Genome-wide search for atopy susceptibility genes in Dutch families with asthma

BACKGROUND: Atopy is a phenotype associated with asthma that has a heritable component. However, the role of atopysusceptibility genes in the development and expression of asthma and allergic disorders is not understood. OBJECTIVE: We sought to study the familial aggregation and co-occurrence of atopic phenotypes within family members of patients with asthma and to identify chromosomal regions that may contain genes that regulate different atopic phenotypes. METHODS: In 200 families (n = 1174) ascertained through a proband with asthma, genome-wide screen and linkage analysis was performed for the following atopic phenotypes: (1) specific IgE to common aeroallergens (Phadiatop assay); (2) specific IgE to Der p 1; (3) positive skin test responses to house dust mite; (4) positive skin test responses to 1 or more of 16 allergens; and (5) peripheral blood eosinophils. Results were compared with the linkage results for total serum IgE levels. RESULTS: There was clear familial aggregation of atopy. A high total serum IgE level in combination with a positive Phadiatop result or a normal total IgE level in combination with a negative Phadiatop result was found in 56.1% of the probands and 66.9% of the offspring. Several chromosomal regions that showed evidence for linkage to an atopic phenotype (ie, 2q, 6p, 7q, and 13q) also showed evidence of linkage with total serum IgE (Xu et al. Am J Hum Genet 2000;67:1163-73). Specific regions of interest for atopic traits were also detected on chromosomes 11q, 17q, and 22q. CONCLUSIONS: Atopic phenotypes show familial aggregation, although family members may differ in expression of atopy. Specific chromosomal regions appear to be important in susceptibility to different phenotypes of atopic responsiveness.     

Mesenteric lymph nodes are critical for the induction of high-dose oral tolerance in the absence of Peyer's patches

We have previously demonstrated the loss of oral tolerance (OT) in lymphotoxinalpha-/- (LTalpha-/-) and TNFalpha / lymphotoxinalpha deficient (TNFalpha / LTalpha-/-) mice which have defective Peyer's patches (PP) and lymph node (LN) development. We have now studied OT in BALB / c mice with differential defects of the gut-associated lymphoid tissue (GALT) caused by inhibition of LTbetaR signaling during fetal development. Treatment of pregnant mice with LTbetaR-IgG (LTbetaRIgG) and TNFR I55-IgG (TNFR55IgG) abrogates the formation of PP (LTbetaRIgG) or of PP and mesenteric LN (MLN) (LTbetaRIgG / TNFRIgG) without genetically deleting the respective cytokine pathways. OT was readily induced in mice without PP but retaining MLN (PP null / LN +). In contrast, OTcould not be induced in mice lacking both MLN and PP (PP null / MLN null) as shown by the inability of these mice to suppress IFN-gamma secretion or DTH reactions. We next assessed OT in 129 x B6 LTalpha-/- mice with and without MLN. Timed treatment of pregnant LTalpha-/- mice with an agonist anti-LTbetaR mAb induces formation of MLN but not of PP in LTalpha-/- mice. LN + LTalpha-/- mice developed OT while LN LTalpha-/- mice were resistant to OT induction. Taken collectively, the data show that in the presence of MLN PP are not required for OT induction and that the presence of MLN is sufficient for OT induction in the LTalpha-/- model.     

Immunohistochemical study of alveolar and embryonal rhabdomyosarcoma

Paraffin-embedded sections of 11 alveolar and 12 embryonal rhabdomyosarcomas, 12 lymphomas, five neuroblastomas, five extraskeletal neoplasms resembling Ewing's sarcoma, and six epithelial tumors were tested for immunoreactivity against myosin, myoglobin, and isozymes BB and MM of creatine kinase with a peroxidase-antiperoxidase method. Of the 23 cases of rhabdomyosarcomas 17 were positive for at least three of the antigenic determinants. In contrast, the other investigated tumors were consistently negative for all markers, with the exception of breast and prostatic carcinomas. Our results establish that the presence of three or four of the above markers in a tumor is strongly suggestive of a rhabdomyosarcoma and helpful in the distinction of alveolar and embryonal rhabdomyosarcomas from lymphomas, neuroblastomas, and extraskeletal neoplasms resembling Ewing's sarcoma.     

Resolving the composite trait of hypertension into its pharmacogenetic determinants by acute pharmacological modulation of blood pressure regulatory systems

Acute pharmacogenetic analysis was carried out in an intercross F2 population derived from Prague hypertensive-hypertriglyceridemic and Lewis rats. Quantitative trait loci (QTL) mapping was performed for baseline blood pressure (BP) and for BP after blockade of the renin-angiotensin system by losartan, of the sympathetic nervous system (SNS) by pentolinium, and of the nitric oxide system by N(G)-nitro- L-arginine methyl ester. Two significant loci for baseline BP were found on chromosome (Chr) 3 (logarithm of likelihood, LOD, 3.8) and Chr 5 (LOD 3.6), and one suggestive locus on Chr 1 (LOD 2.7). The QTL on Chr 3 persisted after treatment with the three agents while the QTL on Chr 5 and Chr 1 disappeared after pentolinium administration. This suggests independence of the locus on Chr 3 from each acute BP regulatory system examined, whereas the loci on Chr 5 and Chr 1 appeared to be controlled mainly by the SNS. Although not apparent at baseline, a significant locus appeared on Chr 8 (LOD 7.0) after blockade of the SNS, and NO system blockade led to the appearance of a new QTL on Chr 1 (LOD 3.6), indicating the contribution of the inhibited systems to these loci. Pharmacogenetic dissection of the BP trait is a powerful tool to unravel the underlying physiological mechanisms of QTL affecting baseline BP and to identify specific QTL for the response to drugs. This pharmocogenetic approach enabled us to determine the main causative acute BP regulatory systems and should lead to better selection of suitable antihypertensive drugs for individual patients.     

Self-perceptions of competence in children with ADHD and comparison children

The self-perceptions of children with attention-deficit/hyperactivity disorder (ADHD; n = 487) were compared with those of children in a local normative comparison group (n = 287), relative to teacher- and parent-rated perceptions of their competence. Children were participants in the ongoing follow-up portion of the Multimodal Treatment Study of Children with ADHD. Children with ADHD were much more likely than comparison children to overestimate their competence relative to adult report, regardless of who was used as the criterion rater (teacher, mother, or father). Examination by comorbidity subgroups revealed that children with ADHD inflated their self-perceptions the most in domains of greatest deficit. Gender effects also are reported.     

Inhibition of anaphylactic inflammation by the gp49B1 receptor on mast cells

gp49B1 is a member of the immunoglobulin (Ig) superfamily expressed on the surface of mast cells, macrophages, and activated natural killer cells. gp49B1 inhibits FcepsilonRI-induced activation of mast cells in vitro by virtue of two immunoreceptor, tyrosine-based inhibitory motifs that recruit the SHP-1 tyrosine phosphatase to the plasma membrane. We created gp49B1 null mice by targeted gene disruption, and found that IgE-dependent mast cell activation is augmented in these animals. Moreover, the ensuing anaphylactic reactions and inflammation are enhanced in the absence of gp49B1. Thus, gp49B1 innately counter-regulates mast cell activation mediated by Ig generated through the adaptive immune response in vivo.     

Characterization of chenodeoxycholic acid as an endogenous antagonist of the G-coupled formyl peptide receptors

OBJECTIVE AND DESIGN: To demonstrate the role of bile acids in immune modulation we examined the ability of select bile acids to inhibit leukocyte migration and chemoattractant receptor function. MATERIALS: To elucidate this mechanism, we employed primary human monocytes, neutrophils and cell lines transfected to express either the high affinity fMLP receptor (FPR) or the low affinity fMLP receptor like 1 (FPRL1). Treatment: Cells were treated with chenodeoxycholic acid (CDCA) and related bile acids in a 0-400 micromolar range. METHOD: Cell viability, chemotaxis and calcium flux analysis were preformed. RESULTS: We observed that pathophysiological levels (< or = 150 micromolar) of CDCA competitively inhibited 3H-fMLP binding to human monocytes, FPR and FPRL1 transfected cells. Additionally, CDCA reduced both the chemotactic and calcium flux responses induced by fMLP or "W" peptide. Further, CDCA inhibited anti-FPR antibody binding to monocytes. CONCLUSIONS: CDCA selectively inhibited human leukocyte chemotaxis and calcium flux induced by fMLP, but not other chemoattractants, suggesting a mechanism for inhibition of inflammation and suppression of innate immune response.     

Assessing treatment progress of individual patients using expected treatment response models

The dosage model provides a normative estimate of the overall pattern of patient improvement in psychotherapy. The phase model further specifies patterns of change in the domains of subjective well-being, symptom remediation, and functioning. The expected treatment response (ETR) approach uses patient characteristics to predict an expected path of progress for each patient. With repeated measures of mental health status, the treatment progress of an individual patient can be assessed against the patient's ETR to support decisions that would enhance the quality of a clinical service while it is being delivered.     

An Association Between a Microsatellite Polymorphism at the DRD5 Gene and the Liability to Substance Abuse: Pilot Study

We have conducted a population-based association study of substance abuse and a microsatellite at the dopamine D5 receptor locus (DRD5) in a sample of European–American males and females with substance dependence (SA) or without any psychiatric disorder. Overrepresentation of the most frequent allele (148 bp) was found in males in the SA group (OR = 2.2, P= .02); this finding was reproduced in females (OR = 5.4, p< .001). The difference in the frequencies of this allele between SA males and SA females was statistically significant. The genotype coded in accordance with the dose of this allele correlated with substance abuse liability in males and females (stronger in females) and with novelty seeking in females. There was no evidence of correlation between the genotypes of spouses that could be induced by assortative mating for the liability to substance abuse. The data suggest that the DRD5 locus is involved in the variation and sex dimorphism of substance abuse liability.CEDAR is a consortium between St. Francis Medical Center and the University of Pittsburgh.