Medicine (Austin & Northern Health) - Research Publications

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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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    Fulminant hepatic failure after intravenous injection of sublingual buprenorphine in a patient with hepatitis C.
    French, J ; Mujumdar, A ; Angus, P ; Gow, P (Wiley, 2015-08)
    A 20-year-old indigenous Australian male was admitted to the intensive care unit with fulminant hepatic failure secondary to intravenous use of buprenorphine, which had been prescribed sublingually for opioid dependence. Intravenous buprenorphine-induced hepatitis is well recognized, however, life-threatening fulminant hepatic failure has not previously been reported.
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    Mycophenolate mofetil toxicity mimicking acute cellular rejection in a small intestinal transplant.
    Apostolov, R ; Asadi, K ; Lokan, J ; Kam, N ; Testro, A (Baishideng Publishing Group Inc., 2017-02-24)
    Mycophenolate mofetil (MMF) is an important medication used for maintenance immunosuppression in solid organ transplants. A common gastrointestinal (GI) side effect of MMF is enterocolitis, which has been associated with multiple histological features. There is little data in the literature describing the histological effects of MMF in small intestinal transplant (SIT) recipients. We present a case of MMF toxicity in a SIT recipient, with histological changes in the donor ileum mimicking persistent acute cellular rejection (ACR). Concurrent biopsies of the patient's native colon showed similar changes to those from the donor small bowel, suggesting a non-graft specific process, raising suspicion for MMF toxicity. The MMF was discontinued and complete resolution of these changes occurred over three weeks. MMF toxicity should therefore be considered as a differential diagnosis for ACR and graft-versus-host disease in SITs.
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    Pericytes and Neurovascular Function in the Healthy and Diseased Brain.
    Brown, LS ; Foster, CG ; Courtney, J-M ; King, NE ; Howells, DW ; Sutherland, BA (Frontiers Media SA, 2019)
    Pericytes are multi-functional cells embedded within the walls of capillaries throughout the body, including the brain. Pericytes were first identified in the 1870s, but little attention was paid to them during the following century. More recently, numerous vascular functions of pericytes have been identified including regulation of cerebral blood flow, maintenance of the blood-brain barrier (BBB), and control of vascular development and angiogenesis. Pericytes can also facilitate neuroinflammatory processes and possess stem cell-like properties. Pericytes form part of the neurovascular unit (NVU), a collection of cells that control interactions between neurons and the cerebral vasculature to meet the energy demands of the brain. Pericyte structure, expression profile, and function in the brain differ depending on their location along the vascular bed. Until recently, it has been difficult to accurately define the sub-types of pericytes, or to specifically target pericytes with pharmaceutical agents, but emerging techniques both in vitro and in vivo will improve investigation of pericytes and allow for the identification of their possible roles in diseases. Pericyte dysfunction is increasingly recognized as a contributor to the progression of vascular diseases such as stroke and neurodegenerative diseases such as Alzheimer's disease. The therapeutic potential of pericytes to repair cerebral blood vessels and promote angiogenesis due to their ability to behave like stem cells has recently been brought to light. Here, we review the history of pericyte research, the present techniques used to study pericytes in the brain, and current research advancements to characterize and therapeutically target pericytes in the future.
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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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    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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    Confirmation of novel type 1 diabetes risk loci in families.
    Cooper, JD ; Howson, JMM ; Smyth, D ; Walker, NM ; Stevens, H ; Yang, JHM ; She, J-X ; Eisenbarth, GS ; Rewers, M ; Todd, JA ; Akolkar, B ; Concannon, P ; Erlich, HA ; Julier, C ; Morahan, G ; Nerup, J ; Nierras, C ; Pociot, F ; Rich, SS ; Type 1 Diabetes Genetics Consortium, (Springer Science and Business Media LLC, 2012-04)
    AIMS/HYPOTHESIS: Over 50 regions of the genome have been associated with type 1 diabetes risk, mainly using large case/control collections. In a recent genome-wide association (GWA) study, 18 novel susceptibility loci were identified and replicated, including replication evidence from 2,319 families. Here, we, the Type 1 Diabetes Genetics Consortium (T1DGC), aimed to exclude the possibility that any of the 18 loci were false-positives due to population stratification by significantly increasing the statistical power of our family study. METHODS: We genotyped the most disease-predicting single-nucleotide polymorphisms at the 18 susceptibility loci in 3,108 families and used existing genotype data for 2,319 families from the original study, providing 7,013 parent-child trios for analysis. We tested for association using the transmission disequilibrium test. RESULTS: Seventeen of the 18 susceptibility loci reached nominal levels of significance (p < 0.05) in the expanded family collection, with 14q24.1 just falling short (p = 0.055). When we allowed for multiple testing, ten of the 17 nominally significant loci reached the required level of significance (p < 2.8 × 10(-3)). All susceptibility loci had consistent direction of effects with the original study. CONCLUSIONS/INTERPRETATION: The results for the novel GWA study-identified loci are genuine and not due to population stratification. The next step, namely correlation of the most disease-associated genotypes with phenotypes, such as RNA and protein expression analyses for the candidate genes within or near each of the susceptibility regions, can now proceed.
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    Evidence of gene-gene interaction and age-at-diagnosis effects in type 1 diabetes.
    Howson, JMM ; Cooper, JD ; Smyth, DJ ; Walker, NM ; Stevens, H ; She, J-X ; Eisenbarth, GS ; Rewers, M ; Todd, JA ; Akolkar, B ; Concannon, P ; Erlich, HA ; Julier, C ; Morahan, G ; Nerup, J ; Nierras, C ; Pociot, F ; Rich, SS ; Type 1 Diabetes Genetics Consortium, (American Diabetes Association, 2012-11)
    The common genetic loci that independently influence the risk of type 1 diabetes have largely been determined. Their interactions with age-at-diagnosis of type 1 diabetes, sex, or the major susceptibility locus, HLA class II, remain mostly unexplored. A large collection of more than 14,866 type 1 diabetes samples (6,750 British diabetic individuals and 8,116 affected family samples of European descent) were genotyped at 38 confirmed type 1 diabetes-associated non-HLA regions and used to test for interaction of association with age-at-diagnosis, sex, and HLA class II genotypes using regression models. The alleles that confer susceptibility to type 1 diabetes at interleukin-2 (IL-2), IL2/4q27 (rs2069763) and renalase, FAD-dependent amine oxidase (RNLS)/10q23.31 (rs10509540), were associated with a lower age-at-diagnosis (P = 4.6 × 10⁻⁶ and 2.5 × 10⁻⁵, respectively). For both loci, individuals carrying the susceptible homozygous genotype were, on average, 7.2 months younger at diagnosis than those carrying the protective homozygous genotypes. In addition to protein tyrosine phosphatase nonreceptor type 22 (PTPN22), evidence of statistical interaction between HLA class II genotypes and rs3087243 at cytotoxic T-lymphocyte antigen 4 (CTLA4)/2q33.2 was obtained (P = 7.90 × 10⁻⁵). No evidence of differential risk by sex was obtained at any loci (P ≥ 0.01). Statistical interaction effects can be detected in type 1 diabetes although they provide a relatively small contribution to our understanding of the familial clustering of the disease.
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    Functionally distinct PI 3-kinase pathways regulate myelination in the peripheral nervous system.
    Heller, BA ; Ghidinelli, M ; Voelkl, J ; Einheber, S ; Smith, R ; Grund, E ; Morahan, G ; Chandler, D ; Kalaydjieva, L ; Giancotti, F ; King, RH ; Fejes-Toth, AN ; Fejes-Toth, G ; Feltri, ML ; Lang, F ; Salzer, JL (Rockefeller University Press, 2014-03-31)
    The PI 3-kinase (PI 3-K) signaling pathway is essential for Schwann cell myelination. Here we have characterized PI 3-K effectors activated during myelination by probing myelinating cultures and developing nerves with an antibody that recognizes phosphorylated substrates for this pathway. We identified a discrete number of phospho-proteins including the S6 ribosomal protein (S6rp), which is down-regulated at the onset of myelination, and N-myc downstream-regulated gene-1 (NDRG1), which is up-regulated strikingly with myelination. We show that type III Neuregulin1 on the axon is the primary activator of S6rp, an effector of mTORC1. In contrast, laminin-2 in the extracellular matrix (ECM), signaling through the α6β4 integrin and Sgk1 (serum and glucocorticoid-induced kinase 1), drives phosphorylation of NDRG1 in the Cajal bands of the abaxonal compartment. Unexpectedly, mice deficient in α6β4 integrin signaling or Sgk1 exhibit hypermyelination during development. These results identify functionally and spatially distinct PI 3-K pathways: an early, pro-myelinating pathway driven by axonal Neuregulin1 and a later-acting, laminin-integrin-dependent pathway that negatively regulates myelination.
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    The Affymetrix DMET Plus platform reveals unique distribution of ADME-related variants in ethnic Arabs.
    Wakil, SM ; Nguyen, C ; Muiya, NP ; Andres, E ; Lykowska-Tarnowska, A ; Baz, B ; Tahir, AI ; Meyer, BF ; Morahan, G ; Dzimiri, N (Hindawi Limited, 2015)
    BACKGROUND: The Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus Premier Pack has been designed to genotype 1936 gene variants thought to be essential for screening patients in personalized drug therapy. These variants include the cytochrome P450s (CYP450s), the key metabolizing enzymes, many other enzymes involved in phase I and phase II pharmacokinetic reactions, and signaling mediators associated with variability in clinical response to numerous drugs not only among individuals, but also between ethnic populations. MATERIALS AND METHODS: We genotyped 600 Saudi individuals for 1936 variants on the DMET platform to evaluate their clinical potential in personalized medicine in ethnic Arabs. RESULTS: Approximately 49% each of the 437 CYP450 variants, 56% of the 581 transporters, 56% of 419 transferases, 48% of the 104 dehydrogenases, and 58% of the remaining 390 variants were detected. Several variants, such as rs3740071, rs6193, rs258751, rs6199, rs11568421, and rs8187797, exhibited significantly either higher or lower minor allele frequencies (MAFs) than those in other ethnic groups. DISCUSSION: The present study revealed some unique distribution trends for several variants in Arabs, which displayed partly inverse allelic prevalence compared to other ethnic populations. The results point therefore to the need to verify and ascertain the prevalence of a variant as a prerequisite for engaging it in clinical routine screening in personalized medicine in any given population.