interval (CI), 1.08–1.20; adjusted OR=1.11, 95% CI, 1.03–1.19) and girls (OR=1.37, 95% CI, 1.26–1.50; adjusted OR=1.38, 95% CI, 1.23–1.56). Adjusting for forced expiratory volume in 1 s had a negligible impact on these associations, but these were attenuated following adjustment for allergic sensitisation, particularly in girls (girls: OR=1.25; 95% CI, 0.96–1.60; boys: OR=1.09, 95% CI, 0.99–1.19). Conclusions: BMI is associated with asthma in pre-pubertal Saudi boys and girls; this effect does not appear to be mediated through respiratory obstruction, but in girls this may at least partially be mediated through increased risk of allergic sensitisation

Detecting undiagnosed atrial fibrillation in UK primary care: Validation of a machine learning prediction algorithm in a retrospective cohort study

Aims To evaluate the ability of a machine learning algorithm to identify patients at high risk of atrial fibrillation in primary care. Methods A retrospective cohort study was undertaken using the DISCOVER registry to validate an algorithm developed using a Clinical Practice Research Datalink (CPRD) dataset. The validation dataset included primary care patients in London, England aged ≥30 years from 1 January 2006 to 31 December 2013, without a diagnosis of atrial fibrillation in the prior 5 years. Algorithm performance metrics were sensitivity, specificity, positive predictive value, negative predictive value (NPV) and number needed to screen (NNS). Subgroup analysis of patients aged ≥65 years was also performed. Results Of 2,542,732 patients in DISCOVER, the algorithm identified 604,135 patients suitable for risk assessment. Of these, 3.0% (17,880 patients) had a diagnosis of atrial fibrillation recorded before study end. The area under the curve of the receiver operating characteristic was 0.87, compared with 0.83 in algorithm development. The NNS was nine patients, matching the CPRD cohort. In patients aged ≥30 years, the algorithm correctly identified 99.1% of patients who did not have atrial fibrillation (NPV) and 75.0% of true atrial fibrillation cases (sensitivity). Among patients aged ≥65 years (n = 117,965), the NPV was 96.7% with 91.8% sensitivity. Conclusions This atrial fibrillation risk prediction algorithm, based on machine learning methods, identified patients at highest risk of atrial fibrillation. It performed comparably in a large, real-world population-based cohort and the developmental registry cohort. If implemented in primary care, the algorithm could be an effective tool for narrowing the population who would benefit from atrial fibrillation screening in the United Kingdom

Identification of undiagnosed atrial fibrillation patients using a machine learning risk prediction algorithm and diagnostic testing (PULsE-AI): Study protocol for a randomised controlled trial.

Atrial fibrillation (AF) is associated with an increased risk of stroke, enhanced stroke severity, and other comorbidities. However, AF is often asymptomatic, and frequently remains undiagnosed until complications occur. Current screening approaches for AF lack either cost-effectiveness or diagnostic sensitivity; thus, there is interest in tools that could be used for population screening. An AF risk prediction algorithm, developed using machine learning from a UK dataset of 2,994,837 patients, was found to be more effective than existing models at identifying patients at risk of AF. Therefore, the aim of the trial is to assess the effectiveness of this risk prediction algorithm combined with diagnostic testing for the identification of AF in a real-world primary care setting. Eligible participants (aged ≥30 years and without an existing AF diagnosis) registered at participating UK general practices will be randomised into intervention and control arms. Intervention arm participants identified at highest risk of developing AF (algorithm risk score ≥ 7.4%) will be invited for a 12‑lead electrocardiogram (ECG) followed by two-weeks of home-based ECG monitoring with a KardiaMobile device. Control arm participants will be used for comparison and will be managed routinely. The primary outcome is the number of AF diagnoses in the intervention arm compared with the control arm during the research window. If the trial is successful, there is potential for the risk prediction algorithm to be implemented throughout primary care for narrowing the population considered at highest risk for AF who could benefit from more intensive screening for AF. Trial Registration: NCT04045639

Cubic exact solutions for the estimation of pairwise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool 'CubeX'

<p>Abstract</p> <p>Background</p> <p>The frequency of a haplotype comprising one allele at each of two loci can be expressed as a cubic equation (the 'Hill equation'), the solution of which gives that frequency. Most haplotype and linkage disequilibrium analysis programs use iteration-based algorithms which substitute an estimate of haplotype frequency into the equation, producing a new estimate which is repeatedly fed back into the equation until the values converge to a maximum likelihood estimate (expectation-maximisation).</p> <p>Results</p> <p>We present a program, "CubeX", which calculates the biologically possible exact solution(s) and provides estimated haplotype frequencies, D', r²and <it>χ</it>²values for each. CubeX provides a "complete" analysis of haplotype frequencies and linkage disequilibrium for a pair of biallelic markers under situations where sampling variation and genotyping errors distort sample Hardy-Weinberg equilibrium, potentially causing more than one biologically possible solution. We also present an analysis of simulations and real data using the algebraically exact solution, which indicates that under perfect sample Hardy-Weinberg equilibrium there is only one biologically possible solution, but that under other conditions there may be more.</p> <p>Conclusion</p> <p>Our analyses demonstrate that lower allele frequencies, lower sample numbers, population stratification and a possible |D'| value of 1 are particularly susceptible to distortion of sample Hardy-Weinberg equilibrium, which has significant implications for calculation of linkage disequilibrium in small sample sizes (eg HapMap) and rarer alleles (eg paucimorphisms, q < 0.05) that may have particular disease relevance and require improved approaches for meaningful evaluation.</p