Association of cyclophilin A with renal brush border membranes: redistribution by cyclosporine A

BACKGROUND: Administration of the immunosuppressive agent cyclosporine A (CsA) is associated with nephrotoxicity. The main target for CsA, cyclophilin A (CypA), was found in high levels in epithelial cells of renal proximal tubules. In the present study, CypA was immunodetected and characterized following CsA treatment in subcellular fractions of renal cortex. METHOD: The renal content and distribution of CypA was evaluated in untreated rats and in rats treated with a subcutaneous injection of CsA (10 mg. kg-1. day-1) for 10 days. RESULTS: In untreated rats, membrane-bound CypA represents 0.25% of total brush border membrane (BBM) proteins, similar to the proportion found in the soluble fraction. High ionic strength treatment was unable to extract CypA from BBMs, whereas alkaline treatment (Na2CO2, pH 11) and detergent 3 - [(3 - cholamidopropyl) - dimethyl - ammonio] - 1 - propanesulfate (CHAPS) released it from BBMs. These results indicate that CypA is associated with renal BBMs, and that hydrophobic interactions are involved in this association. The CypA distribution was strongly modified in both BBMs and the soluble fraction after CsA treatment, but its affinity for CsA estimated by photoaffinity labeling was unaffected. The CypA expression level decreased by 45% in BBMs, while it increased by 33% in the soluble fraction, compared with control rats. CypA remained associated with the membranes following in vitro incubation of renal BBMs with CsA. However, incubation of CypA with one of its substrates released CypA from renal BBMs. CONCLUSIONS: These experiments suggest that renal BBMs contain a significant amount of CypA and chronic exposure to CsA, and acute exposure to one of CypA substrates may modify its subcellular distribution.     

Comparative hospitalization of hemodialysis and peritoneal dialysis patients in Canada

BACKGROUND: Most comparisons of hemodialysis (HD) and peritoneal dialysis (PD) have used mortality as an outcome. Relatively few studies have directly compared the hospitalization rates, an outcome of perhaps equal importance, of patients using these different dialysis modalities. METHODS: Eight hundred twenty-two consecutive patients at 11 Canadian institutions with irreversible renal failure had an extensive assessment of comorbid illness and initial mode of dialysis collected prospectively immediately prior to starting dialysis therapy. The cohort was assembled between March 1993 and November 1994. The mean follow-up was 24 months. Admission data were used to compare hospitalization rates in HD and PD. RESULTS: Thirty-four percent of patients at baseline and 50% at three months used PD. Twenty-five percent of HD and 32% of PD patients switched dialysis modality at least once after their first treatment (P = NS). Nine percent of HD patients and 30% of PD patients switched modality after three months (P < 0. 001). Total comorbidity was higher in HD patients at baseline (P < 0. 001) and at three months (P = 0.001). The overall hospitalization rate was 40.2 days per 1000 patient days after baseline and 38.0 days per 1000 patient days after three months. When an adjustment was made for baseline comorbid conditions, patients on PD had a lower rate of hospitalization in intention-to-treat analysis according to the type of dialysis in use at baseline (RR 0.85, 95% CI, 0.82 to 0.87, P < 0.001), but a higher rate according to the type of dialysis in use three months after study entry (RR 1.31, 95% CI, 1.27 to 1.34, P < 0.001). In analyses based on the amount of time actually spent on each treatment modality, PD was associated with a higher rate of hospitalization when analyzed according to the type of dialysis in use at baseline (RR 1.10, 95% CI, 1.07 to 1.13, P < 0.001) and according to the type of dialysis in use three months after study entry (RR 1.26, 95% CI, 1.23 to 1.30, P < 0.001). CONCLUSIONS: Conclusions regarding comparative hospitalization rates are heavily dependent on the analytic starting point and on whether intention-to-treat or treatment-received analyses are used. When early treatment switches are accounted for, HD is associated with a lower rate of hospitalization than PD, but the effect is modest.     

Ploidy profile of morphologically normal squamous epithelium adjacent to high grade cervical intraepithelial neoplasia

We have investigated the ploidy profile of morphologically normal mucosa adjacent to high grade CIN (   n = 16  ) and also from normal cervix ( n = 18). DNA ploidy was assessed using flow cytometry and image analysis. All cases were diploid by both modalities. Our results show that morphologically normal squamous mucosa has a stable ploidy profile even when it lies adjacent to high grade CIN. This finding supports the view that high grade CIN is a neoplastic expansion of transformed cells rather than the result of a field change effect.     

Oocyte quality in polycystic ovaries revisited: Identification of a particular subgroup of women

Purpose: Our purpose was to assess the endocrine status of women with polycystic ovaries (PCO) undergoing IVF, and to compare oocyte quality with endocrine markers of the syndrome, in an attempt to define a subpopulation with poor quality oocytes. Methods: This was a retrospective study. Patients were first endocrinologically analyzed: serum levels of androgens (T, androstenedione, DHEAS), FSH, and LH as well as glucose and insulin after an oral glucose tolerance test (OGTT) were recorded and are expressed as absolute values and area under the curve (AUC). Subsequently, they were followed over a 2-year period in which patients underwent several attempts of IVF as well as serving as oocyte donors. Patients were divided into three groups: group I (n=4) was women who displayed embryos unable to implant in 15 IVF cycles and 10 ovum donation cycles in which they served as donors; group II (n=16) was PCO patients in whom IVF (n=38) and/or oocyte donation cycles (n=42) resulted in pregnancies; and group III (n=13) was IVF patients with normal appearance of the ovaries by ultrasound. The endocrine status was compared with the IVF results. Results: There was no difference among groups in the endocrinological parameters tested, except for the OGTT which identified women in group I as having higher serum glucose and insulin levels than patients in groups II and III. Similarly, the OGTT showed higher serum glucose values in group II compared to group III. Women in group I were also obese. Patients in group III were older than PCO patients and needed more gonadotropins to reach an ovarian response which resulted in a reduced number of oocytes retrieved. Fertilization was also impaired in group I, in which no pregnancy was recorded. Conclusions: This study shows that there is a particular subgroup of PCO patients with lower fertilization rates and embryos unable to implant. These patients are obese and nonhyperandrogenic and show derangements of insulin secretion.     

Bayesian analysis of an epidemiologic model of Plasmodium falciparum malaria infection in Ndiop, Senegal

Plasmodium falciparum has a complex transmission cycle. Public health planning and research would benefit from the ability of a calibrated model to predict the epidemiologic characteristics of populations living in areas of malaria endemicity. This paper describes the application of Bayesian calibration to a malaria transmission model using longitudinal data gathered from 176 subjects in Ndiop, Senegal, from July 1, 1993, to July 31, 1994. The model was able to adequately predict P. falciparum parasitemia prevalence in the study population. Further insight into the dynamics of malaria in Ndiop was provided. During the dry season, the estimated fraction of nonimmune subjects goes down to 20% and then increases up to 80%. The model-predicted time-weighted average incidences contributed by nonimmune and immune individuals are 0.52 cases per day and 0.47 cases per day, respectively. The median times needed to acquire infection (conversion delay) for nonimmune and immune individuals are estimated at 39 days and 285 days, respectively.     

Immunomodulator properties of ecstasy (MDMA)

In vitro exposure to ecstasy (3,4-methylenedioxymethamphetamine, MDMA) alters some immune parameters such as T-cell regulatory function, cytotoxic T-lymphocyte activity, natural killer cell activity and macrophage function. Administration of MDMA in rats produces a suppression of lympho-proliferation response and a decrease in circulating lymphocytes, accompanied by an increase in plasma corticosterone. It was postulated a direct action of MDMA on lymphocytes or rather an indirect action mediated by the hypothalamic pituitary adrenal axis (HPA-AXIS) and/or the sympathetic nervous system (SNS). Acute MDMA treatment effected on healthy-volunteers produces an immune dysfunction associated with pharmaceutical characteristics and so with MDMA plasma concentrations. There is a decrease in CD4+ T-cells and functional responsiveness of lymphocytes, while percentage of natural killer cells increases. A contemporary rise of cortisol plasma concentrations supports the hypothesis of MDMA-induced release of corticotrophin-releasing factor from the hypothalamus and subsequent HPA-axis and SNS activation.