Medicine (St Vincent's) - Research Publications
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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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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.
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ItemHigh-grade urothelial carcinoma in a kidney transplant recipient with BK virus infection.(Oxford University Press (OUP), 2009-06)Bladder malignancy in the kidney transplant recipient is rare and compared with the general population tends to be of high grade and have an aggressive clinical course. In this report, we describe a case of urothelial carcinoma developing in a kidney transplant recipient 6 years after the diagnosis of polyomavirus nephropathy (PVN). BK virus (BKV) DNA was identified in urine and serum by PCR. The diffuse strong staining of SV40 T-antigen and p53 within both the in situ and invasive carcinoma suggest that BKV may play a role in the oncogenic pathway in this clinical setting.
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ItemBad news for beta-cell apoptosis.(American Diabetes Association, 2009-08)
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ItemLate recovery of renal failure after autologous haematopoietic stem cell transplantation for multiple myeloma: a report of two cases.(Oxford University Press (OUP), 2009-06)Acute renal failure is a frequent feature in patients with multiple myeloma (MM). MM-related renal insufficiency may improve after autologous haematopoietic stem cell transplantation (autoHSCT) even in patients initially requiring dialysis. Herein, we report on two unusual cases of late improvement in renal function occurring over more than 5 years after autoHSCT for MM. Clinicians must be aware that slow and progressive improvement in renal function may occur over years in patients with MM-associated renal failure. Our data underline the need for an aggressive treatment, including autoHSCT, in MM patients presenting with severe renal dysfunction.
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ItemA Novel Method for Detection of Phosphorylation in Single Cells by Surface Enhanced Raman Scattering (SERS) using Composite Organic-Inorganic Nanoparticles (COINs)(PUBLIC LIBRARY SCIENCE, 2009-04-15)BACKGROUND: Detection of single cell epitopes has been a mainstay of immunophenotyping for over three decades, primarily using fluorescence techniques for quantitation. Fluorescence has broad overlapping spectra, limiting multiplexing abilities. METHODOLOGY/PRINCIPAL FINDINGS: To expand upon current detection systems, we developed a novel method for multi-color immuno-detection in single cells using "Composite Organic-Inorganic Nanoparticles" (COINs) Raman nanoparticles. COINs are Surface-Enhanced Raman Scattering (SERS) nanoparticles, with unique Raman spectra. To measure Raman spectra in single cells, we constructed an automated, compact, low noise and sensitive Raman microscopy device (Integrated Raman BioAnalyzer). Using this technology, we detected proteins expressed on the surface in single cells that distinguish T-cells among human blood cells. Finally, we measured intracellular phosphorylation of Stat1 (Y701) and Stat6 (Y641), with results comparable to flow cytometry. CONCLUSIONS/SIGNIFICANCE: Thus, we have demonstrated the practicality of applying COIN nanoparticles for measuring intracellular phosphorylation, offering new possibilities to expand on the current fluorescent technology used for immunoassays in single cells.
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ItemInterleukin-21 Is Required for the Development of Type 1 Diabetes in NOD Mice(AMER DIABETES ASSOC, 2009-05)OBJECTIVE: Interleukin (IL)-21 is a type 1 cytokine that has been implicated in the pathogenesis of type 1 diabetes via the unique biology of the nonobese diabetic (NOD) mouse strain. The aim of this study was to investigate a causal role for IL-21 in type 1 diabetes. RESEARCH DESIGN AND METHODS: We generated IL-21R-deficient NOD mice and C57Bl/6 mice expressing IL-21 in pancreatic beta-cells, allowing the determination of the role of insufficient and excessive IL-21 signaling in type 1 diabetes. RESULTS: Deficiency in IL-21R expression renders NOD mice resistant to insulitis, production of insulin autoantibodies, and onset of type 1 diabetes. The lymphoid compartment in IL-21R-/- NOD is normal and does not contain an increased regulatory T-cell fraction or diminished effector cytokine responses. However, we observed a clear defect in autoreactive effector T-cells in IL-21R-/- NOD by transfer experiments. Conversely, overexpression of IL-21 in pancreatic beta-cells induced inflammatory cytokine and chemokines, including IL-17A, IL17F, IFN-gamma, monocyte chemoattractant protein (MCP)-1, MCP-2, and interferon-inducible protein-10 in the pancreas. The ensuing leukocytic infiltration in the islets resulted in destruction of beta-cells and spontaneous type 1 diabetes in the normally diabetes-resistant C57Bl/6 and NOD x C57Bl/6 backgrounds. CONCLUSIONS: This work provides demonstration of the essential prodiabetogenic activities of IL-21 on diverse genetic backgrounds (NOD and C57BL/6) and indicates that IL-21 blockade could be a promising strategy for interventions in human type 1 diabetes.
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ItemAn Interesting Case of Recurrent Small Bowel Obstruction.(S. Karger AG, 2009-11-21)Sclerosing mesenteritis is associated with a spectrum of diseases which include mesenteric lipodystrophy and mesenteric panniculitis. This inflammatory and fibrosing disorder can affect the small and large bowel wall and mesenteric vessels by exerting a mass effect. The following case highlights the difficulties with diagnosing and managing this unusual disease. A 64-year-old man presented with acute central abdominal pain, radiating to his back, and profuse vomiting. He was diagnosed clinically with small bowel obstruction. He had had an episode of small bowel obstruction 6 years earlier. At this time, he underwent an exploratory laparotomy, and a mass was identified in the small bowel mesentery. The features were thought to be in keeping with sclerosing mesenteritis. He had a dramatically favourable response to the initiation of prednisolone. He continued to be well and asymptomatic for a further 5 years on long-term maintenance low-dose steroids and 6-mercaptopurine. He re-presented in 2009 (six years after initial presentation) with very severe acute abdominal pain and vomiting. He had no recent change in weight or appetite, and had not had time off work. He underwent a second laparotomy and the tissue diagnosis was of metastatic carcinoid tumour involving the small bowel mesentery. This is the first case to our knowledge where sclerosing mesenteritis has been confirmed histologically on biopsy and then subsequently diagnosed with histologically proven carcinoid tumour. For this particular reason it must be always remembered that sclerosing mesenteritis is a 'pathological' and not a radiological diagnosis and that a large proportion of cases are associated with neoplasia.