Medicine (Austin & Northern Health) - Research Publications

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    Effects of Salt Supplementation on the Albuminuric Response to Telmisartan With or Without Hydrochlorothiazide Therapy in Hypertensive Patients With Type 2 Diabetes Are Modulated by Habitual Dietary Salt Intake
    Ekinci, EI ; Thomas, G ; Thomas, D ; Johnson, C ; MacIsaac, RJ ; Houlihan, CA ; Finch, S ; Panagiotopoulos, S ; O'Callaghan, C ; Jerums, G (AMER DIABETES ASSOC, 2009-08)
    OBJECTIVE This prospective randomized double-blind placebo-controlled crossover study examined the effects of sodium chloride (NaCl) supplementation on the antialbuminuric action of telmisartan with or without hydrochlorothiazide (HCT) in hypertensive patients with type 2 diabetes, increased albumin excretion rate (AER), and habitual low dietary salt intake (LDS; <100 mmol sodium/24 h on two of three consecutive occasions) or high dietary salt intake (HDS; >200 mmol sodium/24 h on two of three consecutive occasions). RESEARCH DESIGN AND METHODS Following a washout period, subjects (n = 32) received 40 mg/day telmisartan for 4 weeks followed by 40 mg telmisartan plus 12.5 mg/day HCT for 4 weeks. For the last 2 weeks of each treatment period, patients received either 100 mmol/day NaCl or placebo capsules. After a second washout, the regimen was repeated with supplements in reverse order. AER and ambulatory blood pressure were measured at weeks 0, 4, 8, 14, 18, and 22. RESULTS In LDS, NaCl supplementation reduced the anti-albuminuric effect of telmisartan with or without HCT from 42.3% (placebo) to 9.5% (P = 0.004). By contrast, in HDS, NaCl supplementation did not reduce the AER response to telmisartan with or without HCT (placebo 30.9%, NaCl 28.1%, P = 0.7). Changes in AER were independent of changes in blood pressure. CONCLUSIONS The AER response to telmisartan with or without HCT under habitual low salt intake can be blunted by NaCl supplementation. By contrast, when there is already a suppressed renin angiotensin aldosterone system under habitual high dietary salt intake, the additional NaCl does not alter the AER response.
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    Laparoscopic adjustable gastric band in an obese unrelated living donor prior to kidney transplantation: a case report.
    Koshy, AN ; Wilkinson, S ; Coombes, JS ; Fassett, RG (Springer Science and Business Media LLC, 2010-04-19)
    INTRODUCTION: Obese living donors who undergo donor nephrectomy have higher rates of intra-operative and post-operative complications. Many centres exclude obese donors from living donor transplant programs. Diet, exercise and medication are often ineffective weight loss interventions for donors, hence bariatric surgery should be considered. CASE PRESENTATION: We report the case of a 53-year-old Caucasian woman who underwent laparoscopically adjustable gastric banding. The procedure enabled her to lose sufficient weight to gain eligibility for kidney donation. After losing weight, she had an uncomplicated laparoscopic donor nephrectomy surgery, and the recipient underwent successful kidney transplantation. CONCLUSION: Laparoscopically adjustable gastric banding should be considered for obese potential living kidney donors whenever transplantation units restrict access to donor nephrectomy based on the increased surgical risk for donors.
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    Genetics of type 1 diabetes: what's next?
    Pociot, F ; Akolkar, B ; Concannon, P ; Erlich, HA ; Julier, C ; Morahan, G ; Nierras, CR ; Todd, JA ; Rich, SS ; Nerup, J (American Diabetes Association, 2010-07)
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    Tests for genetic interactions in type 1 diabetes: linkage and stratification analyses of 4,422 affected sib-pairs.
    Morahan, G ; Mehta, M ; James, I ; Chen, W-M ; Akolkar, B ; Erlich, HA ; Hilner, JE ; Julier, C ; Nerup, J ; Nierras, C ; Pociot, F ; Todd, JA ; Rich, SS ; Type 1 Diabetes Genetics Consortium, (American Diabetes Association, 2011-03)
    OBJECTIVE: Interactions between genetic and environmental factors lead to immune dysregulation causing type 1 diabetes and other autoimmune disorders. Recently, many common genetic variants have been associated with type 1 diabetes risk, but each has modest individual effects. Familial clustering of type 1 diabetes has not been explained fully and could arise from many factors, including undetected genetic variation and gene interactions. RESEARCH DESIGN AND METHODS: To address this issue, the Type 1 Diabetes Genetics Consortium recruited 3,892 families, including 4,422 affected sib-pairs. After genotyping 6,090 markers, linkage analyses of these families were performed, using a novel method and taking into account factors such as genotype at known susceptibility loci. RESULTS: Evidence for linkage was robust at the HLA and INS loci, with logarithm of odds (LOD) scores of 398.6 and 5.5, respectively. There was suggestive support for five other loci. Stratification by other risk factors (including HLA and age at diagnosis) identified one convincing region on chromosome 6q14 showing linkage in male subjects (corrected LOD = 4.49; replication P = 0.0002), a locus on chromosome 19q in HLA identical siblings (replication P = 0.006), and four other suggestive loci. CONCLUSIONS: This is the largest linkage study reported for any disease. Our data indicate there are no major type 1 diabetes subtypes definable by linkage analyses; susceptibility is caused by actions of HLA and an apparently random selection from a large number of modest-effect loci; and apart from HLA and INS, there is no important susceptibility factor discoverable by linkage methods.
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    Genome-wide scan for linkage to type 1 diabetes in 2,496 multiplex families from the Type 1 Diabetes Genetics Consortium.
    Concannon, P ; Chen, W-M ; Julier, C ; Morahan, G ; Akolkar, B ; Erlich, HA ; Hilner, JE ; Nerup, J ; Nierras, C ; Pociot, F ; Todd, JA ; Rich, SS ; Type 1 Diabetes Genetics Consortium, (American Diabetes Association, 2009-04)
    OBJECTIVE: Type 1 diabetes arises from the actions of multiple genetic and environmental risk factors. Considerable success at identifying common genetic variants that contribute to type 1 diabetes risk has come from genetic association (primarily case-control) studies. However, such studies have limited power to detect genes containing multiple rare variants that contribute significantly to disease risk. RESEARCH DESIGN AND METHODS: The Type 1 Diabetes Genetics Consortium (T1DGC) has assembled a collection of 2,496 multiplex type 1 diabetic families from nine geographical regions containing 2,658 affected sib-pairs (ASPs). We describe the results of a genome-wide scan for linkage to type 1 diabetes in the T1DGC family collection. RESULTS: Significant evidence of linkage to type 1 diabetes was confirmed at the HLA region on chromosome 6p21.3 (logarithm of odds [LOD] = 213.2). There was further evidence of linkage to type 1 diabetes on 6q that could not be accounted for by the major linkage signal at the HLA class II loci on chromosome 6p21. Suggestive evidence of linkage (LOD > or =2.2) was observed near CTLA4 on chromosome 2q32.3 (LOD = 3.28) and near INS (LOD = 3.16) on chromosome 11p15.5. Some evidence for linkage was also detected at two regions on chromosome 19 (LOD = 2.84 and 2.54). CONCLUSIONS: Five non-HLA chromosome regions showed some evidence of linkage to type 1 diabetes. A number of previously proposed type 1 diabetes susceptibility loci, based on smaller ASP numbers, showed limited or no evidence of linkage to disease. Low-frequency susceptibility variants or clusters of loci with common alleles could contribute to the linkage signals observed.
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    Induction of delayed-type hypersensitivity to azobenzenearsonate by a monoclonal anti-idiotype antibody.
    Thomas, WR ; Morahan, G ; Walker, ID ; Miller, JF (Rockefeller University Press, 1981-03-01)
    Azobenzenearsonate (ABA)-specific sensitivity was induced in A/J mice by injecting a monoclonal anti-idiotype reagent, 14A, directed against a determinant present on a minor subpopulation of immunoglobulin molecules within the anti-ABA antibodies of A/J mice. Sensitivity was transferrable by purified T cells and this was abrogated by treating the cells with 14A, rabbit anti-mouse immunoglobulin and complement, not by treatment with only the last two reagents. The transfer was restricted by the K-end of the major histocompatibility complex.
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    A human type 1 diabetes susceptibility locus maps to chromosome 21q22.3.
    Concannon, P ; Onengut-Gumuscu, S ; Todd, JA ; Smyth, DJ ; Pociot, F ; Bergholdt, R ; Akolkar, B ; Erlich, HA ; Hilner, JE ; Julier, C ; Morahan, G ; Nerup, J ; Nierras, CR ; Chen, W-M ; Rich, SS ; Type 1 Diabetes Genetics Consortium, (American Diabetes Association, 2008-10)
    OBJECTIVE: The Type 1 Diabetes Genetics Consortium (T1DGC) has assembled and genotyped a large collection of multiplex families for the purpose of mapping genomic regions linked to type 1 diabetes. In the current study, we tested for evidence of loci associated with type 1 diabetes utilizing genome-wide linkage scan data and family-based association methods. RESEARCH DESIGN AND METHODS: A total of 2,496 multiplex families with type 1 diabetes were genotyped with a panel of 6,090 single nucleotide polymorphisms (SNPs). Evidence of association to disease was evaluated by the pedigree disequilibrium test. Significant results were followed up by genotyping and analyses in two independent sets of samples: 2,214 parent-affected child trio families and a panel of 7,721 case and 9,679 control subjects. RESULTS- Three of the SNPs most strongly associated with type 1 diabetes localized to previously identified type 1 diabetes risk loci: INS, IFIH1, and KIAA0350. A fourth strongly associated SNP, rs876498 (P = 1.0 x 10(-4)), occurred in the sixth intron of the UBASH3A locus at chromosome 21q22.3. Support for this disease association was obtained in two additional independent sample sets: families with type 1 diabetes (odds ratio [OR] 1.06 [95% CI 1.00-1.11]; P = 0.023) and case and control subjects (1.14 [1.09-1.19]; P = 7.5 x 10(-8)). CONCLUSIONS: The T1DGC 6K SNP scan and follow-up studies reported here confirm previously reported type 1 diabetes associations at INS, IFIH1, and KIAA0350 and identify an additional disease association on chromosome 21q22.3 in the UBASH3A locus (OR 1.10 [95% CI 1.07-1.13]; P = 4.4 x 10(-12)). This gene and its flanking regions are now validated targets for further resequencing, genotyping, and functional studies in type 1 diabetes.
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    Identification of a T1D susceptibility gene.
    Morahan, G (Hindawi Limited, 2001-05-01)
    It is not known what causes type 1 diabetes (T1D) which affects over 1 million people in the U.S. alone. Each year, 30,000 young people in the U.S. develop this disease and depend on insulin injections thereafter. Because of the huge cost to the individual, the family, and to society in increased health care costs, it is important to find what makes these people susceptible. The disease process itself is clear: the individual's immune system, the T lymphocytes in particular, attack and destroy the body's insulin-producing cells. But how and why this autoimmune process starts or proceeds unregulated is still not known.
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    Rescue of skeletal muscle alpha-actin-null mice by cardiac (fetal) alpha-actin.
    Nowak, KJ ; Ravenscroft, G ; Jackaman, C ; Filipovska, A ; Davies, SM ; Lim, EM ; Squire, SE ; Potter, AC ; Baker, E ; Clément, S ; Sewry, CA ; Fabian, V ; Crawford, K ; Lessard, JL ; Griffiths, LM ; Papadimitriou, JM ; Shen, Y ; Morahan, G ; Bakker, AJ ; Davies, KE ; Laing, NG (Rockefeller University Press, 2009-06-01)
    Skeletal muscle alpha-actin (ACTA1) is the major actin in postnatal skeletal muscle. Mutations of ACTA1 cause mostly fatal congenital myopathies. Cardiac alpha-actin (ACTC) is the major striated actin in adult heart and fetal skeletal muscle. It is unknown why ACTC and ACTA1 expression switch during development. We investigated whether ACTC can replace ACTA1 in postnatal skeletal muscle. Two ACTC transgenic mouse lines were crossed with Acta1 knockout mice (which all die by 9 d after birth). Offspring resulting from the cross with the high expressing line survive to old age, and their skeletal muscles show no gross pathological features. The mice are not impaired on grip strength, rotarod, or locomotor activity. These findings indicate that ACTC is sufficiently similar to ACTA1 to produce adequate function in postnatal skeletal muscle. This raises the prospect that ACTC reactivation might provide a therapy for ACTA1 diseases. In addition, the mouse model will allow analysis of the precise functional differences between ACTA1 and ACTC.
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