Early elimination of cyclosporine in kidney transplant recipients receiving sirolimus prevents progression of chronic pathologic allograft lesions

Cyclosporine elimination in a regimen including sirolimus has been shown to be a safe and effective approach to improve graft function. Nevertheless, it is still unknown whether the functional benefit of CyA withdrawal coincides with a subsequent reduction in histologic lesions of chronic damage or development of chronic allograft nephropathy. This consideration would forecast a reduction in the rate of long-term graft loss. We analyzed 114 graft biopsies from a subgroup of 57 patients that had been included in a randomized study to eliminate CyA at 3 months posttransplant from a regimen including sirolimus either in group A CyA + SRL vs group B of SRL with CyA elimination at 3 months. Every patient had two biopsies, one at transplantation and another at 1 year. The biopsy reading was performed in a blinded manner by a central pathologist using the Banff 1997 and the CADI classifications. A significantly lower rate of progression of tubular and interstitial chronic lesions between basal and 1-year biopsies was observed for group B patients. In addition, the incidence of new cases of chronic allograft nephropathy during the first year was significantly lower in the group in which CyA had been eliminated at 3 months posttransplant. We conclude that early elimination of CyA in the first months posttransplant, when SRL is used as the main immunosuppressant, reduces the appearance or worsening of chronic histologic lesions, probably as a consequence of long-term CyA toxicity prevention

Early cyclosporine a withdrawal in kidney-transplant recipients receiving sirolimus prevents progression of chronic pathologic allograft lesions

BACKGROUND: Nephrotoxicity of calcineurin inhibitors (CNIs) is partially responsible for the development of chronic allograft nephropathy (CAN). Sirolimus has demonstrated its potential to substitute for CNIs because it lacks significant nephrotoxicity and shows a short-term immunosuppressive capacity comparable with that of cyclosporine. This results in the maintenance of better renal function when cyclosporine is eliminated, but it has not been demonstrated whether this benefit is associated with an improvement in the pathologic substrate and a reduction in CAN. METHODS: We analyzed pretransplant and 1-year renal-allograft biopsies from 64 patients enrolled in a multicenter trial. Patients received cyclosporine and sirolimus during the first 3 months after transplant and were then randomly assigned to continue with cyclosporine or have it withdrawn. Histologic chronic allograft lesions were compared between groups. RESULTS: The percentage of patients in whom chronic pathologic lesions progressed was lower in the group of cyclosporine elimination. Significant differences were observed in chronic interstitial and tubular lesions (70% vs. 40.9% [P<0.05] and 70% vs. 47.8% [P<0.05], respectively), whereas no differences were observed in acute lesions (subclinical rejection). Prevalence of CAN at 1 year was lower in this group, as was the severity and incidence of new cases (P<0.05). CONCLUSIONS: Early cyclosporine withdrawal associated with sirolimus administration is followed by an improvement in renal function, a reduction in the progression of chronic pathologic allograft lesions, and a lower incidence of new cases and severity of CAN during the first year after transplantation. This benefit may result in better long-term graft outcome

Low income, community poverty and risk of end stage renal disease

BACKGROUND: The risk of end stage renal disease (ESRD) is increased among individuals with low income and in low income communities. However, few studies have examined the relation of both individual and community socioeconomic status (SES) with incident ESRD. METHODS: Among 23,314 U.S. adults in the population-based Reasons for Geographic and Racial Differences in Stroke study, we assessed participant differences across geospatially-linked categories of county poverty [outlier poverty, extremely high poverty, very high poverty, high poverty, neither (reference), high affluence and outlier affluence]. Multivariable Cox proportional hazards models were used to examine associations of annual household income and geospatially-linked county poverty measures with incident ESRD, while accounting for death as a competing event using the Fine and Gray method. RESULTS: There were 158 ESRD cases during follow-up. Incident ESRD rates were 178.8 per 100,000 person-years (105 py) in high poverty outlier counties and were 76.3 /105 py in affluent outlier counties, p trend = 0.06. In unadjusted competing risk models, persons residing in high poverty outlier counties had higher incidence of ESRD (which was not statistically significant) when compared to those persons residing in counties with neither high poverty nor affluence [hazard ratio (HR) 1.54, 95% Confidence Interval (CI) 0.75-3.20]. This association was markedly attenuated following adjustment for socio-demographic factors (age, sex, race, education, and income); HR 0.96, 95% CI 0.46-2.00. However, in the same adjusted model, income was independently associated with risk of ESRD [HR 3.75, 95% CI 1.62-8.64, comparing the &lt; 20,000 income group to the > 75,000 group]. There were no statistically significant associations of county measures of poverty with incident ESRD, and no evidence of effect modification. CONCLUSIONS: In contrast to annual family income, geospatially-linked measures of county poverty have little relation with risk of ESRD. Efforts to mitigate socioeconomic disparities in kidney disease may be best appropriated at the individual level

A cytoplasmic Slo3 isoform is expressed in somatic tissues

Slo3 is a pH-sensitive and weakly voltage-sensitive potassium channel that is essential for male fertility in mouse and whose expression is regarded as sperm-specific. These properties have proposed Slo3 as a candidate target for male contraceptive drugs. Nonetheless, the tissue distribution of Slo3 expression has not been rigorously studied yet. Applying computational and RT-PCR approaches, we identified expression of two short Slo3 isoforms in somatic mouse tissues such as brain, kidney and eye. These isoforms, which seem to result of transcription starting sites between exons 20 and 21, have an identical open reading frame, both encoding the terminal 381 amino acids of the cytosolic Slo3 domain. We corroborated the expression of these isoforms in mouse brain and testis by Western-blot. The complete isoform encoding the Slo3 ion channel was uniquely detected in testis, both at transcript and protein level. Although the functional role of the cytosolic Slo3 isoforms remains to be established, we propose that they may have a functional effect by modulating Slo channels trafficking and/or activity. This study confirms that expression of full-length Slo3 is sperm-specific but warns against developing contraceptive drugs targeting the C-terminal tail of Slo3 channels

Diagnóstico molecular de los síndromes de prader-willy y angelman a través de la técnica me-pcr

Desarrollar una técnica basados en métodos moleculares, Metilación Específica PCR para comprobar el diagnóstico clínico de pacientes afectados por los síndromes de Prader-Willi y Angelman

Litio como terapia neuroprotectora en el modelo appsl/ps1m146l de la enfermedad de Alzheimer

El litio se utiliza desde hace varias décadas en el tratamiento de trastornos bipolares y la depresión, y recientemente se debate su uso potencial en patologías neurodegenerativas como la enfermedad de Alzheimer (AD)

Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

Background: Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals. Methods: We defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established. Results: We found significantly increased radiosensitivity in the cohort of healthy BRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher’s exact test) for healthy BRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % of BRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene. Conclusions: We show that BRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD

The influence of age on the female/male ratio of treated incidence rates in depression

BACKGROUND: Poor data exist on the influence of psychosocial variables on the female/male ratio of depression because of the small number of cases and the resulting limited numbers of variables available for investigation. For this investigation a large number of first admitted depressed patients (N = 2599) was available which offered the unique opportunity to calculate age specific sex ratios for different marital and employment status categories. METHODS: Age and sex specific population based depression rates were calculated for first ever admissions for single year intervals. Moving averages with interpolated corrections for marginal values in the age distribution were employed. RESULTS: For the total group the female/male ratio of depression showed an inverted U-shape over the life-cycle. This pattern was influenced by the group of married persons, which showed a sex-ratio of 3:1 between the age of 30–50, but ratios of around 1:1 at younger and older ages. For not married persons the female/male ratio was already around 2:1 at the age of 18 and rose to 2.5:1 in mid-life and declined to 1 at around 55. The almost parallel decline of depression rates in employed men and women resulted in a female/male ratio of about 2:1 from age 18 to age 50 and became 1 after the age of 60. The female/male ratio among the not employed was about 1, in mid-life it became negative. CONCLUSIONS: Our analyses show that the gender-gap in first admitted depressed patients is age dependent and that psychosocial factors modify the sex ratio