In vitro evaluation of the PEtU-PDMS material immunocompatibility: the influence of surface topography and PDMS content.

The aim of the present work is to evaluate the in vitro immunocompatibility of an elastomeric material with feasible applications in the cardiovascular field. In particular, since it is well known that surface chemistry and topography play a key role in the foreign body response, their influence on human monocytes was evaluated. The material, constituted by a poly(ether)urethane (PEtU) and a polydimethylsiloxane (PDMS), was synthesized to manufacture films and small-diameter vascular grafts with three different surface topographical features, smooth, rough and porous, and siloxane rates, 10, 30 and 40. Human THP-1 monocytes have been cultured for 72 h on the films and human blood has been circulating for 2 h into the grafts to assess leukocyte adhesion and cytokine releases. Materials extracts were utilized to evaluate monocyte apoptosis. Smooth films showed lower cell adhesion degrees than rough and porous ones. All the PEtU-PDMS (poly(ether)urethane-polydimethylsiloxane) films and vascular grafts induced a narrow inflammatory response, as demonstrated by slight cytokine secretion levels, in particular samples with the highest PDMS contents (30 and 40%) induced the lowest IL-1b secretion. Moreover, an absence of monocyte apoptosis advises that the negligible release values have not to be ascribed to material toxicity. In the end, surface topography showed to affect only monocyte adhesion while siloxane content the cytokine release. Therefore, the possibility to modify the above tested parameters during material synthesis and manufacture could allow to bound the inflammatory potency of the PEtU-PDMS devices and render them excellent candidates for cardiovascular reconstruction.

Silicone based polyurethane materials: a promising biocompatible elastomeric formulation for cardiovascular applications.

The biocompatibility of a new material for cardiovascular applications constituted by a poly(ether)urethane (PEtU) and a silicone [polydimethylsiloxane (PDMS)] was evaluated. The achieved material shows properties similar to both polyurethanes and silicones. The material was transformed into porous membranes by a spray-deposition technique. Since any material preparation and manufacturing procedure may introduce some toxicity, in vitro cytotoxicity screening tests were carried out. Human umbilical vein endothelial cells (HUVECs) and a mouse fibroblasts cell line (L929) were cultivated with extracts obtained from materials containing 10, 40 and 100% (w/w) of PDMS. The commercially available Estane 5714-F1 and Cardiothane 51 were used as controls. Extracts were incubated up to 72 hours with HUVECs and L929 cells. The cytotoxic effect was evaluated by light microscopy, cell viability (MTT reduction and neutral red uptake) and proliferation (5-bromo-2'-deoxyuridine incorporation) tests. In vivo studies were carried out using materials containing the same PDMS percentages as for in vitro experiments. The same commercial controls were used. Results obtained with cell culture studies agreed with those obtained in the in vivo experiments and showed that the material preparation and manufacturing procedure do not introduce any toxicity in the products at each PDMS concentration investigated.

[Viral hepatitis E. Current knowledge and future problems]. / Epatite virale E. Conoscenze attuali e problematiche future.

Hepatitis E is the principal enterically-transmitted non-A, non-B, non-C hepatitis, responsible for large epidemics of acute hepatitis associated with fecal contamination of drinking water in under-developed and developing countries. In contrast, in the industrialized world, the infection occurs rarely and sporadically, usually in individuals who originated from or traveled to regions of known endemism. However, serological and virological studies have provided evidence that hepatitis E virus may be circulating in geographical areas not previously considered to be endemic. Hepatitis E is a self-limiting, acute disease with an overall mortality rate of 0.4-4%, although a more severe course has been observed in pregnant women, in whom mortality can rise to 20%. Enzyme immunoassays and polymerase chain reaction are available for definitive diagnosis. The immune serum globulins have not evidenced certain beneficial effects during hepatitis E epidemics, and candidate vaccines have not yet reached the clinical trial stage.

The incidence of biopsy-proven glomerulonephritis in Australia.

BACKGROUND: There is limited population-based epidemiological data on renal disease. An insight into the spectrum of clinically significant glomerulonephritis can be obtained from renal biopsy diagnoses. This is a descriptive report of biopsy-proven glomerulonephritis within a defined population. METHODS: A retrospective review of the pathology reports of all native renal biopsies performed in the Australian state of Victoria in 1995 and 1997 was undertaken. Trends in the average annual age- and sex-specific incidence rates for biopsy-proven glomerulonephritis were calculated. Comparisons were made with the incidence of end-stage renal disease due to glomerulonephritis confirmed on renal biopsy. RESULTS: The most common glomerulonephritides in adults are IgA disease, focal glomerulosclerosis, lupus nephritis and vasculitis, and in children are lupus nephritis, focal glomerulosclerosis, IgA disease and minimal change disease. A male predominance is seen for all glomerulonephritides, except lupus nephritis, in both adults and children. An increase in incidence of disease with age, particularly in males, is seen for vasculitis and focal glomerulosclerosis. The most common glomerulonephritides on renal biopsy are reflected in the most common causes of end-stage renal disease due to glomerulonephritis. CONCLUSIONS: This review has provided population-based descriptive epidemiological data on clinically significant glomerulonephritis. This data provides important clues for further studies relating to the identification of risk factors for the various types of glomerulonephritis.

The effects of Chinese medicinal herbs on postmenopausal vasomotor symptoms of Australian women. A randomised controlled trial.

OBJECTIVE: To evaluate the effects of a defined formula of Chinese medicinal herbs (CMH) on menopausal symptoms. DESIGN: A double-blind randomised placebo-controlled trial. METHODS: Between August 1998 and April 1999, 55 postmenopausal Australian women recruited from an urban population completed 12 weeks of intervention with either a defined formula of CMH (n = 28) or placebo (n = 27) taken twice daily as a beverage. MAIN OUTCOME MEASURES: The primary end-point was change in frequency of vasomotor events (hot flushes and night sweats). The secondary end-points were changes in score for the domains measured in the Menopause Specific Quality of Life (MENQOL) Questionnaire. RESULTS: There was a reduction in average weekly frequency of vasomotor events with CMH (-15%; 95% CI, -31% to +1%) and with placebo (-31%; 95% CI, -42% to -21%). The difference between groups favoured the use of placebo; however, this was not significant (P=0.09). Although significant reductions in scores for the various domains of the MENQOL Questionnaire were observed for both CMH and placebo, there were no significant differences between the two treatment groups for any domain. There was evidence for effect modification by previous use of natural therapies for the vasomotor, physical and sexual domains of the MENQOL Questionnaire: women with no prior use of natural therapies for their menopausal symptoms responded to therapy, whereas prior users did not. CONCLUSIONS: The defined formula of CMH was no more effective than placebo in reducing vasomotor episodes in Australian postmenopausal women, or in improving any of the four symptom domains in the MENQOL Questionnaire. Three of the MENQOL Questionnaire domains were modified by prior use of natural therapies. This finding has implications for future studies.

Role of gancyclovir and HAART administration in the treatment of a rare complication of HIV disease: cytomegalovirus-associated Guillain-Barré syndrome.

Peripheral nerve disorders are very common in patients with HIV infection, including inflammatory demyelinating polyneuropathies, such as Guillain-Barré syndrome. Causes of these neuropathies are probably multiple, and often dictated by the stage of the underlying HIV disease. Acute demyelinating polyneuropathy is usually preceded by infections, generally sustained by cytomegalovirus or Campylobacter jejuni, and a co-infection with HIV may represent the initial etiopathogenetic event leading to the neurological disorder. An extraordinary case report of a cytomegalovirus-associated Guillain-Barré syndrome occurred in one of our patients with advanced HIV infection, who was cured by gancyclovir and HAART administration, and gives us the opportunity to briefly discuss the intriguing pathogenetic and clinical correlations among HIV disease, cytomegalovirus infection, this neurological syndrome, and its specific treatment.

Lipid lowering and coronary heart disease risk: how appropriate are the national guidelines?

OBJECTIVE: To assess the effectiveness of current Australian guidelines for prescribing lipid-lowering drugs in identifying high-risk individuals in primary prevention of coronary heart disease. DESIGN AND SETTING: Coronary heart disease risk profiles were obtained for 280 consecutive patients dispensed lipid-lowering drugs in rural Victoria. Their 10-year absolute risk of coronary heart disease was determined using the Framingham formula. PATIENTS were categorised according to their eligibility for lipid-lowering drugs as defined by current Pharmaceutical Benefits Scheme (PBS) and National Heart Foundation (NHF) guidelines. PATIENTS: Complete data were available for 230 patients dispensed lipid-lowering drugs. Of these, the 138 patients (60%) with no history of vascular disease are the subjects of our study. MAIN OUTCOME MEASURES: Proportion of patients with various 10-year coronary heart disease thresholds (15%, 20% and 30%), compared with their eligibility for lipid-lowering drugs based on Australian PBS and NHF guidelines. RESULTS: Twenty-six per cent of patients with no history of vascular disease who are currently dispensed lipid-lowering drugs do not fulfil PBS guidelines for treatment. Of patients conforming with PBS guidelines as suitable for lipid-lowering drugs, 39% (95% CI, 30%-49%) had a 10-year risk of coronary heart disease of less than 15%. A similar proportion (41% [95% CI, 32%-50%]) had a 10-year risk of coronary heart disease of less than 15%, but were eligible for lipid-lowering drugs according to NHF guidelines. Adherence to PBS and NHF guidelines in patients currently dispensed lipid-lowering drugs would result in as many as 14% (95% CI, 8%-21%) and 7% (95% CI, 3%-12%) of patients, respectively, not being eligible for treatment, despite having a 10-year risk of coronary heart disease greater than 15%. CONCLUSIONS: Australian guidelines for prescribing of lipid-lowering drugs are poor discriminators of absolute risk of coronary heart disease in primary prevention. Strategies based on the continuous relationship between risk-factor intensity and absolute coronary heart disease risk, such as the Framingham risk estimates, provide a more rational basis for formulating treatment guidelines.

Phytoestrogens and breast cancer in postmenopausal women: a case control study.

OBJECTIVE: To examine the association between isoflavones, androgens, and dietary composition and the risk of breast cancer in Australian postmenopausal women. DESIGN: Eighteen women with recently diagnosed breast cancer before surgery and 20 controls were recruited over a 12-month period. Both cases and controls were similarly assessed for urinary isoflavones, serum and urinary sex steroids, and dietary intake. RESULTS: Women with breast cancer had lower 24-h urinary daidzein compared with controls (cases: 31 [95% CI: 4, 234] nmol/day; controls: 427 [95% CI: 4, 234] nmol/day; p = 0.03), and there was a trend to lower urinary genistein excretion (cases: 25 [95% CI: 5, 132] nmol/day; controls: 155 [95% CI: 43, 550] nmol/day; p = 0.08). Total testosterone was higher in women with breast cancer compared with controls (cases: 1.3 [95% CI: 1.1, 1.5] nmol/L; controls: 1.0 [95% CI: 0.8, 1.11 nmol/L; p = 0.05). No significant differences were found for serum sex hormone binding globulin, free androgen index, dehydroepiandrosterone sulphate, estradiol and progesterone, or in urinary androgen metabolites, or in dietary intake with regard to fat, carbohydrate, protein, or fiber consumption between cases and controls. CONCLUSIONS: This preliminary study is the first report of low urinary daidzein and genistein in postmenopausal women with breast cancer. These findings are in keeping with the increasing observational data demonstrating a protective effect from phytoestrogens on breast cancer risk.

[Influenza]. / Influenza.

Influenza outbreaks remain today among the most serious and intractable health problems owing to high rates of morbidity and high economic costs. Periodical epidemics and pandemics in temperate regions of the world are due to high genetic variability of influenza viruses, which concerns primarily haemagglutinin and neuraminidase antigens (antigenic drift and shift). Most influenza infections are self-limited, but they cause increased mortality in high-risk groups of population (such as the elderly and the subjects with chronic diseases) and increased morbidity in the general population, with loss of productivity and high health costs. During the past thirty years, efforts to control influenza have focused on the use of inactivated vaccines in high-risk groups and of two antiviral drugs, amantadine and rimantadine. However, the wide spread of influenza in all population groups and the limits of adamantane compounds induced to investigate novel approaches for prevention and control of flu. The new live attenuated, cold-adapted, trivalent intranasal vaccine was shown to be highly effective in children against influenza A (H3N2) and B viruses. The new antiviral drugs (zanamivir and oseltamivir), neuraminidase inhibitors, reduced the median time to alleviation of the major symptoms of influenza by 1-2 days. These advances in the last few years will certainly modify our approaches to influenza treatment and prevention.

Polymorphism of the vitamin D receptor gene and corticosteroid-related osteoporosis.

Corticosteroid therapy (CST) is associated with reduced intestinal calcium absorption, bone loss and increased fracture risk. As polymorphisms of the vitamin D receptor (VDR) gene may be associated with bone mineral density (BMD) and intestinal calcium absorption, we asked whether patients with a given VDR genotype receiving CST may be at increased or decreased risk for corticosteroid-related bone loss and osteoporosis. We measured areal BMD (g/cm2) by dual-energy X-ray absorptiometry in 193 women (50 premenopausal, 143 postmenopausal) and 70 men with rheumatoid arthritis (n = 44), obstructive airway diseases (n = 128) and other corticosteroid-treated diseases (n = 91). All patients received a cumulative dose greater than 1.8 g per year or a minimum of 5 mg daily of prednisolone or equivalent for at least 1 year. VDR alleles were typed by polymerase chain reaction assay based on the polymorphic BsmI and TaqI restriction sites. BMD in patients was expressed as a Z-score (mean +/- SEM) derived from age- and gender-matched controls. BMD was reduced in patients at the lumbar spine (bb, -0.52 +/- 0.12; Bb, -0.47 +/- 0.11; BB, -0.65 +/- 0.18 SD; p < 0.01), femoral neck (bb, -0.46 +/- 0.10; Bb, -0.34 +/- 0.10; BB, -0.54 +/- 0.14 SD; p < 0.01), Ward's triangle (bb, -0.44 +/- 0.10; Bb, -0.31 +/- 0.10; BB, -0.45 +/- 0.13 SD; p < 0.01), and trochanter (bb, -0.50 +/- 0.10; Bb, -0.30 +/- 0.10; BB, -0.44 +/- 0.14 SD; p < 0.01). However, there was no significant difference in the deficit in BMD in any of the genotypes, either before or after adjusting for age, sex, body mass index, disease type, age at onset of disease, disease duration, cumulative steroid dosage, smoking status and dietary calcium intake. Similarly, there were no detectable differences between the BsmI genotypes and the rate of bone loss in 79 patients with repeated BMD measurements at an interval of 4-48 months. The data suggest that the VDR genotypes may not be a means of identifying patients at greater risk of corticosteroid-related bone loss.

Number needed to treat: a useful new method of assessing the magnitude of treatment effect and its application to the management of diabetic retinopathy.

The magnitude of treatment effect from randomized controlled trials can be measured in various ways. The number needed to treat is a recently described measure that has been shown to offer several advantages in the clinical interpretation and application of reported treatment effects. It quantifies the number of patents that must be treated in order to prevent one patient from developing the specified outcome. The methods necessary to calculate traditional measures of treatment effect, as well as the number needed to treat, are outlined using the management of diabetic retinopathy as an example. The uses and limitations of the number needed to treat are also discussed.

Three year follow-up of body composition changes in pre-menopausal women with systemic lupus erythematosus.

OBJECTIVES: To measure the change in body composition in a pre-menopausal female systemic lupus erythematosus (SLE) population over 3 yr, and to identify predictors of change in body composition including the effects of disease-, corticosteroid (CS)- and patient-related variables. METHODS: All 55 pre-menopausal females with SLE who participated in a cross-sectional study of body composition in 1994 were invited to undergo interview, examination, medical record review, and body composition assessment by dual-energy X-ray absorptiometry (DXA). RESULTS: Twenty-eight subjects participated with a mean (S.E.M.) age of 34.4 (1.6) yr, duration of SLE of 6.8 (0.8) yr and mean (range) time to follow-up of 3.2 (2.9-3.4) yr. Seventeen subjects were exposed to CS during the study period with a mean (range) daily dose of prednisolone of 12.0 (2.8-22.9) mg. There was a significant increase in body mass index (BMI) (24.53+/-0.83 vs 25.37+/-1.04, P = 0.03) and fat-free mass (41.04+/-0.83 vs 41.53+/-0.92, P = 0.05) over the 3 yr period. Univariate analysis revealed that change in fat-free mass was significantly associated with change in total body bone mineral density (BMD) (P = 0.03). Stepwise multiple linear regression analysis revealed a significant independent association of disease activity with increases in both BMI (r2 = 0.41, P = 0.006) and fat mass (r2 = 0.39, P = 0.007), and of exercise and Modified Health Assessment Questionnaire with an increase in fat-free mass (r2 = 0.51, P = 0.007). Age at SLE diagnosis and smoking were significant independent predictors for loss of total body BMD, while CS duration was predictive of an increase in total body BMD (r2 = 0.80, P < 0.0001). CONCLUSION: In this SLE population, disease activity was predictive of deleterious changes in body composition, including increases in BMI and fat mass. Patient-related variables were also important predictors of body composition change with exercise independently predicting an increase in fat-free mass, and smoking predictive of loss of total body BMD. In contrast, CS-related variables were not found to have harmful effects on body composition. Change in fat-free mass, and not fat mass, was predictive of change in total body BMD.

Three year followup of bone mineral density change in premenopausal women with systemic lupus erythematosus.

OBJECTIVE: To measure the change in bone mineral density (BMD, g/cm2) in a female population with systemic lupus erythematosus (SLE) over 3 years, to identify factors predictive of bone loss, including the role of corticosteroid and disease related variables, and to determine the predictive value of urinary collagen crosslinks for bone loss. METHODS: All premenopausal women with SLE who participated in a cross sectional study of BMD in 1994 were invited to undergo a standardized interview, examination, medical record review, and BMD measurement of the lumbar spine and femoral neck by dual energy x-ray absorptiometry. RESULTS: Thirty-two women participated with a mean (SEM) age of 35.2 (1.5) years, duration of SLE of 7.0 (0.8) years, and mean (range) time to followup of 3.2 (2.9-3.4) years. Twenty-one subjects were exposed to corticosteroids during the study period with a mean (range) daily dose of prednisolone of 11.1 (2.8-22.9) mg. There was no significant change over the 3 years in BMD at the lumbar spine (1.161+/-0.122 vs. 1.169+/-0.022; p = 0.39) or femoral neck (0.944+/-0.023 vs. 0.955+/-0.020; p = 0.47) for the group as a whole, or when subjects were divided according to corticosteroid exposure. However, in the corticosteroid exposed subgroup, patients treated with > or = 7.5 mg/day (n = 14) lost lumbar spine BMD (-0.50%/yr) in contrast to those receiving <7.5 mg/day, who gained 1.06%/yr (p = 0.02). Furthermore, no participant receiving <7.5 mg/day lost lumbar spine BMD, while 57% of patients receiving > or =7.5 mg/day lost lumbar spine BMD (p = 0.01). In the corticosteroid exposed subgroup only, subjects who did not exercise regularly lost femoral neck BMD, while those who did gained femoral neck BMD (-0.54%/yr vs. 1.39%/yr; p = 0.02). Disease related variables (disease severity, activity, duration, functional capacity) and baseline urinary collagen crosslink levels were not predictive of BMD change. CONCLUSION: Loss of lumbar spine and femoral neck BMD in this premenopausal female SLE population was minimal for the group as a whole; however, a daily dose of prednisolone of > or =7.5 mg was associated with loss of lumbar spine BMD. In corticosteroid exposed patients, regular exercise was protective of femoral neck BMD loss. A single baseline measurement of urinary collagen crosslinks was not predictive of bone loss.

Bone mass, areal, and volumetric bone density are equally accurate, sensitive, and specific surrogates of the breaking strength of the vertebral body: an in vitro study.

The validity of the bone mineral density (BMD) measurement depends on its accuracy as a predictor of the breaking strength of bone. As the breaking strength is proportional to the square of the apparent density, a small error in the calculation of BMD may result in a larger error in the predicted bone strength. The aims of this study were (i) to determine whether inaccuracies in the measurement of the dimensions, projected area, and volume of the vertebral body (used to derive the areal and volumetric BMD) result in errors in the predicted breaking strength and (ii) to compare the accuracy, sensitivity, and specificity of bone mineral content (BMC), areal BMD, volumetric BMD, and volumetric bone mineral apparent density (BMAD) as surrogates of bone strength. We measured the BMC (by densitometry), dimensions and volume (using calipers, densitometry, the Carter et al. and Peel and Eastell methods), and breaking strength (using the Instron 1114 apparatus, Newtons, N) of 22 vertebral body specimens. All methods resulted in errors in height, width, and depth between -11.3 +/- 1.0 and 30.4 +/- 1.8% relative to the "gold" standard caliper method. The vertebral body volume (of 38.0 +/- 1.2 cm3) measured by submersion was used as the gold standard to derive the volumetric BMD gold standard (of 0.162 +/- 0.01 g/cm3). All methods, except the Peel and Eastell method, resulted in errors ranging between -10.7 +/- 1.5 and 56.9 +/- 3.4% in vertebral body volume and -35.6 +/- 1.5 to 12.6 +/- 1.8% in volumetric BMD (all p < 0.0005). The same absolute value for volumetric BMD predicted a breaking strength that differed according to the method used to derive BMD. For example, a volumetric BMD of 0.162 g/cm3 predicted a breaking strength of 6208 N (submersion method), 5473 N (caliper method), 6095 N (Peel and Eastell method), 7697 N (DXA method), and 9470 N (Carter et al. method). The mean volumetric BMD derived by each method differed (0.181, 0.165, 0.133, and 0.104 g/cm3, respectively). However, all were accurate; each predicted a similar breaking strength (6177, 6217, 6209, and 6221 N respectively). Likewise, breaking strengths predicted by the mean BMC, areal BMD by calipers, and areal BMD by dual-energy X-ray absorptiometry (DXA) were 6267, 6214, and 6244 N, respectively. The methods were equally sensitive; a 1 standard deviation (SD) decrease in volumetric BMD resulted in a similar decrease in the breaking strength of 1818 (caliper), 2080 (Peel and Eastell), 2001 (DXA), and 1625 N (BMAD by Carter et al). A 1 SD decrease in BMC, areal BMD (using calipers) and areal BMD (using DXA) predicted a decrease in the breaking strength of 2019, 1738, and 1825 N, respectively. All methods were equally specific; the variance in bone strength explained by bone mass did not differ for volumetric BMD (38-61% depending on the method), BMC (58%), or areal BMD (48%). In conclusion, despite errors in the measurement of the dimensions of the vertebral body, bone mass, areal, and volumetric bone density are equally accurate, sensitive, and specific surrogates of the breaking strength of bone in vitro.

Successful long-term outcome with prolonged ischemic time cardiac allografts.

BACKGROUND: The limited availability of cardiac allografts together with the increasing number of patients on the waiting list restricts treatment of this population with heart transplantation. An increase in the available donor pool has been facilitated by the use of allografts with prolonged ischemic time (> 240 minutes). METHODS: Short- and long-term outcomes were compared in 150 heart transplant recipients on the basis of allograft ischemic time (< 241 minutes, 241 to 300 minutes, and > 300 minutes). RESULTS: No difference was found in allograft functional capacity, the development of transplant-associated coronary disease, or actuarial survival in the short and long term. CONCLUSIONS: Improved population treatment with prolonged ischemic time cardiac allografts can be safely undertaken without long-term risk to heart transplant recipients.

Techniques and results in bilateral sequential single lung transplantation. The National Heart & Lung Replacement Service.

Lung transplantation continues to evolve as a therapeutic option for patients with end-stage lung disease. Bilateral sequential single lung transplantation (BSSLTx) is a recent addition to the lung transplant surgeon's armamentarium that incorporates the benefits of single lung transplantation in patients who require double lung replacement while avoiding the morbidity inherent in the en bloc double lung transplant procedure. Between November 1992 and October 1993, 17 recipients underwent 18 bilateral BSSLTx procedures for a variety of indications. In 53% of patients, the procedure was completed without the requirement for cardiopulmonary bypass. Telescoping of the bronchial anastomosis has proved satisfactory. Induction cytolytic therapy has not been utilized. Patients received methyl prednisolone from day 1 and as maintenance prednisolone therapy. Actuarial 1-year survival is 87%; 12 of the 15 survivors are in Functional Class I. BSSLTx is an evolving transplant option for patients who require double lung replacement. Definitive clinical diffusion of the procedure will depend upon intermediate and long-term outcomes for specific recipient pathologies.