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Noble J.A.,Childrens Hospital Oakland Research Institute
Journal of Autoimmunity | Year: 2015

Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing beta cells in the pancreas. Prevention of T1D will require the ability to detect and modulate the autoimmune process before the clinical onset of disease. Genetic screening is a logical first step in identification of future patients to test prevention strategies. Susceptibility to T1D includes a strong genetic component, with the strongest risk attributable to genes that encode the classical Human Leukocyte Antigens (HLA). Other genetic loci, both immune and non-immune genes, contribute to T1D risk; however, the results of decades of small and large genetic linkage and association studies show clearly that the HLA genes confer the most disease risk and protection and can be used as part of a prediction strategy for T1D. Current predictive genetic models, based on HLA and other susceptibility loci, are effective in identifying the highest-risk individuals in populations of European descent. These models generally include screening for the HLA haplotypes "DR3" and "DR4." However, genetic variation among racial and ethnic groups reduces the predictive value of current models that are based on low resolution HLA genotyping. Not all DR3 and DR4 haplotypes are high T1D risk; some versions, rare in Europeans but high frequency in other populations, are even T1D protective. More information is needed to create predictive models for non-European populations. Comparative studies among different populations are needed to complete the knowledge base for the genetics of T1D risk to enable the eventual development of screening and intervention strategies applicable to all individuals, tailored to their individual genetic background. This review summarizes the current understanding of the genetic basis of T1D susceptibility, focusing on genes of the immune system, with particular emphasis on the HLA genes. © 2015 Elsevier Ltd. Source


Krauss R.M.,Childrens Hospital Oakland Research Institute
Current Opinion in Lipidology | Year: 2010

PURPOSE OF REVIEW: Subfractions of LDL and HDL defined by differences in particle size and density have been associated to varying degrees with risk of cardiovascular disease (CVD). Assessment of these relationships has been clouded by lack of standardization among the various analytic methodologies as well as the strong correlations of the subfractions with each other and with standard lipid and lipoprotein risk markers. This review summarizes the properties of the major LDL and HDL particle subclasses, and recent evidence linking their measurement with risk of atheroscierosis and CVD. RECENT FINDINGS: Several recent studies have shown independent relationships of levels of LDL and HDL-size subclasses to risk of both coronary artery and cerebrovascular disease. However, the two largest studies, employing nuclear magnetic resonance and ion mobility, respectively, did not find evidence that these measurements improved risk assessment compared with standard lipoprotein assays. In the latter study, principal component analysis was used to group multiple subfraction measurements into three distinct and statistically independent clusters that were related both to cardiovascular outcomes and to genotypes that may reflect underlying metabolic determinants. SUMMARY: Although there is as yet inconclusive evidence as to the extent to which LDL and HDL subfraction measurements improve clinical assessment of CVD risk beyond standard lipid risk markers, recent studies suggest that more refined analyses of lipoprotein subspecies may lead to further improvements in CVD risk evaluation and particularly in identification of appropriate targets for therapeutic intervention in individual patients. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source


Granoff D.M.,Childrens Hospital Oakland Research Institute
Clinical Infectious Diseases | Year: 2010

No broadly effective vaccines are available for prevention of group B meningococcal disease, which accounts for >50% of all cases. The group B capsule is an autoantigen and is not a suitable vaccine target. Outermembrane vesicle vaccines appear to be safe and effective, but serum bactericidal responses in infants are specific for a porin protein, PorA, which is antigenically variable. To broaden protection, outer-membrane vesicle vaccines have been prepared from >1 strain, from mutants with >1 PorA, or from mutants with genetically detoxified endotoxin and overexpressed desirable antigens, such as factor H binding protein. Also, recombinant protein vaccines such as factor H binding protein, given alone or in combination with other antigens, are in late-stage clinical development and may be effective against the majority of group B strains. Thus, the prospects have never been better for developing vaccines for prevention of meningococcal disease, including that caused by group B strains. © 2010 by the Infectious Diseases Society of America. All rights reserved. Source


Fischer H.,Childrens Hospital Oakland Research Institute
Wiley Interdisciplinary Reviews: Membrane Transport and Signaling | Year: 2012

The properties of the voltage-dependent H+ channel have been studied in lung epithelial cells for many years, and recently voltage-dependent H+ channel 1 (HVCN1) messenger RNA expression has been linked directly to H+ channel function in lung epithelium. The H+ channel is activated by strong membrane depolarization, intracellular acidity, or extracellular alkalinity. Early on it was noted that these are surprising physiological channel characteristics when considering that lung epithelial cells have rather stable membrane potentials and a well pH-buffered intracellular milieu. This raised the question under which conditions the H+ channel is active in lung epithelium and what is its physiological function there. Current understanding of the HVCN1 H+ channel in lung epithelial acid secretion, its activation by an alkaline mucosal extracellular pH, and its role in the regulation of the mucosal pH of the lung has resulted in a model of mucosal pH regulation based on the parallel function of the HVCN1 H+ channel and the CFTR HCO3 - channel, which suggests that HVCN1 is a critical factor that maintains a neutral surface pH in the lung. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Patent
Childrens Hospital Oakland Research Institute | Date: 2013-07-10

The invention provides compositions and methods for delivery of a bioactive agent to an individual. Delivery vehicles are provided that include a bioactive agent in disc shaped particles that include one or more lipid binding polypeptides circumscribing the perimeter of a lipid bilayer in which the bioactive agent is localized. Chimeric lipid binding polypeptides are also provided and may be used to add additional functional properties to the delivery particles.

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