Dual function nitroimidazoles less toxic than RSU 1069: selection of candidate drugs for clinical trial (RB 6145 and/or PD 130908.

Following the toxicity and synthetic difficulties encountered with the hypoxic cell radiosensitizer RSU 1069, efforts have focused on development of a superior analogue. Two compounds, RB 6145 and PD 130908, have emerged from this program which overcome the instability and synthetic problems associated with RSU 1069 while retaining favorable biological activity. Both agents show comparable radiosensitizing activity to RSU 1069 following oral or i.p. administration to mice bearing the KHT or RIF-1 tumors. Sensitizing efficiency is about 10 X greater than that observed for misonidazole or etanidazole. Toxicity toward hypoxic tumor cells in vivo is demonstrated by clamping tumors (for 60 min) following administration of PD 130908 or RB 6145. Both are effective hypoxic cytotoxins, but less potent than RSU 1069. Systemic toxicity is substantially reduced following oral drug administration. Further, doses achievable following fractionated drug treatments are sufficiently high to produce significant levels of radiosensitization.     

Do discrepancies in interpersonal perception predict relapse?: A comparison of remitted depressed patients and collaterals

In an effort to examine whether disturbed interpersonal relationships are associated with relapse in depression, discrepancies in self-ratings provided by formerly depressed patients and their collateral informants were compared. Thirty-eight remitted depressed patients and their collateral informants were asked to monitor moods, life events, and stress levels on a bimonthly basis for a 1-year period. It was hypothesized that patient/collateral dyads displaying a greater discrepancy in interpersonal perception would have a higher risk of relapse than dyads who showed more agreement in their ratings. Results indicated that while discrepancies in the perceptions of patients' life events were associated with the duration of a relapse once it occurred, discrepancies were generally not related to the emergence of new episodes of depressive disorder. The implications of these findings for models seeking to integrate cognitive and interpersonal models of depression, through the study of environmentally determined and personally appraised adversity, is discussed.This research was supported by grants to the first and third authors from the Canadian Psychiatric Research Foundation and the Laidlaw Foundation.     

The repeatability of measurement of the ocular components.

Studies of the ocular components of refraction typically neglect issues of repeatability of measurement methods or analyze method comparison/repeatability data inappropriately using correlation. The authors have examined the repeatability of refractive error measures (retinoscopy, subjective refraction, and Canon R-1 autorefraction, noncycloplegic and cycloplegic), axial dimension measures (Allergan-Humphrey A-scan ultrasound), and corneoscopy (keratometry and KERA photokeratoscopy), and the agreement between different refractive error and corneal measurement methods on 40 pre-presbyopic normal adults. The authors plotted the difference versus the mean of two different measurement occasions (repeatability), or two different methods (agreement), to determine the bias (mean of the differences relative to zero) and 95% limits of agreement of each technique. The most reliable measure of refractive error was autorefraction with cycloplegia, with 95% limits of agreement of +/- 0.32 diopters. Cycloplegic autorefraction had no statistically significant bias compared to cycloplegic subjective refraction. Cycloplegic retinoscopy was the least reliable refractive error measure, with repeat measures on two separate occasions extending over 95% limits of agreement of +/- 0.95 D. Anterior chamber depth was reliable to +/- 0.29 mm, lens thickness to +/- 0.20 mm, and vitreous chamber depth to +/- 0.37 mm. Corneal curvature measures show keratometry to be more reliable (to +/- 0.87 D) than photokeratoscopy (+/- 2.02 D) with a statistically significant bias (paired t-test, P less than 0.0001) of 0.57 D flatter for photokeratoscopy.     

Endocrine stress response in cataract operations with local anesthesia]

This study was undertaken to investigate the endocrine stress response during cataract surgery in local anaesthesia (LA) with or without additional sedation with midazolam (Dormicum). 20 patients for cataract surgery in LA were randomly allocated to the midazolam-group (before injection of LA, sedation with single doses of 1 mg midazolam until the patient was sleeping, but awakeable), and to the control-group without sedation. Premedication and LA were standardized. The investigation was performed at 7 measuring points starting at the arrival in the preparation room up to 30 min after surgery. Adrenaline in plasma was significantly lower in the midazolam-group. Intraoperatively, adrenaline increased in the control-group and decreased in the midazolam-group. In time course, noradrenaline in plasma decreased in the midazolam-group, in contrast to the control-group. With respect to ADH, ACTH and cortisol, no significant differences were found in group levels or time course, and concentrations remained within normal range. In contrast to the control-group, mean arterial pressure decreased in the midazolam-group during the course of time. There were no differences in heart rate or arterial oxygen saturation between the two groups. Local anaesthesia and premedication were sufficient to prevent psychic and surgical stressors. The slight sympathoadrenergic response in the control-group was significantly reduced by small doses of midazolam. Thus, a careful supplementation of local anaesthesia with midazolam appears advantageous for patients with cardiovascular disorders.     

Sampling Patients Within and Across Health Care Providers: Multi-Stage Non-Nested Samples in Health Services Research

In order to better inform study design decisions when sampling patients within and across health care providers we develop a simulation-based approach for designing complex multi-stage samples. The approach explores the tradeoff between competing design goals such as precision of estimates, coverage of the target population and cost.We elicit a number of sensible candidate designs, evaluate these designs with respect to multiple sampling goals, investigate their tradeoffs, and identify the design that is the best compromise among all goals. This approach recognizes that, in the practice of sampling, precision of the estimates is not the only important goal, and that there are tradeoffs with coverage and cost that should be explicitly considered. One can easily add other goals. We construct a sample frame with all phase III clinical cancer treatment trials that are conducted by cooperative oncology groups of the National Cancer Institute from October 1, 1998 through December 31, 1999. Simulation results for our study suggest sampling a different number of trials and institutions than initially considered.Simulations of different study designs can uncover efficiency gains both in terms of improved precision of the estimates and in terms of improved coverage of the target population. Simulations enable us to explore the tradeoffs between competing sampling goals and to quantify these efficiency gains. This is true even for complex designs where the stages are not strictly nested in one another.     

Physiotherapy rehabilitation of the smile after long-term facial nerve palsy using video self-modeling and implementation intentions.

OBJECTIVE: To improve smiling after long-term facial nerve palsy (FNP). Physiotherapy rehabilitation of an adapted (more symmetrical) smile was investigated in FNP subjects 1 year post-onset, using video self-modeling (video replay of only best adapted smiles) and implementation intentions (preplanning adapted smiles for specific situations). STUDY DESIGN AND SETTING: Prospective, blinded clinical trial. Facial-Nerve-Palsy Clinic. RESULTS: After video self-modeling: 1) reaction time (RT) to initiation of adapted smiles became 224 ms faster whereas RT for everyday (asymmetrical) smiles became 153 ms slower; 2) adapted smiles were completed 544 ms faster; 3) adapted smiles had higher overall quality, movement control, and symmetry ratings; and 4) Facial Disability Index scores also improved. Implementation intentions after video self-modeling ensured transfer of adapted smile to everyday situations. CONCLUSION: Following intervention the smile improved, with significant changes in availability, execution speed, and quality. SIGNIFICANCE: This study supports these rehabilitation techniques to maximize quality of smiling following FNP. EBM rating: B-2b.