Treatment of diabetic nephropathy in its early stages

Diabetic nephropathy is one of the most frequent causes of end-stage renal disease (ESRD), and, in recent years, the number of diabetic patients entering renal replacement therapy has dramatically increased. The magnitude of the problem has led to numerous efforts to identify preventive and therapeutic strategies. In normoalbuminuric patients, optimal glycemic control (HbA(1c) lower than 7.5%) plays a fundamental role in the primary prevention of ESRD [weighted mean relative risk reduction (RRR) approximately 37% for metabolic control versus trivial renoprotection for intensive anti-hypertensive therapy or ACE-inhibitors (ACE-I)]. In the microalbuminuric stage, strict glycemic control probably reduces the incidence of overt nephropathy (weighted mean RRR approximately 50%), while blood pressure levels below 130/80 mmHg are recommended according to the average blood pressure levels obtained in various studies. In normotensive patients, ACE-I markedly reduce the development of overt nephropathy almost regardless of blood pressure levels; in hypertensive patients, ACE-I are less clearly active (weighted mean RRR approximately 23% versus other drugs), whereas angiotensin-receptor blockers (ARB) appear strikingly renoprotective. Once overt proteinuria appears, it is uncertain whether glycemic control affects the progression of nephropathy. In type 1 diabetes, various anti-hypertensive treatments, mainly ACE-I, are effective in slowing down the progression of nephropathy; in type 2 diabetes, two recent studies demonstrate that ARB are superior to conventional therapy or calcium channel blockers (CCB). In clinical practice, pharmacological tools are not always used to the best benefit of the patients. Therefore, clinicians and patients need to be educated regarding the renoprotection of drugs inhibiting the renin-angiotensin system (RAS) and the overwhelming importance of achieving target blood pressure.     

Mercury exposure in Munduruku Indians from the community of Sai Cinza,State of Pará, Brazil

The objective of this cross-sectional study was to evaluate mercury exposure and health status among Munduruku Indians from the community of Sai Cinza, State of Pará, Brazil. The population studied included 330 indians, who submitted to a questionnaire, clinical exams, and collection of hair, blood, urine, and feces. Mercury was measured in hair and fish. Although no person was found to have overt mercury intoxication, the mean levels of mercury in hair were elevated (14.45 micrograms/g for children from 7 to 12 years old, 15.70 micrograms/g for women between 14 and 44 years old, and 14.1 micrograms/g for the remaining population). Mercury levels in fish were below levels recommended by the World Health Organization, but rates of fish consumption were high. These results place this indigenous populations as a group under risk of mercury toxicity from the gold production.     

Technical skills for weight loss: preliminary data from a randomized trial

BACKGROUND: Optimal behavioral interventions for sustainable weight loss are uncertain. We therefore conducted a study among overweight/obese women comparing conventional dietary counseling of individuals (counseling-based intervention) to a novel, group-based skill-building intervention. METHODS: Eighty subjects were randomly assigned to either the counseling-based or to the skill-building intervention. Outcomes included weight loss, dietitian hours per group and per unit weight loss, and dollars spent per group and per unit weight lost. RESULTS: Weight loss at 6 months (follow-up rate 61.3%) in the counseling-based group was 8.8 lb (P = 0.0001), and in the skill-building group was 3.8 lb (P = 0.01). A total of 160 dietitian hours were required for the counseling-based group, and 131 for the skilled-building group. The counseling-based group cost an average of $21 per pound lost, while the skill-building cost an average of $48 per pound lost (P = 0.16). CONCLUSIONS: At 6 months, individualized office-based counseling produced more weight loss than a skill-building approach and cost less than half as much per pound of weight loss. Longer-term follow-up is required to determine if, as hypothesized, the skill-building intervention produces more sustainable weight loss.     

Body mass and stage of breast cancer at diagnosis

Obesity is a well-known risk factor for postmenopausal breast cancer. In contrast, the relationship between obesity and stage of breast cancer at diagnosis is less clear. We hypothesized that increased breast size in obese women may delay discovery of breast tumors. Thus, the purpose of our study was to examine whether there is an association between body mass and stage of breast cancer at diagnosis using hospital medical records. Newly diagnosed breast cancer cases (n = 966) in the Baltimore metropolitan area from 1991 to 1997 were included in our study. Patient information including age, ethnicity, weight, height and pathology data were obtained from hospital medical records. High body mass was significantly associated with late stage of breast cancer at diagnosis. Women who were obese (body mass index [BMI] > or = 27.3) were more likely to be at an advanced stage at diagnosis compared with women with a BMI of < 27.3 (multivariate-adjusted odds ratio [OR] 1.57, 95% confidence interval [CI] 1.15-2.14). The association between body mass and stage at diagnosis was stronger among women younger than 50 years (OR 2.34, 95% CI 1.34-4.08) compared with women 50 years or older (OR 1.30, 95% CI 0.89-1.91). Our study suggests that higher body mass is associated with advanced stage of breast cancer at diagnosis. This finding may be of considerable concern, given the increasing prevalence of obesity in women in the United States and the poor prognosis associated with late-stage tumors.     

Localization of the human oxytocin receptor in caveolin-1 enriched domains turns the receptor-mediated inhibition of cell growth into a proliferative response

In this study, we investigated the functional role of the localization of human OTR in caveolin-1 enriched membrane domains. Biochemical fractionation of MDCK cells stably expressing the WT OTR-GFP indicated that only minor quantities of receptor are partitioned in caveolin-1 enriched domains. However, when fused to caveolin-2, the OTR protein proved to be exclusively localized in caveolin-1 enriched fractions, where it bound the agonist with increased affinity and efficiently coupled to Galpha(q/11). Interestingly, the chimeric protein was unable to undergo agonist-induced internalization and remained confined to the plasma membrane even after prolonged agonist exposure (120 min). A striking difference in receptor stimulation was observed when the OT-induced effect on cell proliferation was analysed: stimulation of the human WT OTR inhibited cell growth, whereas the chimeric protein had a proliferative effect. These data indicate that the localization of human OTR in caveolin-1 enriched microdomains radically alters its regulatory effects on cell growth; the fraction of OTR residing in caveolar structures may therefore play a crucial role in regulating cell proliferation.     

Encephalopathy and stroke after coronary artery bypass grafting: incidence,consequences, and prediction

BACKGROUND: In contrast to perioperative stroke, much less attention has been paid to those with evidence of diffuse brain encephalopathy, presenting as delirium, confusion, coma, and seizures in the immediate postoperative period. OBJECTIVE: To determine the incidence, consequences, and predictive factors for encephalopathy and stroke following coronary artery bypass grafting. METHODS: In a prospective evaluation of 2711 patients operated on between January 1, 1997, and December 31, 2000, preoperative risk factors were obtained before surgery and postoperative outcomes, encephalopathy and stroke, were determined on a daily basis. All strokes were confirmed by neurologic consultation and, in most instances, by imaging. Logistic regression analyses were performed to determine risk factors for these outcomes. RESULTS: The incidence of encephalopathy was 6.9% and of stroke, 2.7%. For patients without either of these outcomes, the average length of stay in the hospital was 6.6 days and the mortality was 1.4%. In contrast, patients with encephalopathy had a length of stay of 15.2 days and a mortality of 7.5%, and those with stroke, a length of stay of 17.5 days and a mortality of 22.0%. Predictive models were developed for encephalopathy involving 5 preoperative factors (age, past stroke, carotid bruit, hypertension, and diabetes) and 1 perioperative factor (time on cardiopulmonary bypass). The model for stroke involved only 3 preoperative risk factors (past stroke, hypertension, and diabetes). CONCLUSIONS: Encephalopathy or stroke is associated with significant increases in length of stay and mortality after coronary artery bypass grafting. Patients at higher risk for these outcomes can be identified before surgery.     

Renal and cardiovascular protection in type 2 diabetes mellitus: angiotensin II receptor blockers

Aggressive treatment of hypertension is effective in reducing both microvascular and macrovascular complications in type 2 diabetes, and target BP less than 130/85 or 130/80 mmHg are now recommended. Inhibition of renin angiotensin aldosterone system (RAAS) plays an essential role in the treatment of hypertension and diabetes-related complications. Studies focusing on renal end-points suggest that angiotensin-converting enzyme inhibitors (ACE-I) are more effective than other traditional agents in reducing the onset of clinical proteinuria in both type 1 and type 2 diabetic patients with incipient nephropathy, mainly in normotensive ones (secondary prevention). However, several small trials in type 2 diabetic patients with overt nephropathy (tertiary prevention) failed to demonstrate a specific renoprotective role for ACE-I, at variance with type 1 diabetes. Three recent large trials address the question of whether angiotensin II receptor blockers (ARB) prevent the development of clinical proteinuria or delay the progression of nephropathy in type 2 diabetes. The IRMA study showed that irbesartan is more effective than conventional therapy in preventing the development of clinical proteinuria and in favoring the regression to normoalbuminuria for comparable BP control in patients with incipient nephropathy. The IDNT and RENAAL trials showed that ARB are more effective than traditional antihypertensive therapies in reducing progression toward end-stage renal failure (ESRF) in type 2 diabetic patients with overt nephropathy independently of changes in BP. Moreover, a reduction in hospitalizations for heart failure was demonstrated for ARB-treated patients compared with placebo. Furthermore, the LIFE study showed that losartan is more effective than conventional therapy in reducing cardiovascular morbidity and mortality in a cohort of diabetic patients with hypertension and left ventricular hypertrophy. In conclusion, ARB seem to be effective in both preventing renal damage and reducing progression toward ESRF in type 2 diabetic patients. Thus, the guidelines for the prevention and treatment of diabetic nephropathy are now changed. In type 1 diabetes ACE-I are the first-choice drug; in type 2 diabetes, ARB are considered first-choice drugs in secondary prevention as well as ACE-I and have been now elected the unique first-choice drug in tertiary prevention of ESRF. Finally, ARB should be considered as the first-choice drug in cardiovascular prevention too, as well as ACE-I.     

Increase of faecal bifidobacteria due to dietary oligosaccharides induces a reduction of clinically relevant pathogen germs in the faeces of formula-fed preterm infants

In a previous study on formula-fed preterm infants, we were able to demonstrate that dietary oligosaccharides (a mixture of 90% galacto-oligosaccharides and 10% fructo-oligosaccharides in a concentration of 1 g/dl) stimulate the growth of faecal bifidobacteria. In the present explorative analysis of this study, we focus on the effect of the dominance of bifidobacteria on the presence of clinically relevant pathogens ( Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Pseudomonas aeruginosa, Enterobacter, Klebsiella, Proteus, Streptococcus group B, Clostridium difficile, Bacillus subtilis and Acinetobacter ).
Conclusion : The data demonstrate that stimulation of bifidobacteria by prebiotic oligosaccharides reduces the presence of clinically relevant pathogens in the faecal flora, indicating that prebiotic substances might have the capacity to protect against enteral infections.     

A phase I and pharmacokinetic study of ecteinascidin-743 on a daily x 5 schedule in patients with solid malignancies.

PURPOSE: The purpose of this study was to (a) assess the feasibility of administering ecteinascidin-743 (ET-743), a novel DNA minor-groove disrupting agent of marine origin, administered as a daily i.v. infusion for 5 days every 3 weeks; (b) recommend a dose for Phase II studies; (c) characterize its pharmacokinetic behavior; and (d) seek preliminary evidence of anticancer activity. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with escalating doses of ET-743 as a daily 1-h i.v. infusion for 5 days every 3 weeks. Plasma and urine were sampled on both days 1 and 5 of the first course. Pharmacokinetic parameters were related to the principal toxicities. RESULTS: Forty-two patients were treated with 118 courses of ET-743 at doses ranging from 6 to 380 microg/m(2)/day. Elevations in hepatic transaminases were common at ET-743 dose levels > or =216 microg/m(2)/day, resolved rapidly, and were never dose limiting nor cumulative. Instead, hematological toxicity was the principal toxicity that precluded dose escalation. The maximum tolerated dose of ET-743 that could be administered repetitively was 325 microg/m(2)/day. Antitumor activity was noted in three patients with leiomyosarcoma and primary peritoneal and ovarian carcinomas. The pharmacokinetics of ET-743 were dose independent, and drug accumulation over the 5 days of treatment was modest, with the ratio of the area under the plasma-versus-time curve on day 5 to that on day 1 averaging 2.05. The volume of distribution at steady state was large (mean, 1037 liters/m(2)), and the mean terminal half life on day 5 was 26.81 h. CONCLUSIONS: The maximum tolerated dose of ET-743 that can be administered repetitively is 325 microg/m(2)/day daily x 5 every 3 weeks, which is recommended for disease-directed clinical trials. The acceptable toxicity profile of ET-743 on the divided-dose schedule evaluated in this trial, as well as the generally superior antitumor activity associated with divided-dose schedules in preclinical studies, provides a rationale for further evaluation of ET-743 on this administration schedule.