Novel association suggests multiple independent QTLs within chromosome 5q21-33 region control variation in total humans IgE levels.

Asthma is a common, heterogeneous, complex disease accompanied by raised total and specific immunoglobulin-E (IgE) antibody levels. Despite numerous previous reports of linkage and association of asthma, atopy and serum IgE levels to genes within the 5q21-33 region, definitive, replicable results are still not available. We used the classical twin design to (i) estimate the relative contributions of genes and environment to variation in total IgE levels, (ii) assess genetic linkage, and (iii) examine allelic association of 11 microsatellite markers spanning the 5q21-33 region to total IgE. Variation in total IgE level was shown to be highly heritable (65%). Although evidence for linkage of the 11 microsatellites to IgE was not observed, the omnibus test of association, not confounded by population substructure, showed positive association of D5S393 and D5S673 to IgE. Genes in the vicinity of D5S673 include hepatitis A virus receptor (HAVCR-1) and IL-12B. Recently, the mouse orthologue of HAVCR-1, the T-cell membrane family of proteins, have been shown to be in strong association with expression of airway hyperactivity in a mouse model of human asthma and atopy. IL-12B subserves many proinflammatory functions and also induces B cells proliferation.

Concordance and interrelationship of atopic diseases and markers of allergic sensitization among adult female twins.

BACKGROUND: Previous twin studies of asthma and allergy implicate both genetic and environmental factors in disease risk, but few have related the occurrence of clinical disease to objective markers of allergic sensitization in twins. OBJECTIVE: We sought to investigate the concordance and interrelationships of self-reported allergic disease and total and aeroallergen-specific IgE levels within pairs of British adult female twins. METHODS: Three hundred forty monozygotic and 533 dizygotic pairs, aged 18 to 72 years, completed questionnaires about allergic disease. Of these, 282 monozygotic and 270 dizygotic pairs were tested for total IgE and specific IgE to Der p 1, mixed grass pollen, and cat dander by means of fluoroimmunoassay. RESULTS: Concordance rates for all variables were higher for monozygotic than for dizygotic twins, significantly (P < .05) so for hay fever, eczema, and specific IgE positivity but not (P > .05) for self-reported asthma or allergies. Within-pair correlations of log-transformed IgE were 0.59 for monozygotic twins and 0.29 for dizygotic twins, implying heritability of 60%. Within both monozygotic and dizygotic pairs discordant for hay fever or reported allergies, the affected twin had significantly higher total and specific IgE levels. Within pairs who were doubly discordant for 3 allergic diseases, associations between diseases were of similar strength for monozygotic and dizygotic pairs. CONCLUSIONS: These results confirm that genetic factors influence susceptibility to aeroallergen sensitization and clinical allergic disease. However, genetically identical twins are often discordant in their expression of atopy, suggesting a substantial modifying role for environmental factors.

Diarrhea reduces the rates of cardiac protein synthesis in myofibrillar protein fractions in rats in vivo.

Although chronic diarrhea affects heart function and morphology, the pathogenic mechanisms are unknown. It was our hypothesis that diarrhea imposes metabolic stress to inhibit the synthesis of new contractile proteins. To test this hypothesis, we investigated the effects of lactose-induced diarrhea in rats. The groups were: 1) freely fed controls, 2) rats with lactose-induced diarrhea or 3) pair-fed rats. After 1 wk, hearts from the rats were subjected to subcellular fractionation techniques to isolate the major protein fractions, including myofibrillar proteins. The rates of protein synthesis were measured with concomitant assay of cardiac composition and plasma analytes. In comparison with the control group, diarrhea induced the following changes (P < 0.05): a decrease in heart weight, reduced RNA and mixed protein contents and a reduction in the fractional rate of mixed protein synthesis. There was a reduction in the content of all protein fractions. The fractional synthesis rate was reduced only for the myofibrillar fraction. Plasma insulin-like growth factor-I, but not corticosterone, was reduced. Plasma cholesterol and triglyceride concentrations were also reduced. In comparison with the pair-fed group, diarrhea induced the following changes (P < 0.05): a reduction in heart weight and fractional rate of mixed protein synthesis, reduced myofibrillar absolute synthesis rate and increased sarcoplasmic/myofibrillar fractional synthesis rate ratio. Plasma bicarbonate, triglyceride and urea concentrations were reduced, with an increase in albumin. Diarrhea impaired cardiac biochemistry, including a reduction in protein content and synthesis. A substantial proportion of these changes is due to anorexia, but the selective reduction in the synthesis of contractile proteins is a feature exclusive to the diarrhea group and may be due to reductions in plasma insulin-like growth factor-I.

Thermodynamics of denaturation of hisactophilin, a beta-trefoil protein.

Hisactophilin is a histidine-rich pH-dependent actin-binding protein from Dictyostelium discoideum. The structure of hisactophilin is typical of the beta-trefoil fold, a common structure adopted by diverse proteins with unrelated primary sequences and functions. The thermodynamics of denaturation of hisactophilin have been measured using fluorescence- and CD-monitored equilibrium urea denaturation curves, pH-denaturation, and thermal denaturation curves, as well as differential scanning calorimetry. Urea denaturation is reversible from pH 5.7 to pH 9.7; however, thermal denaturation is highly reversible only below pH approximately 6.2. Reversible denaturation by urea and heat is well fit using a two-state transition between the native and the denatured states. Urea denaturation curves are best fit using a quadratic dependence of the Gibbs free energy of unfolding upon urea concentration. Hisactophilin has moderate, roughly constant stability from pH 7.7 to pH 9.7; however, below pH 7.7, stability decreases markedly, most likely due to protonation of histidine residues. Enthalpic effects of histidine ionization upon unfolding also appear to be involved in the occurrence of cold unfolding of hisactophilin under relatively mild solution conditions. The stability data for hisactophilin are compared with data on hisactophilin function, and with data for two other beta-trefoil proteins, human interleukin-1beta, and basic fibroblast growth factor.

The diffusion of decision support systems in healthcare: are we there yet?

Clinical decision support (CDS) systems, with the potential to minimize practice variation and improve patient care, have begun to surface throughout the healthcare industry. This study reviews historic patterns of information technology (IT) in healthcare, analyzes barriers and enabling factors, and draws three lessons. First, the widespread adoption of clinical IT, including CDS systems, depends on having the right organizational and individual financial incentives in place. Second, although CDS systems and clinical IT in general are powerful tools that can be used to support the practice of medicine, they alone cannot redefine the workflow or processes within the profession. Healthcare managers counting on technology to restructure or monitor clinicians' work patterns are likely to encounter substantial resistance to CDS systems, even those that generate valuable information. Third, while the pace of implementing IT systems in healthcare has lagged behind that of other industries, many of the obstacles are gradually diminishing. However, several factors continue to inhibit their widespread diffusion, including the organizational turmoil created by large numbers of mergers and acquisitions, and the lack of uniform data standards.

Do HMOs make a difference?

The growth of managed care has prompted questions about the effects of health maintenance organizations (HMOs) on consumers. This Issue Brief reports the results from a large national study of the privately insured population. No detectable difference was found between HMOs and other types of insurance in the use of three costly services--inpatient care, emergency room use and surgeries--and differences in reports of unmet need or delayed care are negligible. Differences for other measures pose a trade-off for consumers: HMOs provide more primary and preventive services and lower financial barriers to care, but they provide less specialist care and raise administrative barriers to care. In addition, patients in HMOs report less satisfaction, less trust in physicians and lower ratings of physician visits. These findings have implications for the current policy debate about managed care.

Do HMOs make a difference? Use of health services.

This study analyzes the effects of health maintenance organizations (HMOs) on the use of health services by the privately insured, nonelderly population. After controlling for population and location differences, HMOs increase physician visits, nonphysician practitioner visits, and total ambulatory visits by modest but significant margins, while shifting the mix of physician care from specialists to primary care physicians. HMOs also increase use of two preventive services: mammography screening and flu shots. Contrary to expectation, however, the study finds no significant differences between HMO and non-HMO enrollees in the use of hospital, surgery, and emergency room services.

Defects of insulin action on fatty acid and carbohydrate metabolism in familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is a common cause of premature myocardial infarction, but its metabolic basis is unknown. Insulin resistance has been suggested in some patients by the presence of fasting hyperinsulinemia. We studied insulin action on carbohydrate and fatty acid metabolism in FCHL patients and healthy control subjects by a two-step euglycemic, hyperinsulinemic clamp. During low-dose insulin infusion, steady-state nonesterified fatty acids (NEFAs) were higher in patients than in control subjects (0.36 mmol/L [95% confidence limits, 0.19, 0.53] versus 0.19 mmol/L [0.10, 0.28]; P = .05). The ratio of steady-state to basal NEFAs was increased by 88% in patients compared with control subjects (P = .005). During high-dose insulin infusion, insulin sensitivity for peripheral glucose disposal was reduced by 60% in FCHL patients compared with control subjects (P = .03). Hepatic glucose production at baseline and during the clamp was similar in the two groups. In multiple regression analysis, increased upper-body fat in the patient group accounted for the impairment of insulin-mediated glucose disposal but did not influence the defect in insulin-mediated NEFA suppression in the FCHL patients. This defect in fatty acid metabolism may be a primary defect in FCHL that contributes to abnormalities in the secretion and composition of lipoproteins in this disorder. Direct study of this defect may facilitate genetic analysis of this disorder.

Cell adhesion to low-Mr proteins extractable from mineralized and soft connective tissues.

Guanidinium chloride (4 M) containing proteinase inhibitors was used to extract proteins from porcine calvariae and long bones. The extracted proteins were separated on polyacrylamide slab gels and transferred electrophoretically to nitrocellulose strips. Proteins with cell-adhesion properties were identified by incubating the strips with cells and staining with Amido Black. In addition to binding to fibronectin, both bone cells and fibroblast-like cells adhered to proteins of Mr approximately 30 000 and approximately 14 000-17 000. 4 M-Guanidinium chloride extracts of porcine skin and gingiva yielded cell-binding proteins with similar Mr values. These data suggest that these low-Mr proteins may have a general cell-adhesion function in both soft and mineralized connective tissues.