Time to research Australian female physician-researchers.

BACKGROUND: Given the concerns that physician-researchers are 'at risk', and ≈50% of Australian medical students are female, the evaluation of female physician-researchers is important. AIMS: To compare over time (i) research-related metrics of male and female physician-researchers from Sydney Medical School; and (ii) National Health and Medical Research Council (NHMRC) Project grant leadership by gender. METHODS: The Sydney Medical School (SMS) PhD award lists from 1989 to 2012 were cross-referenced with the Australian Health Practitioner Regulation Agency database, and registered medical practitioners were searched for in the Scopus database for publications and H-indexes. The gender of medical-practitioner Chief Investigator A (CIA) in Australia on funded NHMRC Project grants in 1990 to 2014 was also compared. RESULTS: Of the medical practitioners awarded University of Sydney PhD, females increased from 14 to 55% in 1989-1990 and 2009-2010 and decreased to 38% in 2011-2012 (overall increase, P = 0.047). PhD award timings relative to MBBS and clinical fellowship completions were similar for both genders (P > 0.05). Post-PhD, as many women as men publish and have similar H-indexes, but women publish fewer papers (0.7 vs 1.0 publications per year, P = 0.028). On medical practitioner-led, funded NHMRC project grants between 1999 and 2014, female CIA increased from 7.5 to 19.5%, P < 0.0001. For the 17% of project grant applications funded to commence in 2014, 21% were medical practitioner-led, of whom 19.5% were female. CONCLUSIONS: Since 1989, more female medical practitioners are completing SMS PhD at similar times in their careers to males. However, relative to their male peers, they publish less. Fewer female than male medical practitioner-researchers hold NHMRC Project Grant CIA status nationally, although the rates are increasing. In addressing physician-researcher workforce issues, including retention, attention should be given to factors impacting females.

Determinants of bone density in 30- to 65-year-old women: a co-twin study.

UNLABELLED: Reported effects of body composition and lifestyle on bone mineral density in pre-elderly adult women have been inconsistent. In a co-twin study, we measured bone mineral density, lean and fat mass, and lifestyle factors. Analyzing within pair differences, we found negative associations between bone mineral density and tobacco use (2.3-3.3% per 10 pack-years) and positive associations with sporting activity and lean and fat mass. INTRODUCTION: Reported effects of body composition and lifestyle of bone mineral density in pre-elderly adult women have been inconsistent. METHODS: In a co-twin study of 146 female twin pairs aged 30 to 65 years, DXA was used to measure bone mineral density at the lumbar spine, total hip, and forearm, total body bone mineral content, and lean and fat mass. Height and weight were measured. Menopausal status, dietary calcium intake, physical activity, current tobacco use, and alcohol consumption were determined by questionnaire. Within-pair differences in bone measures were regressed through the origin against within-pair differences in putative determinants. RESULTS: Lean mass and fat mass were associated with greater bone mass at all sites. A discordance of 10 pack-years smoking was related to a 2.3-3.3% (SE, 0.8-1.0) decrease in bone density at all sites except the forearm, with the effects more evident in postmenopausal women. In all women, a 0.8% (SE, 0.3) difference in hip bone mineral density was associated with each hour per week difference in sporting activity, with effects more evident in premenopausal women. Daily dietary calcium intake was related to total body bone mineral content and forearm bone mineral density (1.4 +/- 0.7% increase for every 1000 mg). Lifetime alcohol consumption and walking were not consistently related to bone mass. CONCLUSION: Several lifestyle and dietary factors, in particular tobacco use, were related to bone mineral density. Effect sizes varied by site. Characterization of determinants of bone mineral density in midlife and thereafter may lead to interventions that could minimize postmenopausal bone loss and reduce osteoporotic fracture risk.

Aldose reductase (AC)(n) microsatellite polymorphism and diabetic microvascular complications in Caucasian Type 1 diabetes mellitus.

A case-control study to investigate whether the aldose reductase (AC)(n) dinucleotide polymorphism (termed 5'-ALR2 polymorphism) is useful as a genetic marker for risk of microvascular complications among Caucasians Type 1 diabetic patients in Australia is reported. This marker was amplified from patient genomic DNA and then fractionated in 5% formamide-urea gels. A total of nine alleles was observed with Z, Z-2 and Z+2 being the major alleles. The distribution of alleles was comparable in diabetic subjects with diabetes and microvascular complications, diabetes without complications and normal non-diabetic control subjects. Similarly, when the distribution of alleles was examined in the patients subcategorized according to the presence of diabetic nephropathy or diabetic neuropathy, no significant association was observed. While the size of the study makes it impossible to exclude a weak linkage, it is concluded that the 5'-ALR2 polymorphism is not useful as a genetic marker for susceptibility to diabetic microvascular complications in Caucasian Type 1 diabetic patients.

Facilitating best practice: transferring the lessons of the Clinical Support Systems Program.

The Clinical Support Systems Program (CSSP) includes the management of clinical practice using clinical and consumer pathways, outcome and performance indicators, clinical measurement and review in a continuous improvement cycle using the best available extant evidence. The Royal Australasian College of Physicians is testing the CSSP model through four consortia around Australia. There are 17 project sites in three States. The funded projects address major clinical problems including congestive heart failure and acute coronary syndromes, acute stroke management, and colorectal cancer care. There is some early evidence of the CSSP influencing change in areas beyond the bounds of the project settings and the College has developed a plan to promote wider adoption of best practice. This approach recognises the College's role in providing Fellows with the practical tools of quality improvement, the means to collect data and compare their practice to other clinicians, while traversing the appropriate educational framework.

Increased vasodilatory prostaglandin production in the diabetic rat retinal vasculature.

PURPOSE: This study was undertaken in order to investigate whether the production of vasodilatory prostaglandins is increased in the retinal vasculature of the diabetic rat. METHODS: Diabetes was induced in male Sprague-Dawley rats using streptozotocin. Diabetic rats were left uncontrolled for 3-4 weeks or were treated with insulin replacement throughout the period of diabetes. Control rats were age-matched. Retinal vessels extracted from retinae removed at sacrifice were incubated in a physiological salts solution. Prostaglandin E and prostaglandin I2 were measured in collected medium. RESULTS: The production of both prostaglandin E and prostaglandin I2 by blood vessels isolated from the retina was increased by approximately 40% in streptozotocin-diabetic rats, compared to controls, within 4 weeks of the onset of diabetes. This increase was reversed by treatment of streptozotocin-diabetic rats with insulin. The increase in prostaglandin production was not due to alteration in the maximal capacity of cyclooxygenase enzyme. CONCLUSIONS: Increased production of vasodilatory prostaglandins occurs in the rat retinal vasculature early in diabetes. Prostaglandins may contribute to altered retinal hemodynamics in early diabetic retinopathy.

Genetic, common environment, and individual specific components of variance for bone mineral density in 10- to 26-year-old females: a twin study.

Lean mass and areal bone mineral density at the lumbar spine, femoral neck, and total forearm were measured in 215 volunteer female twin pairs (122 monozygotic, 93 dizygotic), aged 10-26 years, using dual energy X-ray absorptiometry. The study was conducted in Melbourne from 1990 to 1994. Under the classic twin model, there was evidence for a genetic component of variation in bone mineral density, adjusted for age or for age and lean mass, at all sites. Adjusting for lean mass almost halved the genetic variances in the adolescent years of peak growth, during which genetic variances peaked. Genetic variances were reduced in the late teenage years and increased in early adulthood. The latter may reflect gene-environment interactions or covariation. Importantly, there was evidence for environmental effects shared by twins on lumbar spine and femoral neck bone mineral density, even when adjusted for lean mass as well as age. These were greatest during the late teenage years, abated over the years when pairs started to live apart, and appear to be independent of lean mass during adolescence but not in early adulthood. In summary, the genetic and environmental etiology of bone mineral density is more complex than previously thought.

New concepts for treatment of non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus remains a major cause of morbidity and premature mortality in our community. Although potentially amenable to control by lifestyle modification, this is difficult to achieve in practice. Additional approaches using drugs that enhance insulin secretion, suppress hepatic glucose production, and increase insulin sensitivity are available, and new agents are being developed. The thiazolidinedione drugs hold particular promise as insulin-sensitizing agents; however, at present, insulin administration is often also required. The importance of detection and treatment of risk factors for cardiovascular disease and the earlier detection and management of microvascular and infective complications remain of crucial importance. (Trends Endocrinol Metab 1997;8:187-191). (c) 1997, Elsevier Science Inc.

A co-twin study of the effect of calcium supplementation on bone density during adolescence.

The effect of calcium supplementation on bone mineral density (BMD) was evaluated in female twin pairs aged 10-17 years with a mean age of 14 years. Forty-two twin pairs (22 monozygotic, 20 dizygotic; (including one monozygotic pair from a set of triplets) completed at least 6 months of the intervention: 37 pairs to 12 months and 28 pairs to 18 months. BMD was measured by dual-energy X-ray absorptiometry (DXA). In a double-blind manner, one twin in each pair was randomly assigned to receive daily a 1000 mg effervescent calcium tablet (Sandocal 1000), and the other a placebo tablet similar in taste and appearance to the calcium supplement but containing no calcium. Compliance (at least 80% tablets consumed), as measured by tablet count, was 85% in the placebo group and 83% in the calcium group over the 18 months of the study, on average increasing dietary calcium to over 1600 mg/day. There was no within-pair difference in the change in height or weight. When the effect of calcium supplementation on BMD was compared with placebo at approximately 6, 12 and 18 months, it was found that there was a 0.015 +/- 0.007 g/ cm2 greater increase in BMD (1.62 +/- 0.84%) at the spine in those on calcium after 18 months. At the end of the first 6 months there was a significant within-pair difference of 1.53 +/- 0.56% at the spine and 1.27 +/- 0.50% at the hip. However, there were no significant differences in the changes in BMD after the initial effect over the first 6 months. Therefore, we found an increase in BMD at the spine with calcium supplementation in females with a mean age of 14 years. The greatest effect was seen in the first 6 months; thereafter the difference was maintained, but there was no accelerated increase in BMD associated with calcium supplementation. The continuance of the intervention until the attainment of peak bone mass and follow-up after cessation of calcium supplementation will be important in clarifying the optimal timing for increased dietary calcium and the sustained, long-term effects of this intervention.

Nandrolone decanoate and intranasal calcitonin as therapy in established osteoporosis.

This study used a randomized, 2 x 2 factorial design to evaluate over 2 years the effect of intranasal salmon calcitonin and intramuscular nandrolone decanoate on bone mass in elderly women with established osteoporosis. The study was double masked in relation to calcitonin and open in relation to nandrolone decanoate. One hundred and twenty-three women aged 60-88 years who had sustained a previous osteoporotic fracture, or had osteopenia, were recruited through an outpatient clinic. Women were assigned to one of four groups: (1) daily placebo nasal spray, (2) 400 IU intranasal calcitonin daily, (3) 20 intramuscular injections of 50 mg nandrolone decanoate (given as two courses of 10 injections) plus placebo nasal spray, or (4) 20 injections of 50 mg nandrolone decanoate plus 400 IU intranasal calcitonin daily. All subjects received 1000 mg calcium supplementation daily. Outcomes measured included changes in bone mineral density (BMD) at the lumbar spine, as measured by dual-energy quantitative computed tomography (DEQCT), in BMD of the proximal femur, and BMD and bone mineral content (BMC) of the lumbar spine and forearm, as measured by dual-energy X-ray absorptiometry (DXA). Significant positive changes from baseline in DXA BMC at the lumbar spine were observed over 2 years in the calcitonin group (5.0 +/- 1.9%, mean +/- SE) and in the nandrolone deconate group (4.7 +/- 1.9%) but not in the placebo group (1.1 +/- 2.2%) or the combined therapy group (0.7 +/- 1.8%). Modelling based on the 2 x 2 factorial design revealed that nandrolone decanoate was associated with a 3.8 +/- 1.8% (p < 0.05) gain in DXA BMD at the proximal femur. Modelling also revealed that calcitonin treatment was associated with a loss of 11.5 +/- 4.7% in DEQCT BMD at the lumbar spine and a loss of 3.7 +/- 1.8% in DXA BMD at the proximal femur (p < 0.05). There was in vivo antagonism between the two medications of 7.9 +/- 3.9% for DXA BMC at the lumbar spine. Both agents caused positive changes from baseline in lumbar spine BMC. Nandrolone decanoate had beneficial effects on BMD at the proximal femur. This dose of intranasal calcitonin was associated with deleterious effects on trabecular BMD at the lumbar spine and total BMD at the proximal femur. There may be significant clinical antagonism between these two medications.

Effect of inhibition of aldose reductase on glucose flux, diacylglycerol formation, protein kinase C, and phospholipase A2 activation.

Activation of the polyol pathway under hyperglycemic conditions is proposed to contribute to the development of diabetic nephropathy. The mechanisms by which this activation may lead to functional and structural changes within the kidney are yet to be definitively established. We have examined in vitro the steps linking increased polyol pathway activity resulting from hyperglycemia to prostaglandin production. Following the demonstration of increased prostaglandin E (PGE) levels in glomeruli from diabetic rats (14.9 +/- 2.5 v 59.1 +/- 19.4 ng PGE/mg protein), a specific inhibitor of aldose reductase, HOE-843, was used in vitro to analyze the response to hyperglycemia of the steps preceding prostaglandin production. In explants of glomeruli from control animals, increasing the glucose concentration in vitro from 5.6 mmol/L to 25 mmol/L resulted in a significant increase in the flux of glucose through the pentose phosphate pathway ([PPP] 1.29 +/- 0.08 v 2.00 +/- 0.11 nmol/h), de novo diacylglycerol synthesis (2.2 +/- 0.1 v 3.1 +/- 0.2 micromol/mg protein), membrane protein kinase C (PKC) activity (18.7 +/- 0.5 v 24.3 +/- 0.75 pmol/microg protein), and in vitro phospholipase A2 (PLA2) activity (2.18 +/- 0.46 v 3.83 +/- 1.07 nmol arachidonic acid hydrolyzed/min/mg cytosolic protein). For all parameters measured, the increase resulting from the increased glucose concentration could be prevented by in vitro addition of HOE-843 for 24 hours before measurement. These findings provide evidence to suggest a mechanism linking increased polyol pathway activity and an increase in PLA2 activity to increased prostaglandin production, which is observed in diabetes of recent onset and may ultimately lead to changes associated with the development of diabetic nephropathy.

Lipoprotein-induced prostacyclin production in endothelial cells and effects of lipoprotein modification.

Although lipoprotein modification has been implicated in atherogenesis, the effect of modified forms of lipoproteins on vascular cell function has not been fully resolved. We have investigated lipoprotein-induced prostaglandin production by macrovascular endothelial cells. This study delineates early responses of endothelial cells after exposure to native and modified forms of the lipoproteins. Modification of lipoproteins by oxidation or glycation significantly affected the capacity of lipoproteins to induce prostacyclin (PGI2) production by bovine aortic endothelial cells (BAEC). Modified low-density lipoprotein (LDL) increased PGI2 production in the short term (up to 24 h), but oxidized LDL caused an inhibition of PGI2-producing capacity in longer term incubations (48-72 h). Glycated (Glc) high-density lipoprotein 3 (HDL3) caused higher production of PGI2 in the short term (4-24 h) but reached similar levels as HDL3 over time. Glycation of high-density lipoprotein 2 had no effect on the PGI2-producing capacity of the lipoprotein. Thus modification of the lipoproteins affects their potential to induce PGI2 production in endothelial cells, and this may have an influence on vascular function in disease states such as diabetes and atherosclerosis. Although the changes appear to contradict data from long-term in vivo studies, these results from in vitro studies may reflect the situation in very early lesion development. GlcLDL, while causing an increase in endothelial cell PGI2 production, may be involved in compromised endothelial function, since GlcLDL is prone to oxidation.

Production of hyaluronan by glomerular mesangial cells in response to fibronectin and platelet-derived growth factor.

The formation of the non-sulphated glycosaminoglycan hyaluronan by cells of the renal glomerulus in diabetes may contribute to altered matrix composition. We describe an increased production of hyaluronan from mesangial cell-enriched glomerular cores from diabetic animals, and further show that increased hyaluronan production follows the exposure of non-diabetic and diabetic preparations to fibronectin and to platelet-derived growth factor in vitro. Hyaluronan production appeared dependent on protein kinase C activity, and could not be shown after prolonged phorbol ester preincubation. Stimulation by fibronectin was wholly dependent on cyclooxygenase activity and prior prostaglandin production, while the effect of platelet-derived growth factor showed only a partial dependence.

Norman MacAlister Gregg Lecture. The pathogenesis of diabetic retinopathy.

Diabetic retinopathy remains a major cause of loss of vision. The Diabetes Control and Complications Trial (DCCT) has implicated hyperglycaemia as a probable major direct causative factor in the pathogenesis of diabetic retinopathy. There are several plausible mechanisms by which high glucose concentrations could lead to the functional and later structural changes characterising diabetic retinopathy. These include increased activity of the aldose reductase pathway, increase de novo synthesis of diacylglycerol from glucose, causing protein kinase C activation, increased non-enzymatic glycation and increased oxidative damage. The demonstration of the potential roles of these pathways and the subsequent effects of growth factors in enhancing angiogenesis provide potential new approaches to the prevention and treatment of diabetic retinopathy.

Effect of prostaglandin E2 and hyaluronan on mesangial cell proliferation. A potential contribution to glomerular hypercellularity in diabetes.

Proliferation of mesangial cells is a feature of several forms of human and experimental glomerulopathy, including that seen in diabetes. The nonsulfated glycosaminoglycan hyaluronan participates in the regulation of pericellular matrix assembly and is a mitogen in some cell types. We have shown previously that hyaluronan production is increased in the glomerulus in a glucose- and prostaglandin-dependent manner. We have investigated the effect of diabetes and of addition of hyaluronan and prostaglandin E2 (PGE2) on the uptake of [3H]thymidine by glomerular core preparations enriched in mesangial cells. When compared with nondiabetic controls, it was shown that [3H]thymidine uptake was significantly increased in glomerular core preparations from streptozotocin-induced diabetic rats (to 169 +/- 5%, P < 0.001). In glomerular cores from both experimental groups, hyaluronan (50-250 ng/ml) or PGE2 (10(-12) to 10(-8) mol/l) increased the uptake of [3H]thymidine. Further, mesangial cells from nondiabetic control glomerular cores, when maintained in culture in early passage, responded with increased [3H]thymidine uptake to raised glucose (5.6-25 mmol/l) and to added hyaluronan and PGE2. We propose that prostaglandin and hyaluronan production in response to a raised glucose environment in diabetes can contribute to mesangial hypercellularity.