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.     

A controlled trial of scheduled replacement of central venous and pulmonary-artery catheters.

BACKGROUND. The incidence of infection increases with the prolonged use of central vascular catheters, but it is unclear whether changing catheters every three days, as some recommend, will reduce the rate of infection, It is also unclear whether it is safer to change a catheter over a guide wire or insert it at a new site. METHODS. We conducted a controlled trial in adult patients in intensive care units who required central venous or pulmonary-artery catheters for more than three days. Patients were assigned randomly to undergo one of four methods of catheter exchange: replacement every three days either by insertion at a new site (group 1) or by exchange over a guide wire (group 2), or replacement when clinically indicated either by insertion at a new site (group 3) or by exchange over a guide wire (group 4). RESULTS. Of the 160 patients, 5 percent had catheter-related bloodstream infections, 16 percent had catheters that became colonized, and 9 percent had major mechanical complications. The incidence rates (per 1000 days of catheter use) of bloodstream infection were 3 in group 1, 6 in group 2, 2 in group 3, and 3 in group 4; the incidence rates of mechanical complications were 14, 4, 8, and 3, respectively. Patients randomly assigned to guide-wire-assisted exchange were more likely to have bloodstream infection after the first three days of catheterization (6 percent vs. 0, P = 0.06). Insertions at new sites were associated with more mechanical complications (5 percent vs. 1 percent, P = 0.005). CONCLUSIONS. Routine replacement of central vascular catheters every three days does not prevent infection. Exchanging catheters with the use of a guide wire increases the risk of bloodstream infection, but replacement involving insertion of catheters at new sites increases the risk of mechanical complications.     

Altered gastric emptying in the head-injured patient: relationship to feeding intolerance

Most patients with moderate to severe head injury initially do not tolerate enteral feedings postinjury. This intolerance is more prolonged than that found in patients suffering other types of trauma. The authors prospectively evaluated 12 patients with moderate to severe head injury (Glasgow Coma Scale score between 4 and 10) throughout their hospitalization for liquid gastric emptying as a possible mechanism for intolerance to enteral feeding. During Week 1, the majority of patients displayed a delay in gastric emptying. Patients also displayed an abnormal biphasic response (gastric emptying faster than normal during the early stage but prolonged later). By Week 2, many patients still had delayed and abnormal biphasic responses to gastric emptying. By Week 3, an improvement was observed with the majority of patients exhibiting rapid gastric emptying, but delays and abnormal biphasic responses were still seen. Patients who initially had rapid or normal gastric emptying tolerated full-strength full-rate feedings significantly earlier compared with those who experienced delayed gastric emptying (8.5 +/- 0.5 days vs. 13.7 +/- 3.2 days, p less than 0.001). All patients tolerated full-strength full-rate feedings by Day 16 postinjury (range 7 to 16 days) except the two patients who displayed delayed gastric emptying for prolonged periods of time (mean 25 days). This is the first study to longitudinally evaluate gastric emptying following head injury. The authors suggest that patients with moderate to severe head injury often experience alterations in gastric emptying which may affect their ability to tolerate enteral feedings.     

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.