The serotonin transporter gene as a QTL for ADHD.

Molecular studies of attention deficit hyperactivity disorder (ADHD) have identified susceptibility genes for the categorically diagnosed disorder using operational diagnostic criteria. Here, we take a QTL approach to mapping genes for ADHD using a composite continuous index of ADHD behavior in a large epidemiological sample. Previous studies of clinical ADHD suggest that two functional polymorphisms in the serotonin transporter gene (SLC6A4), one in the 5'-regulatory region of the gene (5-HTTLPR) and the other a VNTR (5-HTTVNTR) in the second intron, as well as a single nucleotide polymorphism in the 3'-untranslated region (3'-UTR SNP), may be associated with the disorder. Here, we investigate these polymorphisms as well as an additional ten SNPs spread across the gene. We found significant association with the long (L) allele of the 5-HTTLPR; P = 0.019, but neither the 5-HTTVNTR nor the 3'-UTR SNP were significantly associated. Significant associations (P < 0.05) were found for a further 5 the 10 other markers tested. We found evidence for two haplotype blocks spanning the region. We found strong evidence for association with the first haplotype block (comprised of four markers), with the significance of a combined primary and secondary test of association reaching an empirical P value = 0.0054 for the global test and an empirical P value = 0.00081 for the largest local test. Thus, we show here that SLC6A4, which has a major influence on brain serotonin availability, may be a QTL for ADHD.     

Prenatal life and post-natal psychopathology: evidence for negative gene-birth weight interaction

BACKGROUND: Many studies suggest that pregnancy and birth complications (PBCs) are environmental risk factors for child psychopathology. However, it is not known whether the effects of PBCs occur independently of genetic predisposition. The current study examined the possibility of gene-environment interaction in a twin design. METHOD: The East Flanders Prospective Twin Survey prospectively records the births of all twin pairs born in East Flanders, Belgium. The current study included 760 twin pairs aged 6-17 years. Multilevel regression analysis was used to assess the effects of several PBCs collected around the time of birth. Using structural equation modelling, ACE models assuming additive genetic (A), shared environmental (C) and unique environmental (E) influences, were compared in order to examine whether the contribution of genetic factors to parent-rated child problem behaviour varied as a function of exposure to dichotomously and continuously defined PBCs. RESULTS: A main independent effect of lower birth weight, corrected for gestational age (small for gestational age--SGA), on child problem behaviour was found. In addition, there was an interaction between genetic influence and SGA, in that being smaller for gestational age resulted in less influence of additive genetic factors on individual differences in problem behaviour. CONCLUSIONS: Results are suggestive of negative gene-birth weight interaction. Children who are SGA are less sensitive to the genetic effects, and those with high genetic vulnerability are less sensitive to the effects of being SGA in bringing about post-natal mental health effects.     

Ixodes scapularis ticks (Acari: Ixodidae) from Louisiana are competent to transmit Borrelia burgdorferi, the agent of Lyme borreliosis

The principal vector of Borrelia burgdorferi, the Lyme borreliosis spirochete, in the Northeast and Midwestern regions of the United States is the blacklegged tick Ixodes scapularis. Because of a favorable environment, I. scapularis is also plentiful in the South; however, a correlation with Lyme borreliosis cases does not exist in this region of the United States. Concern existed that something intrinsic to ticks found in Louisiana could mitigate their ability to transmit B. burgdorferi. Therefore, we set out to assess the ability of I. scapularis ticks from Louisiana to become infected with and transmit B. burgdorferi using mice as hosts. In the laboratory, mating adult female ticks collected in southeastern Louisiana were fed on the ears of rabbits. After oviposition and egg hatching, the resulting larvae were fed on mice that had been needle-inoculated with two different strains of B. burgdorferi sensu stricto, B31 and JD1. Larvae were found to be positive for spirochetes. Additional fed larvae were allowed to molt into the nymphal stage. Flat nymphs remained infected with B. burgdorferi. Infected nymphs were allowed to feed on na?ve mice, all of which became infected as shown by culture of ear biopsy specimens. Na?ve larvae were then fed on these same mice to assess transmissibility. The resulting engorged larvae harbored spirochetes. We have demonstrated that the I. scapularis ticks found in Louisiana are fully competent to carry and transmit B. burgdorferi infection.     

Detection of hepatitis A virus by extraction of viral RNA and molecular hybridization.

Hepatitis A virus (HAV) RNA was extracted from cell culture, serum, liver, and feces and then detected by molecular hybridization with cloned HAV cDNA. Hybridization was approximately 10-fold more sensitive than immune electron microscopy or radioimmunoassay was and less sensitive than was assays of HAV infectivity in primates or in cell culture. As little as 10(3) 50% infective doses of HAV, or approximately 0.1 pg of viral RNA, was detected by this method. Analysis of fecal specimens from an experimentally infected marmoset and an epidemic of hepatitis A showed that HAV excretion could often be detected later in the illness by hybridization than by radioimmunoassay. This technique should be widely applicable for detection and analysis of HAV RNA.     

Life events and depression in a community sample of siblings

BACKGROUND: The overall aim of the GENESiS project is to identify quantitative trait loci (QTLs) for anxiety/depression, and to examine the interaction between these loci and psychosocial adversity. Here we present life-events data with the aim of clarifying: (i) the aetiology of life events as inferred from sibling correlations; (ii) the relationship between life events and measures of anxiety and depression, as well as neuroticism; and (iii) the interaction between life events and neuroticism on anxiety/depression indices. METHODS: We assessed the occurrence of one network and three personal life-event categories and multiple indices of anxiety/depression including General Health Questionnaire, Anhedonic Depression, Anxious Arousal and Neuroticism in a large community-based sample of2150 sib pairs, 410 trios and 81 quads. Liability threshold models and raw ordinal maximum likelihood were used to estimate within-individual and between-sibling correlations of life events. The relationship between life events and indices of emotional states and personality were assessed by multiple linear regression and canonical correlations. RESULTS: Life events showed sibling correlations of 0-37 for network events and between 0-10 and 0.19 for personal events. Adverse life events were related to anxiety and depression and, to a less extent, neuroticism. Trait-vulnerability (as indexed by co-sib's neuroticism, anxiety and depression) accounted for 11% and life events for 3% of the variance in emotional states. There were no interaction effects. CONCLUSIONS: Life events show moderate familiality and are significantly related to symptoms of anxiety and depression in the community. Appropriate modelling of life events in linkage and association analyses should help to identify QTLs for depression and anxiety.     

Prevalence of Antibodies to Hepatitis E Virus in Veterinarians Working with Swine and in Normal Blood Donors in the United States and Other Countries

Hepatitis E virus (HEV) is endemic in many developing and some industrialized countries. It has been hypothesized that animals may be the source of infection. The recent identification of swine HEV in U.S. pigs and the demonstration of its ability to infect across species have lent credence to this hypothesis. To assess the potential risk of zoonotic HEV infection, we tested a total of 468 veterinarians working with swine (including 389 U.S. swine veterinarians) and 400 normal U.S. blood donors for immunoglobulin G anti-HEV. Recombinant capsid antigens from a U.S. strain of swine HEV and from a human HEV strain (Sar-55) were each used in an enzyme-linked immunosorbent assay. The anti-HEV prevalence assayed with the swine HEV antigen showed 97% concordance with that obtained with the human HEV antigen (kappa = 92%). Among the 295 swine veterinarians tested from the eight U.S. states (Minnesota, Indiana, Nebraska, Iowa, Illinois, Missouri, North Carolina, and Alabama) from which normal blood donor samples were available, 26% were positive with Sar-55 antigen and 23% were positive with swine HEV antigen. In contrast, 18% of the blood donors from the same eight U.S. states were positive with Sar-55 antigen and 17% were positive with swine HEV antigen. Swine veterinarians in the eight states were 1.51 times more likely when tested with swine HEV antigen (95% confidence interval, 1.03 to 2.20) and 1.46 times more likely when tested with Sar-55 antigen (95% confidence interval, 0.99 to 2.17) to be anti-HEV positive than normal blood donors. We did not find a difference in anti-HEV prevalence between veterinarians who reported having had a needle stick or cut and those who had not or between those who spent more time (> or = 80% of the time) and those who spent less time (< or = 20% of the time) working with pigs. Similarly, we did not find a difference in anti-HEV prevalence according to four job categories (academic, practicing, student, and industry veterinarians). There was a difference in anti-HEV prevalence in both swine veterinarians and blood donors among the eight selected states, with subjects from Minnesota six times more likely to be anti-HEV positive than those from Alabama. Age was not a factor in the observed differences from state to state. Anti-HEV prevalence in swine veterinarians and normal blood donors was age specific and paralleled increasing age. The results suggest that swine veterinarians may be at somewhat higher risk of HEV infection than are normal blood donors.     

Association of stress proteins with autoantigens: a possible mechanism for triggering autoimmunity?

Patterns of autoantibody production are diagnostic of many autoimmune disorders; the recent observation of additional autospecificities towards stress-induced proteins may also provide insight into the mechanisms by which such responses arise. Grp78 (also known as BiP) is a target of autoaggressive B and T cell responses in our murine model of anti-Ro (SS-A) autoimmunity and also in rheumatoid arthritis. In this report we demonstrate reciprocal intermolecular spreading occurs between Ro52 and Grp78 in immunized mice, reflecting physiological association of these molecules in vivo. Moreover, we provide direct biochemical evidence that Grp78 associates with the clinically relevant autoantigen, Ro52 (SS-A). Due to the discrete compartmentalization of Ro52 (nucleocytoplasmic) and Grp78 (endoplasmic reticulum; ER) we propose that association of these molecules occurs either in apoptotic cells, where they have been demonstrated indirectly to co-localize in discrete apoptotic bodies, or in B cells themselves where both Ro52 and Grp78 are known to bind to immunoglobulin heavy chains. Tagging of molecules by association with Grp78 may facilitate receptor mediated phagocytotsis of the complex; we show evidence that exogenous Grp78 can associate with cell surface receptors on a subpopulation of murine splenocytes. Given the likelihood that Grp78 will associate with viral glycoproteins in the ER it is possible that it may become a bystander target of the spreading antiviral immune response. Thus, we propose a model whereby immunity elicited towards Grp78 leads to the selection of responses towards the Ro polypeptides and the subsequent cascade of responses observed in human disease.     

Purification of hepatitis A antigen from feces and detection of antigen and antibody by immune adherence hemagglutination.

Hepatitis A antigen (HA Ag) was purified from feces collected during acute illness from patients with naturally occurring viral hepatitis, type A. Positive fecal specimens were identified by immune electron microscopy, but for detection of HA Agduring purification immune adherence hemagglutination (IAHA) and microtiter solid-phase radioimmunoassay were used. Isopycnic banding in cesium chloride, rate-zonal separation in sucrose, and preparative zonal electrophoresis were used in various combinations for successive purification, and the purified antigen was successfully used in a test for antibody by IAHA. Seronconversions to HA Ag were demonstrated by IAHA in 20 instances of hepatitis A virus infection, but in none of six cases of type B hepatitis or three cases of post-transfusion hepatitis unrelated to heaptitis A or B viruses, nor in two individuals without hepatitis. In addition, the temporal pattern of antibody development during type A hepatitis was studied in serial sera from an experimentally infected chimpanzee. Antibody titers by IAHA correlated well with antibody ratings determined by immune electron microscopy.