J. A. Scott

Patients with type 2 diabetes have exaggerated brachial and central exercise blood pressure: relation to left ventricular relative wall thickness.

BACKGROUND A hypertensive response to exercise has prognostic significance. Patients with type 2 diabetes have vascular abnormalities which may predispose to exaggerated brachial and central blood pressure (BP) during exercise. This study aimed to test this hypothesis and to determine the clinical significance of high exercise BP by examining its relation to left ventricular (LV) mass. METHODS Brachial and central BP were recorded at rest and in response to maximal exercise in 73 diabetic patients (aged 54 +/- 10 years) and 73 controls (aged 53 +/- 12 years). Brachial BP was recorded using mercury sphygmomanometry and LV mass using 2D-echocardiography. Central BP was estimated by radial tonometry using an exercise-validated generalized transfer function. RESULTS At rest there were no significant (P > 0.05) differences between groups in brachial or central BP. The diabetic patients had significantly increased exercise brachial systolic BP (SBP: 199 +/- 25 mm Hg vs. 185 +/- 21 mm Hg; P = 0.002) and central SBP (158 +/- 17 mm Hg vs. 149 +/- 15 mm Hg; P = 0.002). There was a significantly higher prevalence of an exaggerated exercise BP response (> or =210/105 mm Hg; men and > or =190/105 mm Hg; women) in the diabetic patients (51% vs. 22%; P < 0.01). Compared with those with normal exercise BP, LV relative wall thickness (RWT) was significantly higher (0.41 +/- 0.09 vs. 0.36 +/- 0.08; P < 0.05) and LV hypertrophy was more prevalent (35% vs. 16%; P < 0.05) in those with a hypertensive response. After accounting for other confounding variables, exercise central SBP remained independently associated with LV RWT (beta = 0.22; P = 0.006). CONCLUSION Diabetic patients are more likely to exhibit exaggerated exercise BP. Regardless of disease status, high exercise central SBP may contribute to cardiovascular risk via adverse cardiac remodeling.

Trends in health status and chronic disease risk factors over 10–14 years in a remote Australian community: a matched pair study

Objective: To determine trends in health status over a 10‐year interval in a high‐risk remote Australian Aboriginal community.

Do children born to teenage parents have lower adult intelligence? A prospective birth cohort study

Teenage motherhood has been associated with a wide variety of negative offspring outcomes including poorer cognitive development. In the context of limitations of previous research, this paper assesses the contemporary relevance of this finding. In this study we investigate the long-term cognitive status (IQ) among 21 year adult offspring born to teenage parents using the Mater University Study of Pregnancy- a prospective birth cohort study, which recruited all pregnant mothers attending a large obstetrical hospital in Brisbane, Australia, from 1981 to 1983. The analyses were restricted to a sub-sample of 2643 mother-offspring pair. Offspring IQ was measured using the Peabody Picture Vocabulary Test at 21 year. Parental age was reported at first clinic visit. Offspring born to teenage mothers (<20 years) have -3.0 (95% Confidence Interval (CI): -4.3, -1.8) points lower IQ compared to children born to mothers ≥20 years and were more likely to have a low IQ (Odds Ratio (OR) 1.7; 95% CI: 1.3, 2.3). Adjustment for a range of confounding and mediating factors including parental socioeconomic status, maternal IQ, maternal smoking and binge drinking in pregnancy, birthweight, breastfeeding and parenting style attenuates the association, though the effect remains statistically significant (-1.4 IQ points; 95% CI: -2.8,-0.1). Similarly the risk of offspring having low IQ remained marginally significantly higher in those born to teenage mothers (OR 1.3; 95% CI: 1.0, 1.9). In contrast, teenage fatherhood is not associated with adult offspring IQ, when adjusted for maternal age. Although the reduction in IQ is quantitatively small, it is indicative of neurodevelopmental disadvantage experienced by the young adult offspring of teenage mothers. Our results suggest that public policy initiatives should be targeted not only at delaying childbearing in the population but also at supporting early life condition of children born to teenage mothers to minimize the risk for disadvantageous outcomes of the next generation.

Chronic disease profiles in a high risk Aboriginal community over a 10-year interval

Aim: To identify whether the macrophage CSF-1 receptor promotes macrophage accumulation and the progression of nephropathy in type 2 diabetic mice. Background: Macrophages are the key inflammatory cells associated with the development and progression of diabetic nephropathy. CSF-1, which is up-regulated in diabetic kidneys, is required for the proliferation, differentiation and activation of monocyte-macrophages and exerts its effects through its receptor tyrosine kinase encoded by the c-fms proto-oncogene. Blockade of c-fms in acute renal disease has proved beneficial in an animal model of renal allograft rejection but the role of c-fms in diabetic nephropathy has not been examined. Methods: Obese, diabetic db/db BL/KS mice with established albuminuria were treated with intraperitoneal injections of neutralizing anti-c-fms mAb (AFS98, 50 mg/kg/twice weekly) or isotype matched control IgG (50 mg/kg/twice weekly) from 12 to 18 weeks of age. Results: Administration of AFS98 mAb did not affect obesity, hyperglycaemia, circulating monocyte levels or the established albuminuria of db/db mice. However, treatment with AFS98 suppressed renal inflammation by reducing kidney macrophages (accumulation, activation and proliferation), MCP-1 levels (mRNA and urine protein), kidney activation of proinflammatory pathways (JNK and ATF-2), and TNF-a mRNA. In addition, AFS98 treatment decreased tubular injury (apoptosis and hypertrophy), interstitial damage (cell proliferation and myofibroblast accrual) and renal fibrosis (TGF-b and collagen IV mRNA), indicating that c-fms antibody can also inhibit the damage caused by inflammation in diabetic kidneys. Conclusions: Treatment with a neutralizing c-fms antibody demonstrates that macrophage activation through the CSF-1 receptor induces renal inflammation and injury in type 2 diabetic mice, supporting the concept that macrophages promote diabetic nephropathy.

Further Demonstration of Associations of Low Birthweight with Adult Death and Renal Failure in a Remote Aboriginal Community

021 CELL BASED THERAPY IN COMBINATION WITH SERELAXIN IS CRITICAL FOR PRESERVATION OF VASCULAR INTEGRITY VIA PROMOTION OF ANGIOGENESIS AND ANASTOMOSIS B HUUSKES1, A PINTO2, C SAMUEL3, S RICARDO1 1Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria; 2Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria; 3Department of Pharmacology, Monash University, Clayton, Victoria

Trends in health status and chronic disease risk factors over 10-14 years in a remote Australian Aboriginal community: a matched pair study

Aim: Patency after percutaneous balloon angioplasty (PTA) for haemodialysis fistula stenosis is highly variable. This study aimed to assess factors associated with patency following first episode of treatment with PTA. Background: Restenosis recurs commonly after PTA. Previous studies have shown that some intrinsic fistula and biochemical factors may influence patency after PTA. Methods: We retrospectively reviewed all endovascular procedures performed by nephrologists between 2007 and 2012 at a single centre. Anatomical, clinical, biochemical and medication information was subjected to cox regression analysis to identify factors influencing post-intervention patency. Results: 120 patients were identified as having first episode treatment with PTA. During a median follow-up period of 22.66 months (5.24–53 months), 171 follow-up procedures were performed. Post-intervention primary patency rates at 6, 12 and 18 months were 46%, 25% and 15% respectively. Cumulative (functional) patency rates at 6, 12 and 18 months were 97%, 94 and 92% respectively with 1.4 additional procedures per patient. In univariate cox regression analysis, the presence of multiple lesions (p = 0.037) was associated with early restenosis at 6 months, while upper arm fistulae were associated with early restenosis (p = 0.004) and shorter primary patency (p = 0.001). Other anatomical characteristics (fistula age, lesion length, pre-procedure stenosis), clinical history (diabetes, coronary and peripheral artery disease), medications, and biochemical parameters (HbA1c, CRP, albumin and lipids) did not influence patency. Conclusion: Multiple stenoses and upper arm fistulae may be associated with shorter patency after PTA. More large volume prospective studies are required to further assess factors associated with patency after PTA in haemodialysis fistulae, particularly the role of metabolic and inflammatory markers.

Medication use and chronic disease profiles in one high risk aboriginal community

Disease Jeff S Coombes, Amanda Crawford, Robert G Fassett, 3 Dale A Kunde, Iain K Robertson, Madeleine J Ball, Dominic P Geraghty School of Human Movement Studies, University of Queensland, Brisbane, Queensland, AUSTRALIA School of Human Life Sciences, University of Tasmania, Launceston, Tasmania, AUSTRALIA 3 Royal Brisbane and Womens Hospital, Brisbane, Queensland, AUSTRALIA Project funded by the Clifford Craig Medical Research Trust (C Prosser Green Endowment)

New onset albuminuria, hypertension and diabetes in a high risk aboriginal community over 10 years

Disease Jeff S Coombes, Amanda Crawford, Robert G Fassett, 3 Dale A Kunde, Iain K Robertson, Madeleine J Ball, Dominic P Geraghty School of Human Movement Studies, University of Queensland, Brisbane, Queensland, AUSTRALIA School of Human Life Sciences, University of Tasmania, Launceston, Tasmania, AUSTRALIA 3 Royal Brisbane and Womens Hospital, Brisbane, Queensland, AUSTRALIA Project funded by the Clifford Craig Medical Research Trust (C Prosser Green Endowment)

Birth weight and chronic disease profiles in a high risk Aboriginal community

Aim: To identify whether the macrophage CSF-1 receptor promotes macrophage accumulation and the progression of nephropathy in type 2 diabetic mice. Background: Macrophages are the key inflammatory cells associated with the development and progression of diabetic nephropathy. CSF-1, which is up-regulated in diabetic kidneys, is required for the proliferation, differentiation and activation of monocyte-macrophages and exerts its effects through its receptor tyrosine kinase encoded by the c-fms proto-oncogene. Blockade of c-fms in acute renal disease has proved beneficial in an animal model of renal allograft rejection but the role of c-fms in diabetic nephropathy has not been examined. Methods: Obese, diabetic db/db BL/KS mice with established albuminuria were treated with intraperitoneal injections of neutralizing anti-c-fms mAb (AFS98, 50 mg/kg/twice weekly) or isotype matched control IgG (50 mg/kg/twice weekly) from 12 to 18 weeks of age. Results: Administration of AFS98 mAb did not affect obesity, hyperglycaemia, circulating monocyte levels or the established albuminuria of db/db mice. However, treatment with AFS98 suppressed renal inflammation by reducing kidney macrophages (accumulation, activation and proliferation), MCP-1 levels (mRNA and urine protein), kidney activation of proinflammatory pathways (JNK and ATF-2), and TNF-a mRNA. In addition, AFS98 treatment decreased tubular injury (apoptosis and hypertrophy), interstitial damage (cell proliferation and myofibroblast accrual) and renal fibrosis (TGF-b and collagen IV mRNA), indicating that c-fms antibody can also inhibit the damage caused by inflammation in diabetic kidneys. Conclusions: Treatment with a neutralizing c-fms antibody demonstrates that macrophage activation through the CSF-1 receptor induces renal inflammation and injury in type 2 diabetic mice, supporting the concept that macrophages promote diabetic nephropathy.

Patients with Type 2 diabetes mellitus have an exaggerated brachial and central blood pressure response to exercise: relation to left ventricular hypertrophy

There are two types of familial hyperaldosteronism: FH-I and FH-II. FH-I is caused by a hybrid CYP11B1/CYP11B2 gene mutation. The genetic cause of FH-II, which is more common, is unknown. Adrenal hyperplasia and adenomas are features. We reported linkage of FH-II to a 4 Mb region on chr 7p22. Candidate genes at 7p22 involved in cell cycle control include retinoblastoma-associated Kruppel-associated box gene (RBaK), postmeiotic segregation increased 2 (PMS2) and guanine nucleotide-binding protein alpha-12 (GNA12). RBaK interacts with the retinoblastoma gene product to repress expression of genes activated by E2F transcription factors. PMS2 is involved in DNA mismatch repair and tumor predisposition. GNA12 is a transforming oncogene. We previously reported finding no causative mutations in RBaK and PMS2 coding regions. In the current study, (1) GNA12 exons and proximal promoter were examined in two affected (A1, A2) and two unaffected (U1, U2) subjects from FH-II family 1, and a normotensive control. No mutations were found. (2) The RBaK promoter was sequenced to -1300bp from the transcription start site. Two unreported single nucleotide polymorphisms (SNPs; C-1034G and T-1021C) were found in subjects A1, A2 but not in U1, U2 or the control. Additional subjects from 7p22-linked FH-II families 1, 2 and 3 and 68 controls were therefore genotyped. Results (see table) suggest that the –1034C/-1021T allele may be in linkage disequilibrium with the causative mutation in family 1. Its frequency among controls does not exclude it, since, based on recent data from the Framingham offspring study linking aldosterone/renin ratio to rising BP and chr 7p, it could indicate those predisposed to become hypertensive. Since this sequence alters the binding sites for several transcription factors in the RBaK promoter and may contribute to FH-II phenotype, these SNPs will be genotyped in additional FH-II subjects.Due to differences in pressure amplification, central BP can differ greatly between individuals with similar brachial BP. Recent large trials have highlighted an independent role of central BP for predicting CV events. However, measuring central BP requires extra effort and dedicated equipment. This study sought to identify individuals most likely to clinically benefit from assessment of central BP. Supine brachial BP was recorded by sphygmomanometry and central BP by validated radial tonometry in a heterogeneous population of 765 people (214 healthy, 207 with known or suspected CAD, 219 with type 2 diabetes, 125 at increased risk of CVD). Normal central SBP was defined as 115 mmHg (men) or 109 mmHg (women) based on Framingham data. Amplification of SBP (SBPamp) was the difference between brachial and central SBP. Across all levels of brachial BP, there was wide variation in SBPamp (2 – 33 mmHg, mean SD, 12 5 mmHg). Normal or high-normal brachial SBP was evident in 68% (n 521) of the population. However, 47% (n 246) of these 521 people had above normal central SBP. There was no additional value (in terms of categorizing individuals as having “normal” or “high” BP) in assessing central BP in people with brachial SBP 160 mmHg because central SBP was high (139 mmHg) in all. The table shows individuals grouped according to brachial SBP and the impact of central SBP measurement on BP categorization in. In terms of further assessing whether patients have, or do not have, elevated SBP, people with normal to mild hypertension (160 mmHg) are those most likely to benefit from central BP monitoring. This does not exclude central BP monitoring as being useful in selected individuals from these or other groups.AVS plays a critical role in the diagnostic workup of primary aldosteronism (PAL) as it is the most reliable means of differentiating unilateral forms (e.g. aldosterone-producing adenoma) correctable by unilateral adrenalectomy, from bilateral forms usually treated with aldosterone antagonist medications. Examination of the adrenal/peripheral venous (AV/PV) cortisol ratio permits assessment of the adequacy of AVS. Ratios of 3 indicate adequate sampling. The right adrenal vein (RAV) is often harder to locate than the left (LAV) as it usually is smaller and empties into the inferior vena cava (IVC) rather than the renal vein at a level ranging from upper T11 to mid L1. Thus, even in highly experienced hands, the RAV cannulation success rate (87% at Princess Alexandra Hospital) is lower than that for LAV (94%). Use of contrast CT prior to AVS has contributed to high success rates achieved in our institutions by permitting visualization of the RAV at its point of entry into the IVC. We recently instituted an on-the-spot method of measuring plasma cortisol that permits determination of AV levels within 12 min of collection. Rapid cortisol estimation was performed by competitive fluorescence polarization assay using a TDx analyser and the TDx reagent system for cortisol. The standard assay for cortisol was modified by reducing the original 16 min incubation time to 6 min by following a test protocol on the analyser originally used for measuring ethosuximide. The requirement for only 50 L sample volumes allowed rapid centrifugation (4 min). Measurement of RAV and simultaneously collected PV cortisol levels was undertaken while the radiologist collected samples from the LAV, resulting in minimal or no prolongation of the AVS procedure. Cortisol levels of 1500 nmol/L could be estimated accurately, permitting reliable assessment of cannulation success provided PV levels were 500 nmol/L (which was almost always the case). This method proved accurate when compared with an established competitive chemiluminescent immunoassay (ADVIA Centaur). This approach offers a means of definitively establishing, at the time of AVS, whether AV cannulation has been successful, and thereby promises to reduce the number of samples required and the need for repeat procedures.