Howard Seltman

Evaluation of a Susceptibility Gene for Schizophrenia: Genotype Based Meta-Analysis of RGS4 Polymorphisms from Thirteen Independent Samples

BACKGROUND Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotide polymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles. METHODS In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807). RESULTS The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations. CONCLUSIONS Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted.

Brief Report: Trajectories of Glycemic Control over Early to Middle Adolescence

OBJECTIVES To identify distinct patterns of glycemic control over early to middle adolescence, and to determine whether psychosocial variables predicted those patterns. METHODS We used trajectory analysis to examine glycemic control over 5 years among adolescents with type 1 diabetes who were of age 12 on average at study start (n = 132). Well-being, relationships, and self-care behavior were assessed with in-person interviews. Blood glucose testing was determined from blood glucose meters, and missed clinic appointments and glycosolated hemoglobin were obtained from medical records. RESULTS We identified two distinct clusters of individuals, a stable good glycemic control group and a poorer deteriorating glycemic control group. Individuals in the deteriorating control group were characterized by higher peer conflict, more negative diabetes emotions, fewer blood glucose tests, and more missed clinic appointments. CONCLUSION Psychosocial variables and behavioral markers of self-care may predict the course of glycemic control over early to middle adolescence.

Budd-Chiari syndrome recurring in a transplanted liver

A patient with Budd-Chiari syndrome who underwent orthotopic liver transplantation and developed recurrent disease is described. The immediate postoperative period was complicated by multiple thrombotic episodes, followed by a period of apparent remission associated with the initiation of coumadin and persantine therapy. After discontinuation of such antithrombotic therapy in order to biopsy the liver, the patient experienced another series of clinically overt vascular thromboses and ultimately died of sepsis 15 mo posttransplantation after a prolonged and complicated terminal hospital course. At autopsy, recurrent Budd-Chiari syndrome as well as thromboses in numerous other organs was demonstrated.

CYCLOSPORINE METABOLISM AND PHARMACOKINETICS FOLLOWING INTRAVENOUS AND ORAL ADMINISTRATION IN THE DOG

The influence of assay method on single dose cyclosporine (CsA) pharmacokinetics was studied in nine dogs receiving either i.v. or oral CsA. Samples were drawn from hepatic, portal, and systemic veins at various times after the dose and CsA levels were determined by radiommunoassay (RIA) and high-performance liquid chromatography (HPLC). Blood concentration-time data were analyzed by nonlinear least-squares regression, using two-compartment models. RIA/HPLC ratios for all samples were greater than one, and did not change significantly over time. The mean RIA/HPLC ratios for samples drawn from all three veins were higher after oral than i.v. doses of the drug (P<0.05). Area under the concentration-time curve (AUC) was higher and systemic clearance (Cls) lower than calculated on the basis of RIA results, regardless of the route of administration. AUC calculated for CsA metabolites (RIA-HPLC) was highest in the portal vein after an oral dose of CsA. Bioavailability was 20.4% and 27.0% when estimated using HPLC and RIA data, respectively. The mean CsA metabolite index (CMI), when calculated for hepatic, portal, or systemic vein, was greater when the drug was administered orally. The mean hepatic extraction ratio (HER) of the parent drug and for CsA metabolites was approximately 23% in i.v. and p.o. studies. These results suggest that the gastrointestinal tract may play a role in the metabolism of CsA when the drug is administered orally. In addition, if CsA metabolites not measured by HPLC have either toxic or immunosuppressive properties, the RIA assay may be more useful for monitoring patients.

Properties of cholesterol 7α-hydroxylase in rat liver microsomal acetone powder

Rat liver microsomes were extracted with acetone, and a microsomal powder preparation was obtained. The cholesterol 7 alpha-hydroxylase activity of acetone powder was linear with time, the amount of protein, and the amount of cholesterol in human or rat serum. Unesterified lipoprotein cholesterol was also an effective substrate, and the Km values increased progressively from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) to very-low-density lipoprotein (VLDL), suggesting that HDL-free-cholesterol was the better substrate.

Study of nutritional anemia in male residents of a chronic care facility

Abstract Fifty male residents of a chronic care facility were evaluated for evidence of anemia and/or nutritional deficiencies of folate, B 12 , or iron. Anemia was present in 16%, of which 88% were≥80 years of age. Hemoglobin (=14.2 g/dl), serum iron (=64 ug/dl), and total iron binding capacity (=210 ug/dl) in all residents were significantly lower than age and sex-matched controls, while serum ferritin in the non-anemic residents (=89 ng/dl) was comparable to age-matched controls. Serum ferritin was significantly lower in the anemic compared to the non-anemic in whom a clinical or laboratory diagnosis was unclear. There was no evidence of folate or B 12 deficiency.