Hypertension in pregnancy and long-term cardiovascular mortality: a retrospective cohort study.

BACKGROUND: There is growing evidence that hypertensive disorders of pregnancy are associated with increased long-term cardiovascular mortality in the mother. Hypertension in pregnancy, until recently, however, has been ignored largely as a risk factor for future cardiovascular disease and mortality because the link between the 2 is not fully understood. OBJECTIVE: To determine the association between women with hypertension in pregnancy and long-term cardiovascular disease mortality. STUDY DESIGN: All women who delivered at a metropolitan hospital between the periods of January 1, 1980, and December 31, 1989, were identified by use of the International Statistical Classification of Diseases and Related Health Problems, 9th Revision, Australian Modification. RESULTS: The total number of deliveries in the given time period was 31,656, with 4387 (14%) of the women identified as having had hypertension in their pregnancy. Using information from the New South Wales Births, Deaths and Marriages Registry and the Australian Bureau of Statistics Death Registry, we identified a total of 651 deaths from this cohort (n = 31,656). There were 521 deaths among the women who remained normotensive in their pregnancy and 129 deaths for women who had hypertension during their pregnancy. Overall, the women with hypertensive disorders of pregnancy were at greater risk of death than the women who remained normotensive in their pregnancy (odds ratio 1.56; 95% confidence interval 1.28-1.89; P < .001). CONCLUSION: Women with a history of hypertension in their pregnancy are at an increased risk of future cardiovascular mortality, and this work identifies a group of women who may benefit from early screening and intervention strategies to help decrease their risk of future cardiovascular disease.

Commonwealth pandemic preparedness plans.

This paper describes the work being done by the Australian Government Department of Health and Ageing to prepare for a possible influenza pandemic. It provides an overview of Australian Government initiatives and explains both the purpose and the content of the Australian Health Management Plan for Pandemic Influenza. It summarises efforts to improve regional detection and response capabilities and it explains the role of simulation exercises in Australian pandemic planning.

The Australian response: pandemic influenza preparedness.

Australia's preparedness for a potential influenza pandemic involves many players, from individual health carers to interdepartmental government committees. It embraces a wide number of strategies from the management of the disease to facilitating business continuity. The key strategy underlying Australia's planned response is an intensive effort to reduce transmission of the virus. This includes actions to reduce the likelihood of entry of the virus into the country and to contain outbreaks when they occur. Containment will provide time to allow production of a matched vaccine. The health strategies are outlined in the Australian health management plan for pandemic influenza. The plan is accompanied by technical annexes setting out key considerations and guidelines in the areas of clinical management and infection control. National plans present overall strategies and guidance, but the operational details can only be determined by individual states and territories, regions, and the services themselves. Primary health care practices will be on the frontline of an influenza pandemic. Every practice needs a plan that defines the roles of staff, incorporates infection control and staff protection measures, and considers business continuity. Most importantly, a practice needs to know how to implement that plan.

Antihypertensive drugs clonidine, diazoxide, hydralazine and furosemide regulate the production of cytokines by placentas and peripheral blood mononuclear cells in normal pregnancy.

BACKGROUND: Antihypertensive drugs such as clonidine, diazoxide, hydralazine and furosemide are used in the hypertensive disorders of pregnancy to control blood pressure, but it is not clear if they modulate the production of placental or circulating cytokines. OBJECTIVE: To examine the effect of pharmaceutical doses of well known antihypertensive drugs used for blood pressure control on the production of the cytokines interleukin (IL)-6, IL-10 and tumour necrosis factor (TNF)-alpha in placental tissue and peripheral blood mononuclear cells (PBMCs) in normal pregnancy. DESIGN: Placental biopsies were taken from the decidual surface of placentas after delivery of normal pregnancies (n = 6) and PBMCs were separated from the whole blood of normal term pregnant women (n = 7). Both villous explants and PBMCs were cultured with increasing concentrations of antihypertensive drugs. The dose effect of drugs on the production of placental and circulating cytokines (IL-6, IL-10 and TNF-alpha) were examined by enzyme-linked immunosorbent assay. RESULTS: Placental production of IL-10 was not affected by clonidine, but decreased significantly after incubation of the tissue with diazoxide, hydralazine or furosemide. Production of IL-10 by PBMCs increased significantly: by from 3.4 +/- 2.7% [16.3 pg/ml (range 6.1-21.5 pg/ml)] to 24.5 +/- 3.3% [30.4 pg/ml (range 16.9-34.8 pg/ml)] with increasing concentrations of clonidine (0.08-1.3 microg/ml), and by 8.8 +/- 3.5% [4.1 pg/ml (range 3.0-17.8 pg/ml)] and 17.2 +/- 1.9% [22.6 pg/ml (range 13.2-23.2 pg/ml)] with lower doses of hydralazine (6.3 and 12.5 microg/ml) (all P values < 0.05). There was a stepwise reduction in production of TNF-alpha and IL-6 with increasing doses of diazoxide, hydralazine and furosemide by placentas and PBMCs from these women with normal pregnancies. CONCLUSION: Our data suggest that the antihypertensive drugs clonidine and hydralazine can stimulate production of the circulating anti-inflammatory cytokine IL-10, whereas furosemide and diazoxide inhibit the production of this cytokine and the proinflammatory cytokines TNF-alpha and IL-6 by placentas and PBMCs.

Interleukin-10 regulates arterial pressure in early primate pregnancy.

OBJECTIVES: In pregnancy, the placental contribution of cytokines to maternal immunosuppression has been established, however their role in normal maternal blood pressure regulation has not been identified. We investigate the contribution of interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNF-alpha) to the vasodilation of early pregnancy in non-human primates. We also sequenced the IL-10 baboon gene and compared it with humans. METHODS: The effect of four different treatments, administered sequentially (semi-random-design) on resting 18h, night time, or hourly mean arterial pressure (MAP) and heart rate (HR) were measured using telemetry. An anti-human IL-10 monoclonal antibody (MAb, 1mg, n=7), anti-TNF-alpha antibody (n=3), a combination of anti-IL-10 and anti-TNF-alpha antibodies (n=5) or saline (n=3) control were administered intravenously to baboons in early pregnancy. Plasma and placental IL-10 concentration was measured before and after injection in all animals. RESULTS: Anti-human IL-10 MAb caused a significant increase in MAP of 2.6+/-0.5mmHg over the 18-h period (p<0.05). Administration of TNF-alpha alone or in combination with IL-10 did not alter MAP. There was 97% sequence homology of IL-10 cDNA between humans and baboons. CONCLUSIONS: IL-10 was shown to regulate the vasodilation of early pregnancy in Papio hamadryas. This partial role of IL-10 in the early BP response of primate pregnancy may be relevant to pathophysiological states of human pregnancy such as preeclampsia.

Potential clinical implications of substitution of generic cyclosporine formulations for cyclosporine microemulsion (Neoral) in transplant recipients.

Cyclosporine (CsA) is a critical-dose drug for which a minor change in absorption can have important clinical implications. Generic formulations of CsA are becoming more widely available, but standard criteria for bioequivalence require only that a single study in healthy volunteers demonstrate that mean pharmacokinetic parameters fall within 80-125% of the mean values for Neoral, the reference formulation of CsA. However, CsA absorption is known to differ between healthy volunteers and transplant patients and between different types of transplant patients, such that standard bioequivalence testing may be inadequate to ensure interchangeability of CsA formulations in all patients. The limited available clinical evidence has shown that stable renal transplant patients receiving Neoral have a significant reduction in mean CsA trough level after transfer to the Cicloral formulation. Mean pharmacokinetic values have been reported as equivalent following transfer to Gengraft in one study, but mean CsA trough fell and mean serum creatinine rose significantly in a separate trial. The only clinical outcomes data available are from a retrospective study of de novo renal transplant patients, which reported a significantly higher incidence of biopsy-proven acute rejection in patents receiving Gengraf versus Neoral (39% versus 25%, P<0.05). Until robust clinical data demonstrate that different formulations of CsA are interchangeable, it is advisable to prescribe CsA by brand, and any transfer to a different CsA formulation should be undertaken with close supervision and only at the direction of the transplant physician.

Preeclampsia is associated with a reduced interleukin-10 production from peripheral blood mononuclear cells.

PROBLEM: This study aims to investigate and compare in vitro, immune cell production of the immunosuppresor cytokine interleukin-10 (IL-10) and the proinflammatory cytokine tumor necrosis factor (TNF-alpha) between normal pregnancy (NP) and preeclampsia. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from age-matched patients with preeclampsia and women with a NP (n=3/group) and cultured for 48 hr in the absence and presence of the mitogen phytohaemagluttanin (PHA, 1/100). The concentration of IL-10 and TNF-alpha in the culture medium (CM) was measured by ELISA. RESULTS: Stimulated PBMCs associated with preeclampsia had significantly less IL-10 in the CM compared to NP (347+/-39, preeclampsia vs. 689+/-128, NP; p<0.05) but no difference in TNF-alpha. There was no significant difference in IL-10 or TNF-alpha concentration in the CM of unstimulated PBMCs between preeclampsia and NP. CONCLUSIONS: These findings suggest that under in vitro stimulated conditions preeclampsia is associated with an abnormality characterized by a diminished ability of peripheral immune cells to produce the immunosupressor cytokine interleukin-10.

Women in medicine: a four-nation comparison.

OBJECTIVES: to determine the impact of increasing numbers of women in medicine on the physician work force in Australia, Canada, England, and the United States. METHODS: We collected data on physician work force issues from professional organizations and government agencies in each of the 4 nations. RESULTS: Women now make up nearly half of all medical students in all 4 countries and 20% to 30% of all practicing physicians. Most are concentrated in primary care specialties and obstetrics/gynecology and are underrepresented in surgical training programs. Women physicians practice largely in urban settings and work 7 to 11 fewer hours per week than men do, for lower pay. Twenty percent to 50% of women primary care physicians are in part-time practice. CONCLUSIONS: Work force planners should anticipate larger decreases in physician full-time equivalencies than previously expected because of the increased number of women in practice and their tendency to work fewer hours and to be in part-time practice, especially in primary care. Responses to these changes vary among the 4 countries. Canada has developed a detailed database of work/family issues; England has pioneered flexible training schemes and reentry training programs; and Australia has joined consumers, physicians, and educators in improving training opportunities and the work climate for women. Improved access to surgical and subspecialty fields, training and practice settings that provide balance for work/family issues, and improved recruitment and retention of women physicians in rural areas will increase the contributions of women physicians.

Karyomegalic nephropathy: an uncommon cause of progressive renal failure.

BACKGROUND: Karyomegalic nephropathy, first identified in 1974, represents an increasingly recognized, but perhaps underdiagnosed condition associated with interstitial nephritis. It undoubtedly leads to end-stage renal disease requiring renal support. METHODS AND RESULTS: We present a series of six cases of karyomegalic nephropathy. The age at diagnosis was 9-51 years, median 33 years. Impaired renal function, proteinuria, and haematuria were present in the majority of cases. Non-specific elevated liver enzymes were present in three cases. Two patients died soon after transplantation from overwhelming respiratory sepsis. The classical histological features of large, abnormal hyperchromatic nuclei with irregular outlines within epithelial cells were present in renal epithelial cells. Abnormality of DNA ploidy distributions compared with age- and sex-matched controls, and characterized by the presence of significant numbers of cells with high ploidy values was present in cases but not in controls. Mitotic figures were absent. Proliferation markers, Ki-67 and proliferating cell nuclear antigen/cyclin were not significantly elevated in those cases examined. Human leukocyte antigen analysis did not support the clustering of A9 or B35, in the cases or their families. CONCLUSIONS: The presence of significant renal impairment, positive urine sediment, abnormal liver enzymes, and early age of onset should alert one to the presence of karyomegalic nephropathy. It represents an underdiagnosed disorder with a high degree of ploidy indicative of karyotypic abnormality.