Short-term outcomes of five heroin detoxification methods in the Australian NEPOD Project

This study included 380 participants in five heroin detoxification trials whose data were pooled to enable direct comparison of five detoxification methods in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD). Rapid detoxification achieved similar initial abstinence rates with either anaesthesia or sedation (average 59%), which were higher than was achieved by inpatient detoxification using clonidine plus other symptomatic medications (24%), which in turn was higher than outpatient detoxification using either buprenorphine (12%) or clonidine plus other symptomatic medications (4%). Older participants and those using more illicit drugs were more likely to achieve abstinence. Entry rates into ongoing postdetoxification treatment were as follows: buprenorphine outpatient (65%), sedation (63%), anaesthesia (42%), symptomatic outpatient (27%), and symptomatic inpatient (12%). Postdetoxification treatment with buprenorphine or methadone was preferred over naltrexone. Participants with more previous detoxification attempts were more likely to enter postdetoxification treatment. Given that outpatient detoxification was more effective with buprenorphine than with symptomatic medications and that rapid detoxification was more effective than the symptomatic inpatient method, the roles of the symptomatic methods should be reconsidered.     

Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1

High-throughput screening against the human sirtuin SIRT1 led to the discovery of a series of indoles as potent inhibitors that are selective for SIRT1 over other deacetylases and NAD-processing enzymes. The most potent compounds described herein inhibit SIRT1 with IC50 values of 60-100 nM, representing a 500-fold improvement over previously reported SIRT inhibitors. Preparation of enantiomerically pure indole derivatives allowed for their characterization in vitro and in vivo. Kinetic analyses suggest that these inhibitors bind after the release of nicotinamide from the enzyme and prevent the release of deacetylated peptide and O-acetyl-ADP-ribose, the products of enzyme-catalyzed deacetylation. These SIRT1 inhibitors are low molecular weight, cell-permeable, orally bioavailable, and metabolically stable. These compounds provide chemical tools to study the biology of SIRT1 and to explore therapeutic uses for SIRT1 inhibitors.     

Potent, orally active corticotropin-releasing factor receptor-1 antagonists containing a tricyclic pyrrolopyridine or pyrazolopyridine core

Two new classes of tricyclic-based corticotropin-releasing factor (CRF(1)) receptor-1 antagonists were designed by constraining known 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine ligands. Pyrrole- and pyrazole-based molecules 19g and 22a, respectively, were discovered that potently bind the recombinant CRF(1) receptor (K(i) = 3.5, 2.9 nM) and inhibit adrenocorticotropic hormone (ACTH) release from rat pituitary cell culture (IC(50) = 14, 6.8 nM). These compounds show good oral bioavailabity (F = 24%, 7.0%) and serum half-lives in rats (t(1/2) = 6.3, 12 h) and penetrate the rat brain ([brain]/[plasma] = 0.27, 0.52) but tend toward large volumes of distribution (V(D) = 38, 44 L kg(-1)) and rapid clearances (CL = 70, 43 mL min(-1) kg(-1)). When given orally, both the pyrazole and the pyrrole leads dose-dependently inhibit stress-induced ACTH release in vivo. ACTH reductions of 84-86% were observed for 30 mg kg(-1) doses.     

Systematic review: acute colonic pseudo-obstruction

Acute colonic pseudo-obstruction is the clinical syndrome of acute large bowel dilatation without mechanical obstruction that is an important cause of morbidity and mortality. Acute colonic pseudo-obstruction occurs in hospitalized or institutionalized patients with serious underlying medical and surgical conditions. The pathogenesis of acute colonic pseudo-obstruction is not completely understood but likely results from an imbalance in the autonomic regulation of colonic motor function. Metabolic or pharmacological factors, as well as spinal or retroperitoneal trauma, may alter the autonomic regulation of colonic function, leading to excessive parasympathetic suppression or sympathetic stimulation. This imbalance results in colonic atony and dilatation. Early recognition and appropriate management are critical to minimizing morbidity and mortality. The mortality rate is estimated at 40% when ischaemia or perforation occurs. The best-studied treatment of acute colonic pseudo-obstruction is intravenous neostigmine, which leads to prompt colon decompression in the majority of patients after a single infusion. In patients failing or having contraindications to neostigmine, colonoscopic decompression is the active intervention of choice. Surgery is reserved for those with peritonitis or perforation.     

The management of strabismus in adults--II. Patient and provider perspectives on the severity of adult strabismus and on outcome contributors.

PURPOSE: As part of a larger study intended to evaluate the management of strabismus in adults, we documented and compared patient and provider perspectives on the various factors that may contribute to treatment outcome and value of strabismus care. METHODS: By completing a questionnaire, 170 patients with strabismus (ages 19 to 87 years) and 11 strabismus specialists who performed surgery on these patients each indicated the relative weight of several disease- and treatment-related contributors to the outcome and value of care. In addition, each respondent rated the severity of the strabismus before and after surgery. RESULTS: Overall severity ratings improved as a result of surgery. The improvement perceived by the physicians was 5.1 +/- 1.7 on a 10-point scale and was larger than the 2.6 +/- 3.6 points improvement perceived by the patients ( P < 0.001). Patients and physicians expressed different views on the relative contributions to outcome and value (overall P < 0.001). Both groups indicated "the condition," "the physician," and "the procedures" as the largest contributors, but "condition" was perceived as more important by the physicians than by the patients ( P < 0.001), and "physician" was more important to the patients than to the physicians ( P < 0.001). CONCLUSION: Although in approximate agreement on the main contributors to outcome and value, discrepancies exist between perspectives of patients and physicians on the relative weights of those contributors. Public information, education, and counseling may bring these perspectives better in line and ultimately improve both quality and patient satisfaction.     

Features Predicting Weight Loss in Overweight or Obese Participants in a Web-Based Intervention: Randomized Trial

Background

Obesity remains a serious issue in many countries. Web-based programs offer good potential for delivery of weight loss programs. Yet, many Internet-delivered weight loss studies include support from medical or nutritional experts, and relatively little is known about purely web-based weight loss programs.

Objective

To determine whether supportive features and personalization in a 12-week web-based lifestyle intervention with no in-person professional contact affect retention and weight loss.

Methods

We assessed the effect of different features of a web-based weight loss intervention using a 12-week repeated-measures randomized parallel design. We developed 7 sites representing 3 functional groups. A national mass media promotion was used to attract overweight/obese Australian adults (based on body mass index [BMI] calculated from self-reported heights and weights). Eligible respondents (n = 8112) were randomly allocated to one of 3 functional groups: information-based (n = 183), supportive (n = 3994), or personalized-supportive (n = 3935). Both supportive sites included tools, such as a weight tracker, meal planner, and social networking platform. The personalized-supportive site included a meal planner that offered recommendations that were personalized using an algorithm based on a user’s preferences for certain foods. Dietary and activity information were constant across sites, based on an existing and tested 12-week weight loss program (the Total Wellbeing Diet). Before and/or after the intervention, participants completed demographic (including self-reported weight), behavioral, and evaluation questionnaires online. Usage of the website and features was objectively recorded. All screening and data collection procedures were performed online with no face-to-face contact.

Results

Across all 3 groups, attrition was high at around 40% in the first week and 20% of the remaining participants each week. Retention was higher for the supportive sites compared to the information-based site only at week 12 (P = .01). The average number of days that each site was used varied significantly (P = .02) and was higher for the supportive site at 5.96 (SD 11.36) and personalized-supportive site at 5.50 (SD 10.35), relative to the information-based site at 3.43 (SD 4.28). In total, 435 participants provided a valid final weight at the 12-week follow-up. Intention-to-treat analyses (using multiple imputations) revealed that there were no statistically significant differences in weight loss between sites (P = .42). On average, participants lost 2.76% (SE 0.32%) of their initial body weight, with 23.7% (SE 3.7%) losing 5% or more of their initial weight. Within supportive conditions, the level of use of the online weight tracker was predictive of weight loss (model estimate = 0.34, P < .001). Age (model estimate = 0.04, P < .001) and initial BMI (model estimate = -0.03, P < .002) were associated with frequency of use of the weight tracker.

Conclusions

Relative to a static control, inclusion of social networking features and personalized meal planning recommendations in a web-based weight loss program did not demonstrate additive effects for user weight loss or retention. These features did, however, increase the average number of days that a user engaged with the system. For users of the supportive websites, greater use of the weight tracker tool was associated with greater weight loss.     

Influence of altitude training modality on performance and total haemoglobin mass in elite swimmers

We compared changes in performance and total haemoglobin mass (tHb) of elite swimmers in the weeks following either Classic or Live High:Train Low (LHTL) altitude training. Twenty-six elite swimmers (15 male, 11 female, 21.4 ± 2.7 years; mean ± SD) were divided into two groups for 3 weeks of either Classic or LHTL altitude training. Swimming performances over 100 or 200 m were assessed before altitude, then 1, 7, 14 and 28 days after returning to sea-level. Total haemoglobin mass was measured twice before altitude, then 1 and 14 days after return to sea-level. Changes in swimming performance in the first week after Classic and LHTL were compared against those of Race Control (n = 11), a group of elite swimmers who did not complete altitude training. In addition, a season-long comparison of swimming performance between altitude and non-altitude groups was undertaken to compare the progression of performances over the course of a competitive season. Regardless of altitude training modality, swimming performances were substantially slower 1 day (Classic 1.4 ± 1.3% and LHTL 1.6 ± 1.6%; mean ± 90% confidence limits) and 7 days (0.9 ± 1.0% and 1.9 ± 1.1%) after altitude compared to Race Control. In both groups, performances 14 and 28 days after altitude were not different from pre-altitude. The season-long comparison indicated that no clear advantage was obtained by swimmers who completed altitude training. Both Classic and LHTL elicited ~4% increases in tHb. Although altitude training induced erythropoeisis, this physiological adaptation did not transfer directly into improved competitive performance in elite swimmers.