Professional integrity in clinical research

In response to public concern over abuses in human medical experimentation, the dominant approach to the ethics of clinical research during the past 30 years has been regulation, particularly via institutional review board review and approval of scientific protocols and written consent forms. However, the effectiveness of regulatory mechanisms in ensuring the ethical conduct of clinical research is limited. Little attention has been devoted to the nature and role of professional integrity of physician investigators, a conscientious framework for guiding investigators in the socially important but morally complex activity of clinical research. Professional integrity is vital in forging an ethically sound relationship between investigators and patient volunteers, a relationship that differs in important ways from the patient-physician relationship in standard clinical practice. We examine critically 2 models of the moral identity of physician investigators, the investigator as clinician and the investigator as scientist; in neither of these 2 models can the physician investigator eliminate completely the moral conflicts posed by clinical research. The professional integrity of physician investigators depends on a coherent moral identity that is proper to the enterprise of clinical research. The roles of clinician and scientist must be integrated to manage conscientiously the ethical complexity, ambiguity, and tensions between the potentially competing loyalties of science and care of volunteer patients.     

Modeling of acute spinal cord injury in the rat: neuroprotection and enhanced recovery with methylprednisolone, U-74006F and YM-14673

We used a new injury device that produces consistent spinal cord contusion injuries (T8) in rats to compare the behavioral and histologic effects of methylprednisolone sodium succinate (MPSS) administration, the clinical standard of therapy after acute spinal cord injury (ASCI), with the 21-aminosteroid, U-74006F (U74), and the TRH analogue, YM-14673 (YM), at different trauma doses. Three sequential experiments were conducted: Experiment 1. U74 (3.0/1.5/1.5 mg/kg; 10/5/5 mg/kg; 30/15/15 mg/kg), MPSS (30/15/15 mg/kg), or vehicle were administered intravenously (i.v.) at 5 min, 2 and 6 h after the injury (n = 8/group). U74 (10/5/5 mg/kg) and MPSS animals scored better than controls (Days 8-43) in open field walking (OFW); no other differences were seen between groups. Experiment 2. Dose-response evaluation of MPSS determined more effective doses. Groups (n = 16) receiving 30/30/30/30 mg/kg and 60/60/60/60 mg/kg i.v. at 5 min and 2, 4, and 6 h after the injury had better OFW scores than controls (Days 8-29; Day 29). Both groups performed better than controls (Days 8-29) on inclined plane (IP); 30 mg/kg animals scored higher on Day 29. Percentage tissue spared (%TS) at the lesion center was greater for 60 mg/kg animals (23.4%) than controls (17.3%). Experiment 3. Compounds were administered as in experiment 2 (n = 15/group); MPSS (60/30/30/30 mg/kg) and YM (1/1/1/1 mg/kg and 1 mg/kg/day ip) were most effective. YM and MPSS combination produced no additive effects. YM animals scored better than MPSS and control animals in OFW (Days 8-29) and better than controls on IP (Days 8-29; Day 29) and grid walking (Day 29). MPSS animals scored better than controls on IP (Days 8-29). YM and MPSS groups had greater %TS than controls. This series of experiments demonstrates the utility of this injury model and simple behavioral measures for preclinical assessment of pharmacologic agents. Under these experimental conditions, U74 demonstrated equivalent efficacy to MPSS, and YM demonstrated greater efficacy than MPSS in the treatment of ASCI.     

Modulation of embryonic glutathione peroxidase activity and phenytoin teratogenicity by dietary deprivation of selenium in CD-1 mice

Selenium (Se)-dependent and -independent glutathione (GSH) peroxidases detoxify H2O2 and lipid hydroperoxides, which may mediate the teratogenicity of phenytoin and related xenobiotics. To test this hypothesis, CD-1 mice were placed on Se-deficient diets for 15, 25 or 40 days and bred so that the day of analysis corresponded to gestational day 11. In Se-replete control animals, embryonic peroxidase activities were only 5% of activities in maternal liver (P < .05). After 15 days of Se deprivation, maternal activities for H2O2 (reflecting Se-dependent peroxidase) and cumene hydroperoxide (CmOOH) (reflecting both Se-dependent and -independent peroxidases) were reduced to 20% (P < .05) and 35% of controls, respectively. At this time, the incidence of fetal cleft palates initiated by phenytoin (55 mg/kg intraperitoneally on gestational days 11, 12 and 13) was doubled, from 12% to 25% (P < .05). Selenite rescue (Na2SeO3, 350 micrograms/kg intraperitoneally on day 9) restored maternal and embryonic peroxidase activities and completely inhibited phenytoin-initiated postpartum lethality and fetal resorptions in animals that had been Se depleted for 15 days. After 40 days of Se deprivation, maternal and embryonic peroxidase/H2O2 activities were reduced to < 1% and 27% of Se-replete controls, respectively. In contrast, maternal peroxidase/CmOOH activity was increased to 70% of controls, reflecting induction of Se-independent peroxidase, compared with that with 15 days' depletion. Phenytoin-initiated cleft palates with 40 days' depletion appeared to be reduced (16%) compared with Se-replete controls (24%) (P < .07). In 40-day Se-depleted animals given selenite rescue, the 10% incidence of cleft palates was significantly lower than that in the 40-day Se-replete group (24%) but not the Se-depleted group (16%). This is the first demonstration of reduced Se-dependent GSH peroxidase activities in embryonic tissues with dietary Se-deprivation. The results implicate reactive oxygen species and lipid hydroperoxides in the mechanism of phenytoin teratogenicity and suggest that GSH peroxidases are important embryoprotective enzymes.     

The effect of fibre orientation of the dry sliding wear of borsic-reinforced 2014 aluminium alloy

The effect of fibre orientation on the dry sliding wear of continuous B(SiC) fibre reinforced aluminium alloy composites was investigated using a pin-on-disc wear testing machine. The metal-matrix composites (MMC) samples were tested in the normal (N), parallel (P) and antiparallel (AP) orientations sliding against a steel counter disc at a fixed speed of 1 m s^–1 under loads of from 12 to 60 N.The results showed that for the matrix alloy and MMCs, the average wear increased linearly with load. Wear of the MMCs was insensitive to fibre content but for composites with fibre contents at or above the minimum of 16 vol% used for this work, the wear rate was about 18% of that of the unreinforced matrix. Fibre orientation had a minor effect on wear rate; the N orientation gave the lowest wear rate with the AP orientation slightly higher and the P orientation significantly higher.The average coefficients of friction of the MMCs in N and AP orientations decreased linearly with increased wear rate and non-linearly with increased load, but the P orientation was insensitive to either variable.It was concluded from these results and a metallographic examination that the mechanism of wear of MMCs was essentially oxidative wear of the matrix. The hard fibres modified this to slightly different degrees depending on their orientation relative to the wear surface and sliding direction.     

Electrical pacing of the paralyzed human larynx

This study represents the first attempt to electrically pace the paralyzed human larynx. The goal was to determine if electrical stimulation of the posterior cricoarytenoid muscle could produce functional abduction of the vocal fold in pace with inspiration. An external apparatus was used to sense inspiration and reanimate the unilaterally paralyzed larynx of a thyroplasty patient. Stimuli were delivered through a needle electrode to locate and pace the abductor muscle. The magnitude of electrically induced abduction was comparable to spontaneous movement on the normal side. The abduction was appropriately timed with inspiration: this finding demonstrated that this simple pacing system could effectively modulate stimulation with patient respiration.     

Randomized trial of breast self-examination in Shanghai: methodology and preliminary results

BACKGROUND: The efficacy of breast self-examination in helping to reduce mortality from breast cancer has not been rigorously demonstrated. PURPOSE: To assess efficacy, a large, randomized trial was initiated in Shanghai, China. METHODS: From October 1989 to October 1991, 267040 current and retired female employees associated with 520 factories in the Shanghai Textile Industry Bureau were randomly assigned on the basis of factory to either a self-examination instruction group (133375 women) or a control group (133665 women). The women were born within the period from 1925 through 1958. Women in the instruction group were given intensive training in breast self-examination, including the use of silicone breast models and personalized instruction, plus two subsequent reinforcement sessions and multiple reminders to practice the technique. Women in the control group were asked to attend training sessions on the prevention of low back pain. All women have been followed for the development of breast diseases and for death from breast cancer. RESULTS: A high level of participation during the first 4-5 years of the trial was documented among women in the instruction group. Randomly sampled women in this group demonstrated greater proficiency in detecting lumps in breast models than did randomly sampled women in the control group. Approximately equal numbers of breast cancers were detected in the two groups (331 in the instruction group and 322 in the control group) through 1994, which is the last year for which case-finding efforts have been completed. The breast cancers detected in the instruction group were not diagnosed at an appreciably earlier stage or smaller size than those in the control group. More benign breast lesions were detected in the instruction group than in the control group (1457 versus 623, respectively), suggesting a higher index of suspicion for women who received training. Cumulative breast cancer mortality rates through 5 years from entry into the study were nearly equivalent for the two groups. CONCLUSIONS: Breast self-examination has not led to a reduction in mortality from breast cancer in this study cohort in the first several years since the trial began. A shift toward the diagnosis of disease at a less advanced stage in women given instruction has also not been demonstrated. Longer follow-up of participants in this trial is required before final assessment can be made of the efficacy of breast self-examination. IMPLICATIONS: At this time, there is insufficient evidence to recommend for or against the teaching of breast self-examination.     

Implementation of a hypertext-based curriculum for emergency medicine on the World Wide Web

This project reports the publication of a variety of existing curricular resources for emergency medicine on the global Internet in a format that allows hypertext links between related material, timely updates, and end-user feedback. Curricular elements were converted to Hypertext Markup Language with extensive links between related content. The completed document contains instructions for curriculum development, specific curricula for subspecialty areas within a residency, reading lists for subspecialty curricula, banks of images, and board-type questions with answers. Users are provided with a mechanism to provide immediate feedback to section editors with suggestions for changes, including new references. Access to all or part of the document can be controlled via passwords, but is potentially available to anyone with an Internet connection and a World Wide Web browser. The document may by viewed on the World Wide Web at: http:@www.brown.edu@Administration@emergency_Medicine@ curr.html.     

Keeping calcium in its place: Ca(2+)-ATPase and phospholamban

Electron microscopy is gradually revealing more and more about the structure of the calcium pump from the sarcoplasmic reticulum, Ca(2+)-ATPase. The most recent result reveals the ATP-binding site, and two different avenues are being pursued towards achieving a higher resolution structure. Although no such structures are currently available for phospholamban, various spectroscopies and site-directed mutagenesis have been combined to produce a compelling structural model for its regulation of Ca(2+)-ATPase.