Fragile sites and high-resolution chromosome studies in multiple endocrine neoplasia type 2A

Affected individuals from four kindreds with multiple endocrine neoplasia type 2A syndrome (MEN-2A), were studied for the possible existence of a specific fragile site that might be associated with the MEN-2A gene. The chromosomes were also examined with high-resolution banding with particular emphasis on those chromosomes (#1, 10, 20, and 22) that have been implicated by previous studies from several laboratories as being associated with this disease. There was no evidence for a unique fragile site or a unique high-resolution banding pattern in subjects with MEN-2A. These findings, in combination with all previous cytogenetic studies, indicate that it is unlikely that current techniques will be useful in developing a simple cytogenetic test for this disease.     

Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms

Metformin treatment is associated with a decreased risk and better prognosis of pancreatic cancer (PC) in patients with type 2 diabetes, but the mechanism of metformin’s PC growth inhibition in the context of a prediabetic state is unknown. We used a Panc02 pancreatic tumor cell transplant model in diet-induced obese (DIO) C57BL/6 mice to compare the effects of metformin and the direct mammalian target of rapamycin (mTOR) inhibitor rapamycin on PC growth, glucose regulation, mTOR pathway signaling, and candidate microRNA (miR) expression. In DIO/prediabetic mice, metformin and rapamycin significantly reduced pancreatic tumor growth and mTOR-related signaling. The rapamycin effects centered on decreased mTOR-regulated growth and survival signaling, including increased expression of let-7b and cell cycle–regulating miRs. Metformin (but not rapamycin) reduced glucose and insulin levels and expression of miR-34a and its direct targets Notch, Slug, and Snail. Metformin also reduced the number and size of Panc02 tumor spheres in vitro and inhibited the expression of Notch in spheroids. Our results suggest that metformin and rapamycin can both inhibit pancreatic tumor growth in obese, prediabetic mice through shared and distinct mechanisms. Metformin and direct mTOR inhibitors, alone or possibly in combination, represent promising intervention strategies for breaking the diabetes-PC link.     

FK 506 primary immunosuppression following emergency liver transplantation for fulminant hepatic failure

Abstract The efficacy and safety of an FK 506-compared to a cyclosporin A based immunosuppression regimen was examined in liver recipients who underwent transplantation for fulminant hepatic failure in the European FK 506 liver study. A consistent trend towards improved patient and graft survival noted in the FK 506-treated patients was apparent from the first postoperative week (e. g. patient survival: day 7, 95.5% vs. 82.1% and month 6, 72.7% vs. 60.7%). Acute (in particular intractable) rejection was less frequent in the FK 506 group (e. g. cumulative intractable rejection rate at 6 months, 6.2% vs. 22.6%). In a single centre (Kings College Hospital), 17 patients were studied in more detail. The FK 506 treatment group had improved graft function, lower steroid requirments and episodes of infection. Accompanying these benefits, apache 111 and TISS scores were lower in this group in the early posttransplant period. Intensive care discharge was earlier and both treatment groups experienced similar toxicity.     

Priority-setting in New Zealand: translating principles into practice

In May 1998 the New Zealand Health Funding Authority released a discussion paper which proposed a principles-based approach to setting purchasing priorities that incorporates the economic methods of programme budgeting and marginal analysis, and cost-utility analysis. The principles upon which the process was to be based are effectiveness, cost, equity of health outcomes, Maori health and acceptability. This essay describes and critiques issues associated with translating the principles into practice, most particularly the proposed methods for evaluating the effectiveness and measuring the cost of services. It is argued that the proposals make an important contribution towards the development of a method for prioritizing services which challenges our thinking about those services and their goals, and which is systematic, explicit, and transparent. The shift towards 'thinking at the margin' and systematically reviewing the value for money of competing claims on resources is likely to improve the quality of decision-making compared with the status quo. This does not imply that prioritization can, or should, be undertaken by means of any simple formula. Any prioritization process should always be guided by informed judgement. The approach is more appropriate for some services than for others. Key methodological issues that need further consideration include the choice of instrument for measuring health gains, the identification of marginal services, how to combine qualitative and quantitative information, and how to ensure consistency across different levels of decision-making.     

Establishing guidelines for pharmacotherapy trials in bulimia nervosa and anorexia nervosa

OBJECTIVE: This paper addresses the lack of a standard protocol for pharmacotherapy trials for patients with bulimia nervosa (BN) and anorexia nervosa (AN). METHOD: Twenty-two surveys were sent to established researchers in the field of eating disorders to elicit their opinions regarding medication trials, including baseline laboratory tests, the optimal length/frequency of medication management sessions, and the information that should or should not be included in these sessions. RESULTS: Sixteen of 22 researchers completed and returned the survey. Their answers are the basis of the data presented. DISCUSSION: We propose a battery of screening laboratory tests for both conditions. We suggest 30-45-min initial medication management sessions in both AN and BN trials with 15-min follow-ups to be held weekly for AN subjects, and weekly for 2 weeks, then biweekly for 2 weeks, then monthly, for BN subjects. We also recommend that published trials should include explicit details of medication management.     

Tachyphylaxis associated with continuous cisatracurium versus pancuronium therapy

STUDY OBJECTIVES: To compare dosing requirements over time among patients receiving continuous cisatracurium versus pancuronium therapy, and to identify factors that may account for changes in pancuronium versus cisatracurium infusion requirements over time. DESIGN: Retrospective, comparative cohort analysis. SETTING: A tertiary level 1 trauma center. PATIENTS: Forty-five consecutive adult patients who were admitted to intensive care units at our institution from January 1998-August 2000 and received continuous cisatracurium or pancuronium therapy for at least 48 hours. MEASUREMENTS AND MAIN RESULTS: Dosing requirements of patients treated with pancuronium or cisatracurium were recorded over time throughout the treatment period. Factors that could affect dosing requirements of a neuromuscular blocking agent (NMBA) were stratified as time invariant (admitting service, acute physiology and chronic health evaluation II score, duration of mechanical ventilation, pressure control ventilation, baseline hepatic or renal insufficiency, thermal injury, train-of-four assessment, and concurrent drug administration or disorders affecting neuromuscular transmission) or time variant (concurrent sedation and narcotic analgesia therapy; serum magnesium, potassium, and creatinine concentrations; arterial pH level; temperature; peak airway pressure; and partial pressure of oxygen:fraction of inspired oxygen ratio). Hierarchical linear modeling was used to compare the dosing requirements and to identify confounders affecting the relationship. The infusion rate escalation for the cisatracurium group was greater (0.39 microg/kg/min; 95% confidence interval [CI] 0.22-0.56; 23 patients) than for the pancuronium group (-0.06 microg/kg/min; 95% CI -0.24-0.12; 22 patients; p<0.001) and was associated with an average daily cost/patient significantly higher (p<0.001) with cisatracurium ($258+/-$114) than pancuronium ($11+/-$5). Confounder analysis revealed that only the admitting service and the number of times the NMBA infusion was suspended because no twitch was detected differed between groups. Neither of these confounders significantly affected the temporal relationship between cisatracurium and pancuronium infusion rates. CONCLUSION: Dosing requirements increase over time at a significantly greater rate for cisatracurium than pancuronium infusions. Tachyphylaxis with cisatracurium is associated with substantial drug-related costs and is not accounted for by various disease-, patient-, and therapy-related factors. Further investigation is required to elucidate the mechanisms and risk factors underlying this phenomenon.     

Characteristics of prophylactic antibiotic strategies after penetrating abdominal trauma at a level I urban trauma center: a comparison with the East guidelines

BACKGROUND: Antibiotic prophylaxis, along with surgical intervention, is a key component in reducing infection in patients after penetrating abdominal trauma (PAT). Recent guidelines from the Eastern Association for the Surgery of Trauma (EAST) recommend that prophylaxis for < or = 24 hours is adequate for most patients. We compared antibiotic prophylaxis practices after PAT at our institution with EAST guidelines, quantified the incidence of infection, and identified risk factors for infection. METHODS: This study was a retrospective review of patients with PAT requiring a therapeutic laparotomy between July 1998 and January 2001. RESULTS: Antibiotic prophylaxis met EAST guidelines criteria in 21 of 97 patients (22%). There was a trend toward higher infection rates (18 of 76 vs. 3 of 21; = 0.273) when prophylaxis exceeded EAST recommendations. Multivariate analysis revealed blood transfusions to be the only predictor of infection (odds ratio, 6.9; 95% confidence interval, 2.42-19.95). CONCLUSION: Despite prophylactic antibiotic use often exceeding EAST criteria, many patients still developed infection. Blood transfusion was the only significant risk factor for infection.