Historical background of clinical trials involving women and minorities

The author provides a historical context for the difficult ethical and clinical issues associated with the inclusion of women and members of minority groups in clinical research. He cites as a point of departure the Nuremberg Code of the late 1940s, which declared the fundamental dignity of human beings involved as research subjects, a principle that was quickly endorsed worldwide. From the period following World War II through the 1970s, the prevailing attitude--not always practiced--toward research subjects in the United States was that they should be protected from exploitation. That attitude was reflected in the first broad federal policy on research subjects, created in 1966. During those years, research was widely regarded by the public as dangerous and of little value to individual participants; it is remarkable that so many men and women consented to participate in clinical studies at that time. Furthermore, during the 1970s, for reasons explained by the author, various events--the abortion debate, disclosures from the infamous Tuskegee syphilis study, Nixon's "war on cancer," new federal regulations in 1974 and 1975 (the latter providing additional protection for pregnant women in research), the broad interpretation of the FDA's 1977 policy excluding pregnant or potentially pregnant women from clinical trials, and the tendency of blacks and persons from other minority groups to shun participation in research--tended to deter participation of women and members of minority groups in clinical research.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduced HIV-1 infectability of CD4+ lymphocytes from exposed-uninfected individuals: association with low expression of CCR5 and high production of beta-chemokines

Escherichia coli leader peptidase, an integral membrane protein, is responsible for the cleavage of the signal sequence of many exported proteins. Recent studies suggest that it is a novel serine protease that utilizes a serine-lysine catalytic dyad. In an effort to further understand the mechanism of this enzyme, an internally quenched fluorescent peptide substrate incorporating the leader peptidase cleavage site of maltose binding protein signal peptide, Y(NO2)-F-S-A-S-A-L-A-K-I-K(Abz) (anthraniloyl), was designed and synthesized. In the intact peptide, the fluorescence of the anthraniloyl group is quenched by the 3-nitrotyrosine. This quenched fluorescence is liberated upon cleavage of the peptide by the leader peptidase, resulting in increased fluorescence that could then be monitored fluorometrically. The designed substrate can be cleaved effectively by E. coli leader peptidase as detected by both HPLC and fluorescent spectroscopy. Mass spectra of cleavage products demonstrated that the cleavage occurs at the predicted site (A-K). The cleavage of the peptide substrate has a linear dependence on the enzyme concentration (0.1 to 1.9 microM) and the kcat/K(m) was calculated to be 71.1 M-1 s-1. These data are comparable with the unmodified peptide substrate. This report represents the first direct continuous assay based on fluorescence resonance energy transfer for E. coli leader peptidase.     

Fetal fast MR imaging: reproducibility, technical quality, and conspicuity of anatomy

PURPOSE: To evaluate the normal appearance of fetal anatomy, the conspicuity of fetal organs, the reproducibility of images, and the limitations to image quality with the use of half-Fourier, single-shot rapid acquisition with relaxation enhancement (RARE) magnetic resonance (MR) imaging. MATERIALS AND METHODS: Fifty-four fetuses of 49 pregnancies underwent MR imaging with the half-Fourier, single-shot RARE technique. Two reviewers attempted to identify 47 organs and anatomic regions in each fetus. Organ or region conspicuity, image quality, and the limitations of image quality were graded. RESULTS: Fetal anatomy was well depicted in fetuses over 20 weeks in gestational age. Fetal imaging was limited by gestational age of 20 weeks or less usually owing to the small size of the organ or region being evaluated and, less frequently, by motion. CONCLUSION: Half-Fourier, single-shot RARE MR imaging provided a detailed and reproducible evaluation of normal fetal anatomy, which can be used as a standard of reference in MR imaging of fetal anomalies.     

Accuracy of injury coding in Victorian hospital morbidity data

In Victoria injury surveillance data are drawn from hospital morbidity data. The accuracy and reliability of these data are often questioned. We aimed to ascertain the reliability of injury data in the Victorian inpatient minimum database. A random sample of 546 public hospital separations with principal diagnosis ICD-9-CM codes 800-999 was selected from four metropolitan hospitals. Medical records were reviewed, and the hospital coding was compared with the record content. The frequency of error in any coding field was 73 per cent (349/480); of diagnosis error, 61 per cent (292/480); of procedure error, 45 per cent (168/370); of error in the principal diagnosis, 19 per cent (93/480); and of error in external-cause codes (E-codes), 16 per cent (75/480). Ninety-four per cent of errors (87/93) in the principal diagnosis involved recoding within the same group of codes. Only 6 per cent (6/93) were recoded to principal diagnoses other than injury. Sixty-two per cent (181/292) were errors of omission of codes for comorbid conditions. Nearly half the errors in the principal diagnosis were minor, involving the last two digits. E-codes were more complete than diagnosis codes. The best predictors of error in the principal diagnosis were greater length of stay, type of injury code (poisonings and toxic effects were associated with lower error rates) and death as the outcome. While selection of data from secondary diagnosis fields may not provide complete data, the use of the principal-diagnosis code and E-codes for injury surveillance is feasible and reliable. The database is a valuable source of injury surveillance data, bearing in mind the limitations of coded hospital morbidity data.     

Kinematic analysis of shear displacement as a means for operating mechanotransduction channels in the contact region between adjacent stereocilia of mammalian cochlear hair cells

In sensory hair cells of the cochlea, deflection of the stereociliary bundle results in direct mechanical gating of mechanoelectrical transduction channels, a function generally attributed to the tip link running between the tips of short stereocilia and the sides of adjacent taller ones. However, immunocytochemical experiments indicate that the channels may not be associated with the tip link but occur just below it in a region of contact between the stereocilia. To determine whether transduction channels in this location could be operated during physiologically appropriate deflections as effectively by shear displacement as if they were associated with the tip link, a two dimensional kinematic analysis of relative motion between stereocilia has been performed assuming contact between stereocilia is maintained during deflection. Bundle geometry and dimensions were determined from transmission electron micrographs of hair cells from several frequency locations between 0.27 and 13.00 kHz in the guinea-pig cochlea. The analysis indicates that for a 10 nm deflection of the tallest stereocilia of both inner and outer hair cells, i.e. within the range of the maximum sensitivity of mammalian hair bundles, the average shear displacement in the contact region would be 1.6 nm, but that it increases systematically towards higher frequency regions for outer hair cells. This displacement is comparable in magnitude to tip-link elongation for individual stereociliary pairs.     

Interaction of biotin with streptavidin. Thermostability and conformational changes upon binding

The effect of biotin binding on streptavidin (STV) structure and stability was studied using differential scanning calorimetry, Fourier transform infrared spectroscopy (FT-IR), and fluorescence spectroscopy. Biotin increases the midpoint temperature Tm, of thermally induced denaturation of STV from 75 degrees C in unliganded protein to 112 degrees C at full ligand saturation. The cooperativity of thermally induced unfolding of STV changes substantially in presence of biotin. Unliganded STV monomer has at least one domain that unfolds independently. The dimer bound to biotin undergoes a single coupled denaturation process. Simulations of thermograms of STV denaturation that take into account only the thermodynamic effects of the ligand with a Ka approximately 10(15) reproduce the behavior observed, but the estimated values of Tm are 15-20 degrees C lower than those experimentally determined. This increased stability is attributed to an enhanced cooperativity of the thermal unfolding of STV. The increment in the cooperativity is as consequence of a stronger intersubunit association and an increased structural order upon binding. FT-IR and fluorescence spectroscopy data reveal that unordered structure found in unliganded STV disappears under fully saturating conditions. The data provide a rationale for previous suggestions that biotin binding induces an increase in protein tightness (structural cooperativity) leading, in turn, to a higher thermostability.     

A two-term MEDLINE search strategy for identifying randomized trials in obstetrics and gynecology

In this study, we examined whether endothelin (ET) plays a role in the short-term increase in mean arterial pressure (MAP) after nitric oxide synthase (NOS) inhibition with N(omega)-nitro-L-arginine methyl ester (L-NAME) in stroke-prone spontaneously hypertensive rats (SHRSPs). Experiments were performed by using Inactin-anesthetized male SHRSPs that were pretreated with chlorisondamine to block reflex autonomic cardiovascular effects. Injection of L-NAME (10 mg/kg, i.v.), but not D-NAME, produced rapid and marked increases (74 +/- 3 mm Hg) in MAP that were sustained for >1 h. In SHRSPs that were treated with the ET(A/B) receptor antagonist, L-754,142 (15 mg/kg + 15 mg/kg/h), L-NAME increased MAP by 45 +/- 4 mm Hg (p < 0.0001 compared with L-NAME alone). L-754,142 blocked pressor responses to big ET-1 by >90% but was without effect on pressor responses to norepinephrine. Plasma levels of ET-1 averaged 5 +/- 1 pg/ml in animals given vehicle and were slightly increased in animals given either L-NAME alone (7 +/- 2 pg/ml) or L-754,142 alone (7 +/- 2 pg/ml) but increased markedly when L-NAME and L-754,142 were given together (114 +/- 18 pg/ml). This may relate to an effect of L-754,142 to block ET-receptor-mediated clearance of ET-1. We conclude that ET plays a role in the short-term pressor response after NOS inhibition in SHRSPs.     

Integrated services for treatment of schizophrenic substance abusers: demographics, symptoms, and substance abuse patterns

We have previously described a model of outpatient integrated treatment for patients with comorbid psychoactive substance use disorders and schizophrenia (PSUD/S)(1). Here we review relevant literature on comorbidity and outline the rationale for integrated services. Further, we describe results from 3 related studies: First, we document the approximate incidence of PSUD among a heterogeneous group of 602 schizophrenic inpatient admissions to our hospital. Second, we describe in greater detail the psychiatric symptoms and patterns of substance abuse among a subsample of 106 inpatients with PSUD/S, contrasting them with 112 patients with PSUD and mixed psychotic disorders, but who are not schizophrenic. Third, we present a prospective research project and describe a sample of 30 patients with PSUD/S, detailing demographic characteristics, psychiatric symptoms and substance abuse history. Attention is given to current issues in the differential diagnosis of patients with PSUD/S using standardized instruments.     

Treatment of insomnia. Getting to the root of sleeping problems

Insomnia may be periodic and transient, as caused by situational stress, or persistent, as caused by a chronic sleep disorder. Physicians can gain much information concerning the type, probable cause, onset, and duration of insomnia through history taking. A sleep diary may reveal helpful information, and input from the patient's sleeping partner can also be valuable. Complicating disorders, such as heart failure, prostatism, or depression, should be sought and specific treatment prescribed. Chemical dependency, too, requires appropriate treatment. These measures, institution of good sleep-hygiene practices, and behavior modification may resolve sleeplessness. The primary indication for use of hypnotic agents is transient sleep disruption caused by acute stress. When an agent is chosen, onset of action, metabolism, and side effects should be considered, especially in elderly patients. Addictive agents should not be given to patients with substance abuse problems. If insomnia persists, evaluation at a sleep-disorder center is recommended to facilitate design of an appropriate therapeutic regimen.