ABSTRACT
We have identified a migraine locus on chromosome 19p13.3/2 using linkage and association analysis. We isolated 48 single-nucleotide polymorphisms within the locus, of which we genotyped 24 in a Caucasian population comprising 827 unrelated cases and 765 controls. Five single-nucleotide polymorphisms within the insulin receptor gene showed significant association with migraine. This association was independently replicated in a case-control population collected separately. We used experiments with insulin receptor RNA and protein to investigate functionality for the migraine-associated single-nucleotide polymorphisms. We suggest possible functions for the insulin receptor in migraine pathogenesis.
Subject(s)
Alleles , Migraine Disorders/genetics , Polymorphism, Single Nucleotide , Receptor, Insulin/genetics , Base Sequence , Case-Control Studies , Chromosome Mapping , Chromosomes, Artificial, Bacterial , Chromosomes, Human, Pair 19 , DNA Primers , Female , Genetic Predisposition to Disease , Genotype , Humans , Linkage Disequilibrium , Male , Protein Binding , Receptor, Insulin/metabolism , Reproducibility of Results , White People/geneticsABSTRACT
An investigation into the interaction between human cytomegalovirus (HCMV) protease and several beta-lactams, with characterization of the resulting acylenzymes using mass spectrometry, is reported. The time dependence of the inhibitors is highlighted by making comparisons of values obtained for inhibition and acylation. Analysis of inactivated HCMV protease revealed a beta-lactam: protease stoichiometry of 1. Subsequent enzymatic digestion with trypsin, peptide mapping using liquid chromatography coupled with electrospray ionization mass spectrometry and sequencing by nanoelectrospray tandem mass spectrometry (NanoES-MS/MS) allowed the identification of the site of covalent modification and confirmed Ser 132 as the active site hydroxyl nucleophile. Further, treatment of the protease with a peptide chloromethylketone and sequence analysis using NanoES-MS/MS of the alkylated enzyme confirmed His 63 as the active site imidazole nucleophile.
Subject(s)
Cytomegalovirus/enzymology , Serine Endopeptidases/chemistry , Amino Acid Chloromethyl Ketones/chemistry , Amino Acid Chloromethyl Ketones/pharmacology , Amino Acid Sequence , Base Sequence , Catalytic Domain/genetics , Chromatography, Liquid , Cloning, Molecular , Cytomegalovirus/genetics , DNA, Viral/genetics , Humans , Mass Spectrometry/methods , Molecular Sequence Data , Mutagenesis, Site-Directed , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Saccharomyces cerevisiae/genetics , Serine Endopeptidases/genetics , Trypsin , beta-Lactams/chemistry , beta-Lactams/pharmacologyABSTRACT
Young people leave home for many reasons--a push away from problems, a pull toward the independence and seeming excitement of the street. Once on the street they face serious risks to their health and well-being. Homelessness among youths is a concern in Seattle, with as many as 2,000 on the street in a year's time. The service system is overburdened and poorly coordinated. The City of Seattle examined the problem, inadequacies of the service system, and issues affecting its ability to address the needs of homeless youths and their families. This article presents data on the problem, policies proposed to shape the city's response, and progress made in the last 2 years.
Subject(s)
Adolescent Health Services/supply & distribution , Ill-Housed Persons/statistics & numerical data , Policy Making , Adolescent , Adolescent Health Services/legislation & jurisprudence , Adult , Child , Female , Humans , Male , Public Housing , Runaway Behavior , Social Problems , State Government , Washington/epidemiologyABSTRACT
Two hundred and thirty-six pregnant women were referred for assessment and management of hypertension and/or renal disease. A Unit consisting of a physician, an obstetrician and a perinatologist jointly assessed each patient and advised on management. All patients were hospitalized and at bed rest. Drug therapy was clonidine hydrochloride or methyl dopa and in some patients a vasodilator was added. The decision to deliver was dictated by foetal maturity and wellbeing, in conjunction with maternal condition. There was no maternal mortality and the overall perinatal survival was 97%. The outcome of these pregnancies compares favourably with studies previously reported and reflect a successful approach to management of high risk hypertensive pregnancies.
