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Berry P.A.,Monash University | Maciewicz R.A.,Astrazeneca | Wluka A.E.,Monash University | Wluka A.E.,Baker Heart Research Institute | And 4 more authors.
Annals of the Rheumatic Diseases | Year: 2010

Background: Biomarkers of cartilage metabolism have prognostic potential. Objective: To examine whether serum cartilage biomarkers, cartilage oligomeric matrix protein (COMP), N-propeptide of type IIA procollagen (PIIANP), type II collagen breakdown product (collagen type-II cleavage (C2C)) predict cartilage volume loss and knee joint replacement. Methods: 117 subjects with knee osteoarthritis (OA) had MRI at baseline and 2 years. Cartilage biomarkers were measured at baseline. Change in knee cartilage volume over 2 years and knee joint replacement over 4 years was determined. The population was divided into subgroups with high or low cartilage biomarkers (based on biomarker levels greater than or equal to, or less than, the mean, respectively). The relationships between biomarkers and outcome measures were examined in the whole population, and separately in marker subgroups. Results: The relationship between cartilage biomarkers and cartilage volume loss was not linear across the whole population. In the low (regression coefficient B=-9.7, 95% CI -0.01 to 0.003, p=0.01), but not high (B=-0.46, 95% CI -8.9 to 8.0, p=0.92) COMP subgroup, COMP was significantly associated with a reduced rate of medial cartilage volume loss (p for difference between groups=0.05). Similarly, in the low (B=-8.2, 95% CI -12.9 to -3.5, p=0.001) but not high (B=2.6, 95% CI -3.3 to 8.5, p=0.38) PIIANP subgroup, PIIANP was associated with a significantly reduced rate of medial volume cartilage loss (p for difference=0.003). C2C was not significantly associated with rate of cartilage volume loss. PIIANP was associated with a reduced risk of joint replacement (odds ratio (OR)=0.28, 95% CI 0.10 to 0.93, p=0.04). Conclusion: Cartilage biomarkers may be used to identify subgroups among those with clinical knee OA in whom disease progresses at different rates. This may facilitate our understanding of the pathogenesis of disease and allow us to differentiate phenotypes of disease within a heterogeneous knee OA population.


Rosso R.,Royal Melbourne Hospital | Kistler P.M.,University of Melbourne | Kistler P.M.,Baker Heart Research Institute | Kistler P.M.,Heart Center
Heart | Year: 2010

Focal atrial tachycardia is a relatively uncommon arrhythmia. Nevertheless, the management of highly symptomatic patients with focal atrial tachycardia can be problematic owing to the poor response to medical treatment. Moreover, focal atrial tachycardia can trigger other atrial arrhythmias like atrial fibrillation and flutter. Radiofrequency ablation of focal atrial tachycardia is extremely successful and this approach is becoming the preferred treatment for symptomatic patients.In this review, we describe the pathophysiology, anatomical localisation, clinical features, diagnosis and therapeutic options for the management of focal atrial tachycardia.


Lim A.K.H.,Monash Medical Center | Ma F.Y.,Monash Medical Center | Nikolic-Paterson D.J.,Monash Medical Center | Kitching A.R.,Monash University | And 2 more authors.
Diabetologia | Year: 2010

Aims/hypothesis: Diabetic nephropathy is an inflammatory disease with prominent leucocyte infiltration of the kidneys. While the importance of macrophages in diabetic renal injury has been clearly demonstrated, the role of lymphocytes is still unknown. We therefore examined the development of diabetic renal injury in lymphocyte-deficient mice. Methods: Streptozotocin was used to induce diabetes in Rag1 -/- mice, which lack mature T and B lymphocytes, and in wild-type (Rag1 +/+ ) controls. The development of renal injury was examined over 20 weeks of diabetes. Results: Both groups developed equivalent diabetes, however only Rag1 +/+ mice had kidney infiltration with CD4, CD8, CD22 and forkhead box P3-positive cells, as well as glomerular immunoglobulin deposition. At 20 weeks, Rag1 +/+ mice exhibited renal hypertrophy, increased mesangial and interstitial matrix, kidney macrophage accumulation, tubular injury, progressive albuminuria and a decline in renal function. In comparison, diabetic Rag1 -/- mice showed similar histological damage, matrix expansion, macrophage accrual and loss of renal function, but were protected from increasing albuminuria. This protection was associated with protection against loss of podocytes and glomerular podocin production, and with reduced glomerular macrophage activation. Conclusions/interpretation: These results show that lymphocytes contribute to the development of diabetic albuminuria, which may partly arise from increasing glomerular macrophage activation and podocyte damage. In contrast, lymphocytes do not appear to promote tubular injury, increased matrix deposition or decline in renal function in a mouse model of type 1 diabetes. Our findings suggest that innate immunity rather than adaptive immune responses are the major inflammatory contributor to the progression of diabetic renal injury. © 2010 Springer-Verlag.


Smink P.A.,University of Groningen | Bakker S.J.L.,University of Groningen | Laverman G.D.,University of Groningen | Berl T.,University of Colorado at Denver | And 3 more authors.
Journal of Hypertension | Year: 2012

Objective: Increased levels of serum uric acid (SUA) are thought to be an independent risk marker for cardiovascular complications. Treatment with the angiotensin receptor blocker (ARB) losartan lowers SUA in contrast to other ARBs. Whether reductions in SUA during ARB therapy are associated with cardiovascular protection is unclear. We aimed to investigate this. Method: In a post-hoc analysis of the Reduction of Endpoints in Non insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) and Irbesartan Diabetic Nephropathy (IDNT) trials we determined whether the short-term effect of losartan and of irbesartan on SUA is related with long-term cardiovascular outcome by means of Cox regression. Results: Compared to placebo, losartan significantly changed SUA [-0.16 mg/dl; 95% confidence interval (CI)-0.01 to-0.30; P = 0.031], whereas irbesartan did not (-0.09 mg/dl; (95% CI 0.09 to-0.28; P = 0.30). Each 0.5 mg/dl decrement in SUA during losartan treatment in the first 6 months resulted in a reduction in the risk of cardiovascular outcomes by 5.3% (95% CI 0.9 to 9.9; P = 0.017). Losartan reduced the risk of cardiovascular outcomes by 9.2% (95% CI-7.9 to 23.6). Adjustment for the 6-month change in SUA attenuated the treatment effect to 4.6% (95% CI-16.2 to 22.0), suggesting that part of the cardiovascular protective effect of losartan is attributable to its short-term effect on SUA. Conclusion: Losartan but not irbesartan significantly lowers SUA compared to placebo in patients with type 2 diabetes and nephropathy. The degree of reduction in SUA explains part of the cardiovascular effect of losartan. This supports the hypothesis that SUA is a modifiable risk factor for cardiovascular disease, at least in type 2 diabetics with nephropathy. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Ott C.,Friedrich - Alexander - University, Erlangen - Nuremberg | Schneider M.P.,Friedrich - Alexander - University, Erlangen - Nuremberg | Delles C.,University of Glasgow | Schlaich M.P.,Baker Heart Research Institute | Schmieder R.E.,Friedrich - Alexander - University, Erlangen - Nuremberg
Diabetes | Year: 2011

OBJECTIVE - The barrier function of the glomerular filter has been studied for decades. Albuminuria reflects a malfunction of this barrier, and in animals dysfunctional endothelial nitric-oxide (NO) synthase results in albuminuria. We aimed to analyze the importance of NO for the glomerular barrier function in humans. RESEARCH DESIGN AND METHODS - To assess the effect of endothelial dysfunction on albuminuria, we measured the urine albumin-to-creatinine ratio (UACR) both before and after the blockade of NO synthases (NOSs) with systemic infusion of N G-monomethyl-L-arginine (L-NMMA) in two distinct study populations. In population A, 62 hypertensive patients with type 2 diabetes and, in population B, 22 patients with hypercholesterolemia but without hypertension or type 2 diabetes were examined. All subjects had normal renal function. RESULTS - There was a significant increase in the UACR in response to NOS inhibition with L-NMMA in hypertensive patients with type 2 diabetes (study population A) and in patients with hypercholesterolemia (study population B). Linear regression analyses revealed that the change in mean arterial presssure in response to L-NMMA was not related to the increase in the UACR in response to L-NMMA in either population, even after adjusting for filtration fraction. CONCLUSIONS - NOS inhibition provokes albuminuria that is unrelated to changes in blood pressure. It is noteworthy that this finding was evident in patient groups prone to endothelial dysfunction and albuminuria. Thus, acute deterioration of endothelial function by reducing NO activity causes an increase in albuminuria. © 2011 by the American Diabetes Association.

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