Medicine (St Vincent's) - Research Publications
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ItemNo Preview AvailableMdt1 facilitates efficient repair of blocked DNA double-strand breaks and recombinational maintenance of telomeresv(AMER SOC MICROBIOLOGY, 2007-09)DNA recombination plays critical roles in DNA repair and alternative telomere maintenance. Here we show that absence of the SQ/TQ cluster domain-containing protein Mdt1 (Ybl051c) renders Saccharomyces cerevisiae particularly hypersensitive to bleomycin, a drug that causes 3'-phospho-glycolate-blocked DNA double-strand breaks (DSBs). mdt1Delta also hypersensitizes partially recombination-defective cells to camptothecin-induced 3'-phospho-tyrosyl protein-blocked DSBs. Remarkably, whereas mdt1Delta cells are unable to restore broken chromosomes after bleomycin treatment, they efficiently repair "clean" endonuclease-generated DSBs. Epistasis analyses indicate that MDT1 acts in the repair of bleomycin-induced DSBs by regulating the efficiency of the homologous recombination pathway as well as telomere-related functions of the KU complex. Moreover, mdt1Delta leads to severe synthetic growth defects with a deletion of the recombination facilitator and telomere-positioning factor gene CTF18 already in the absence of exogenous DNA damage. Importantly, mdt1Delta causes a dramatic shift from the usually prevalent type II to the less-efficient type I pathway of recombinational telomere maintenance in the absence of telomerase in liquid senescence assays. As telomeres resemble protein-blocked DSBs, the results indicate that Mdt1 acts in a novel blocked-end-specific recombination pathway that is required for the efficiency of both drug-induced DSB repair and telomerase-independent telomere maintenance.
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ItemNo Preview AvailableVascular endothelial growth factor d is dispensable for development of the lymphatic system(AMER SOC MICROBIOLOGY, 2005-03)Vascular endothelial growth factor receptor 3 (Vegfr-3) is a tyrosine kinase that is expressed on the lymphatic endothelium and that signals for the growth of the lymphatic vessels (lymphangiogenesis). Vegf-d, a secreted glycoprotein, is one of two known activating ligands for Vegfr-3, the other being Vegf-c. Vegf-d stimulates lymphangiogenesis in tissues and tumors; however, its role in embryonic development was previously unknown. Here we report the generation and analysis of mutant mice deficient for Vegf-d. Vegf-d-deficient mice were healthy and fertile, had normal body mass, and displayed no pathologic changes consistent with a defect in lymphatic function. The lungs, sites of strong Vegf-d gene expression during embryogenesis in wild-type mice, were normal in Vegf-d-deficient mice with respect to tissue mass and morphology, except that the abundance of the lymphatics adjacent to bronchioles was slightly reduced. Dye uptake experiments indicated that large lymphatics under the skin were present in normal locations and were functional. Smaller dermal lymphatics were similar in number, location, and function to those in wild-type controls. The lack of a profound lymphatic phenotype in Vegf-d-deficient mice suggests that Vegf-d does not play a major role in lymphatic development or that Vegf-c or another, as-yet-unknown activating Vegfr-3 ligand can compensate for Vegf-d during development.
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ItemNo Preview AvailableStaphylococcal toxic shock syndrome: still a problem - Comment(WILEY, 2005-06-20)
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ItemNo Preview AvailableStaphylococcal toxic shock syndrome: still a problem(Australasian Medical Publishing Company, 2005-06-20)We report a recent case of toxic shock syndrome associated with menstruation which illustrates that this syndrome still occurs, even when tampons are used appropriately. A potential diagnostic test for the syndrome is also discussed.
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ItemOsteoclast Inhibitory Lectin, an Immune Cell Product That Is Required for Normal Bone Physiology in Vivo(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2008-11-07)Osteoclast inhibitory lectin (OCIL or clrb) is a member of the natural killer cell C-type lectins that have a described role mostly in autoimmune cell function. OCIL was originally identified as an osteoblast-derived inhibitor of osteoclast formation in vitro. To determine the physiological function(s) of OCIL, we generated ocil(-/-) mice. These mice appeared healthy and were fertile, with no apparent immune function defect, and phenotypic abnormalities were limited to bone. Histomorphometric analysis revealed a significantly lower tibial trabecular bone volume and trabecular number in the 10- and 16-week-old male ocil(-/-) mice compared with wild type mice. Furthermore, ocil(-/-) mice showed reduced bone formation rate in the 10-week-old females and 16-week-old males while Static markers of bone formation showed no significant changes in male or female ocil(-/-) mice. Examination of bone resorption markers in the long bones of ocil(-/-) mice indicated a transient increase in osteoclast number per unit bone perimeter. Enhanced osteoclast formation was also observed when either bone marrow or splenic cultures were generated in vitro from ocil(-/-) mice relative to wild type control cultures. Loss of ocil therefore resulted in osteopenia in adult mice primarily as a result of increased osteoclast formation and/or decreased bone formation. The enhanced osteoclastic activity led to elevated serum calcium levels, which resulted in the suppression of circulating parathyroid hormone in 10-week-old ocil(-/-) mice compared with wild type control mice. Collectively, our data suggest that OCIL is a physiological negative regulator of bone.
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ItemEffects 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(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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ItemRisk Factors Related to Inflammation and Endothelial Dysfunction in the DCCT/EDIC Cohort and Their Relationship With Nephropathy and Macrovascular Complications(AMER DIABETES ASSOC, 2008-10)OBJECTIVE: Because endothelial cell dysfunction and inflammation are key contributors to the development of complications in type 1 diabetes, we studied risk factors related to endothelial dysfunction and inflammation (C-reactive protein and fibrinogen, soluble vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and E-selectin, and fibrinolytic markers) in a subgroup of patients from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Intervention and Complications (EDIC) study cohort. RESEARCH DESIGN AND METHODS: We determined which of these risk factors or clusters thereof are associated with the presence of and subsequent development of nephropathy and macrovascular complications (reflected by carotid intima-media thickness [IMT]). RESULTS: After adjustment for conventional risk factors (age, sex, DCCT treatment group, diabetes duration, A1C, systolic blood pressure, waist-to-hip ratio, total and HDL cholesterol, and smoking status), fibrinogen remained strongly associated with progression of internal and common carotid IMT (P < 0.01) and soluble E-selectin had a strong association with nephropathy (P < 0.01). CONCLUSIONS: The best predictor for IMT progression in the DCCT/EDIC cohort was plasma fibrinogen, and the levels of soluble E-selectin discriminate patients with albuminuria better than conventional risk factors.
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ItemRetinal Vascular Fractal Dimension and Risk of Early Diabetic Retinopathy A prospective study of children and adolescents with type 1 diabetes(AMER DIABETES ASSOC, 2009-11)OBJECTIVE: To examine the prospective association of retinal vascular fractal dimension with diabetic retinopathy risk in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS: This was a hospital-based prospective study of 590 patients aged 12-20 years with type 1 diabetes free of retinopathy at baseline. All patients had seven-field retinal photographs taken of both eyes. Incident retinopathy was ascertained from retinal photographs taken at follow-up visits. Fractal dimension was measured from baseline photographs using a computer-based program following a standardized protocol. RESULTS: Over a mean +/- SD follow-up period of 2.9 +/- 2.0 years, 262 participants developed mild nonproliferative diabetic retinopathy (15.0 per 100 person-years). After adjusting for age, sex, diabetes duration, A1C, and other risk factors, we found no association between retinal vascular fractal dimension and incident retinopathy. CONCLUSIONS: Retinal vascular fractal dimension was not associated with incident early diabetic retinopathy in this sample of children and adolescents with type 1 diabetes.
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ItemQuantitative Assessment of Early Diabetic Retinopathy Using Fractal Analysis(AMER DIABETES ASSOC, 2009-01)OBJECTIVE: Fractal analysis can quantify the geometric complexity of the retinal vascular branching pattern and may therefore offer a new method to quantify early diabetic microvascular damage. In this study, we examined the relationship between retinal fractal dimension and retinopathy in young individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS: We conducted a cross-sectional study of 729 patients with type 1 diabetes (aged 12-20 years) who had seven-field stereoscopic retinal photographs taken of both eyes. From these photographs, retinopathy was graded according to the modified Airlie House classification, and fractal dimension was quantified using a computer-based program following a standardized protocol. RESULTS: In this study, 137 patients (18.8%) had diabetic retinopathy signs; of these, 105 had mild retinopathy. Median (interquartile range) retinal fractal dimension was 1.46214 (1.45023-1.47217). After adjustment for age, sex, diabetes duration, A1C, blood pressure, and total cholesterol, increasing retinal vascular fractal dimension was significantly associated with increasing odds of retinopathy (odds ratio 3.92 [95% CI 2.02-7.61] for fourth versus first quartile of fractal dimension). In multivariate analysis, each 0.01 increase in retinal vascular fractal dimension was associated with a nearly 40% increased odds of retinopathy (1.37 [1.21-1.56]). This association remained after additional adjustment for retinal vascular caliber. CONCLUSIONS: Greater retinal fractal dimension, representing increased geometric complexity of the retinal vasculature, is independently associated with early diabetic retinopathy signs in type 1 diabetes. Fractal analysis of fundus photographs may allow quantitative measurement of early diabetic microvascular damage.
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ItemRegulatory Effects of Fenofibrate and Atorvastatin on Lipoprotein A-I and Lipoprotein A-I:A-II Kinetics in the Metabolic Syndrome(AMER DIABETES ASSOC, 2009-11)OBJECTIVE: Subjects with the metabolic syndrome have reduced HDL cholesterol concentration and altered metabolism of high-density lipoprotein (Lp)A-I and LpA-I:A-II particles. In the metabolic syndrome, fenofibrate and atorvastatin may have differential effects on HDL particle kinetics. RESEARCH DESIGN AND METHODS: Eleven men with metabolic syndrome were studied in a randomized, double-blind, crossover trial of 5-week intervention periods with placebo, fenofibrate (200 mg/day), and atorvastatin (40 mg/day). LpA-I and LpA-I:A-II kinetics were examined using stable isotopic techniques and compartmental modeling. RESULTS: Compared with placebo, fenofibrate significantly increased the production of both LpA-I:A-II (30% increase; P < 0.001) and apoA-II (43% increase; P < 0.001), accounting for significant increases of their corresponding plasma concentrations (10 and 23% increases, respectively), but it did not alter LpA-I kinetics or concentration. Atorvastatin did not significantly alter HDL concentration or the kinetics of HDL particles. CONCLUSIONS: In the metabolic syndrome, fenofibrate, but not atorvastatin, influences HDL metabolism by increasing the transport of LpA-I:A-II particles.