Adenovirus-mediated XIAP gene transfer reverses the negative effects of immunosuppressive drugs on insulin secretion and cell viability of isolated human islets

Immunosuppressive drugs are routinely used to provide tolerance after whole pancreas and islet cell transplantations. While they are essential in inhibiting graft rejection, little is known about their effect on islet function and beta-cell viability. In this study, we report that tacrolimus, sirolimus, and mycophenolic acid, when added to cultures of freshly isolated human islets, induce a downregulation of the synthesis and secretion of insulin. These functional changes are associated with decreased islet cell viability. All three agents induce a decrease of intracellular levels of Bcl-2 and Bcl-xL, with an increased level of Smac, indicating that they are capable of promoting a downregulation of anti-apoptotic factors and an accumulation of pro-apoptotic mediators. Transduction of islet cells with the anti-apoptotic gene XIAP prevents the negative effects of these drugs on the function and viability of islets. XIAP-infected cells show a higher expression of phospho-CREB (cAMP-responsive element binding protein) and a reduced level of Smac, resulting in a significant reduction of apoptotic cells and a preservation of the glucose-dependent secretion of insulin. In conclusion, the present study demonstrates that genetically modified human islets expressing XIAP are resistant to the negative effects of immunosuppressive drugs on insulin secretion and cell viability.     

Changes in the geographical distribution of tuberculosis patients in Veracruz, Mexico, after reinforcement of a tuberculosis control programme

OBJECTIVE: Geographical information systems are valuable tools for studying tuberculosis (TB) epidemiology, but have been underused for the evaluation of TB control programs. We aimed to compare the geographical distribution of TB before and after the five elements of directly observed therapy, short course (DOTS) were strengthened in a Health Jurisdiction in Mexico in response to recommendations made by the WHO Global Tuberculosis Program. METHODS: All consenting persons detected by passive case finding between March 1995 and February 2000 who were confirmed to have acid-fast bacilli (AFB) in sputum underwent clinical and laboratory evaluation. A TB 'episode' was defined as the period of time between bacteriological diagnosis and treatment discharge by the local control programme. Distances of TB episodes from the nearest urban centre were determined according to recent transmission and multidrug resistance (MDR). RESULTS: During the first half of the study period, MDR episodes were located a median distance of 1.24 km from urban centres, which did not differ significantly from non-MDR episodes (1.14 km, P=0.56). In contrast, the median distance of MDR episodes increased 55% to 1.92 km during the second half, which placed them significantly further away out than non-MDR episodes (1.08 km, P=0.01). No changes in location were detected for recent transmission. CONCLUSION: While reinforcing the TB control programme reduced the incidence of MDR, the remaining episodes were located in poorer and more remote areas.     

Obstruction in patients with colorectal cancer increases morbidity and mortality in association with altered nutritional status

Intestinal obstruction aggravates the prognosis of colorectal cancer (CRC) patients. The aim of this study was to carry out a comparative analysis of nutritional status and inflammatory response in CRC patients with or without intestinal obstruction. The study was carried out on 43 patients with CRC. Twenty-three of these patients had intestinal obstruction. Anthropometric measurements, serum protein content, acute phase reactants, and diagnostic and risk nutritional indices were analyzed. The presence of intestinal obstruction reduced albumin (31 +/- 5.2 vs. 36 +/- 4.2 g/l; P = 0.0025) and prealbumin (0.13 +/- 0.047 vs. 0.21 +/- 0.042 g/l; P = 0.0001) and increased C-reactive protein (49 +/- 43.8 vs. 14 +/- 16.7 mg/l; P = 0.006) and alpha1-antitrypsin (189 +/- 34.7 vs. 148 +/- 35.4 mg/dl; P = 0.0011). Intestinal obstruction was related to malnutrition (86% vs. 33%; P = 0.019) and Mullen's prognostic nutritional index (48 +/- 21.7 vs. 31 +/- 17.9; P = 0.038) in CRC patients. Mullen's nutritional risk index was inversely correlated to total cholesterol (r = -0.51; P = 0.0002) and albumin (r = -0.81; P = 0.0001). No correlation was found between Duke's tumor stages and acute phase response, inflammatory parameters, and malnutrition. In conclusion, intestinal obstruction occurred more frequently in CRC patients with malnutrition. The increased morbidity and mortality of CRC patients was also associated with acute phase response, inflammation, and low serum cholesterol and triglyceride concentration.     

Physicians' attitudes towards end-of-life decisions: a comparison between seven countries

In the context of an European collaborative research project (EURELD), a study on attitudes towards medical end-of-life decisions was conducted among physicians in Belgium, Denmark, Italy, the Netherlands, Sweden and Switzerland. Australia also joined the consortium. A written questionnaire with structured questions was sent to practising physicians from specialties frequently involved in the care of dying patients. 10,139 questionnaires were studied. Response rate was equal to or larger than 50% in all countries except Italy (39%). Apart from general agreement with respect to the alleviation of pain and symptoms with possible life-shortening effect, there was large variation in support--between and within countries--for medical decision that may result in the hastening of death. A principal component factor analysis found that 58% of the variance of the responses is explained by four factors. 'Country' explained the largest part of the variation of the standardized factor scores.     

Amino acid levels in some lethargic mouse brain areas before and after pentylenetetrazole kindling

Genetic animal models have contributed significantly to our understanding of epilepsy causes. Lethargic mice are considered a valid model of absence epilepsy, which have been shown to possess behavioral, electrographic and pharmacological profiles similar to those of humans with absence epilepsies. Single gene mutations that comprise the beta4 subunit of voltage-sensitive Ca2+ channels underlie the spontaneous discharges of the absence, non-convulsive seizures of lethargic mice. There are no available data concerning how the mutant channels actually behave at terminals in response to chemical activation by subconvulsant stimulation with pentylenetetrazole. In this study, we found no significant difference in the convulsive dose 50 between lethargic and control mice. Lethargic mice showed a more rapid development of kindling to pentylenetetrazole than control animals. No significant differences were observed between the groups of mice rechallenged with pentylenetetrazole 30 or 60 days after the end of the chronic treatment. Marked differences in brain amino acid levels were found between the two strains of mice in basal conditions and after kindling. In conclusion, our results indicate that lethargic mice show a range of biochemical and behavioral changes, correlated in particular with a higher susceptibility to develop kindled seizures.