Biomedical subjects
Publications and source records attributed to K White.
A novel, simple approach to retrospective assessment of "blindability" was applied to data on outpatients in a controlled, double-blind clinical comparison of a putative antidepressant, etoperidone, and placebo. A "blind" evaluator proved capable of discriminating between the active drug and placebo on the basis of reported side effects alone, raising questions about the true blindness of the study.
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BACKGROUND: Premenstrual symptoms occur in the setting of other psychiatric disorders, particularly affective disorders. The nosologic issue of whether premenstrual syndrome is an entity distinct from other psychiatric disorders is controversial. METHOD: We review the association between depression and premenstrual syndrome and describe symptoms in a small series of patients (N = 5) with premenstrual syndrome both during and after resolution of major depression. RESULTS: The overall symptom severity decreased after antidepressant treatment, but this decrease was only significant for dysphoria. In two subjects, other cyclical symptoms consistent with premenstrual syndrome became more apparent after treatment of major depression, possibly because background symptoms of depression improved. CONCLUSION: Premenstrual symptoms, including dysphoric changes and irritability, can continue despite effective treatment of major depression.
Data concerning 331 subjects participating in a longitudinal study on anxiety disorders were collected over the first 6 months of the study. Preliminary analyses of somatic treatment according to diagnoses and study site were conducted. The comorbidity of one anxiety disorder with other DSM-III-R diagnoses and other types of anxiety disorders was extensive. Patients with panic disorder received significantly more treatment with a benzodiazepine than patients without panic disorder. Fewer than five percent of the sample were treated with a monoamine oxidase inhibitor. Comorbid depression increased the likelihood of treatment with a newer non-MAOI (non-monoamine oxidase inhibitor), nontricyclic antidepressant. Results suggest a strong effect of treatment site on the pharmacotherapy offered.
As a group, anxiety disorders are the most prevalent class of mental disorders. Over the course of a lifetime, 15% of the population experience one or another anxiety disorder.
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The effect of cholinergic agonists and antagonists on the central pattern generator of the pharyngeal muscles has been studied in third instar larvae of Drosophila. The pharyngeal muscles are a group of rhythmically active fibers involved in feeding. Bath application of the cholinergic agonists carbachol, muscarine, pilocarpine, and acetylcholine (ACh) to a semiintact preparation including the pharyngeal muscles and the central nervous system (CNS), initiated long-lasting endogenous-like bursting activity in the muscles. The muscarinic antagonists, atropine and scopolamine, blocked these responses as well as endogenous activity. Perfusion with nicotine elicited a short, tonic response that was marginally blocked by mecamylamine but not by curare, alpha-bungarotoxin, hexamethonium, or the muscarinic antagonists. This is the first time that a response to cholinergic drugs has been examined in Drosophila. The pharyngeal muscle preparation may prove to be a valuable system for studying mutations of cholinergic metabolism, receptors, and second messengers.
The embryonic lethal abnormal visual system (elav) gene of Drosophila melanogaster is required for the development and maintenance of the nervous system. Transcripts from this locus are distributed ubiquitously throughout the nervous system at all developmental stages. A product of this gene, the ELAV protein, has homology to known RNA binding proteins. The localization of the ELAV protein was studied in all developmental stages using antibodies that were generated against a hybrid protein made in Escherichia coli. In general, these data are consistent with previous results and demonstrate that (1) the ELAV protein is detected in the developing embryonic nervous system at a time coincident with the birth of the first neurons, (2) the ELAV protein is first detected in the majority of neurons of the central and peripheral nervous systems of embryos, larvae, pupae, and adults, (3) the ELAV protein appears to be localized to the nucleus, and (4) the ELAV protein is not detected in neuroblasts or identifiable glia. These data also provide new information concerning elav expression and show that (1) ELAV is not expressed in the ganglion mother cells (GMCs), (2) while the ELAV protein is localized to the nucleus, it is not uniformly distributed throughout this structure, and (3) other Drosophila species do express an ELAV-like antigen. We propose that the elav gene provides a neuronal-housekeeping function that is required for the successful posttranscriptional processing of transcripts from a set of genes the function of which is required for proper neuronal development and maintenance.
The actions of steroid hormones on vertebrate and invertebrate nervous systems include alterations in neuronal architecture, regulation of neuronal differentiation, and programmed cell death. In particular, central nervous system (CNS) metamorphosis in insects requires a precise pattern of exposure to the steroid molting hormone 20-hydroxyecdysone (ecdysterone). To test whether the effects of steroid hormones on the insect nervous system are due to changes in patterns of gene expression, we examined Drosophila mutants of the ecdysterone-regulated locus, the Broad Complex (BR-C). This report documents aspects of CNS reorganization which are dependent on BR-C function. During wild-type metamorphosis, CNS components undergo dramatic morphogenetic movements relative to each other and to the body wall. These movements, in particular, the separation of the subesophageal ganglion from the thoracic ganglion, the positioning of the developing visual system, and the fusion of right and left brain hemispheres, are deranged in BR-C mutants. In addition, a subset of mutants shows disorganization of optic lobe neuropil, both within and among optic lobe ganglia. Optic lobe disorganization is found in mutants of the br and l(1)2Bc complementation groups, but not in those of the rbp complementation group. This suggests that the three complementation groups of this complex locus represent distinct but overlapping functions necessary for normal CNS reorganization. This study demonstrates that ecdysterone-regulated gene expression is essential for CNS metamorphosis, illustrating the utility of Drosophila as a model system for investigating the genetic basis of steroid hormone action on the nervous system.
Drosophila virilis genomic DNA corresponding to the D. melanogaster embryonic lethal abnormal visual system (elav) locus was cloned. DNA sequence analysis of a 3.8-kb genomic piece allowed identification of (i) an open reading frame (ORF) with striking homology to the previously identified D. melanogaster ORF and (ii) conserved sequence elements of possible regulatory relevance within and flanking the second intron. Conceptual translation of the D. virilis ORF predicts a 519-amino-acid-long ribonucleoprotein consensus sequence-type protein. Similar to D. melanogaster ELAV protein, it contains three tandem RNA-binding domains and an alanine/glutamine-rich amino-terminal region. The sequence throughout the RNA-binding domains, comprising the carboxy-terminal 346 amino acids, shows an extraordinary 100% identity at the amino acid level, indicating a strong structural constraint for this functional domain. The amino-terminal region is 36 amino acids longer in D. virilis, and the conservation is 66%. In in vivo functional tests, the D. virilis ORF was indistinguishable from the D. melanogaster ORF. Furthermore, a D. melanogaster ORF encoding an ELAV protein with a 40-amino-acid deletion within the alanine/glutamine-rich region was also able to supply elav function in vivo. Thus, the divergence of the amino-terminal region of the ELAV protein reflects lowered functional constraint rather than species-specific functional specification.
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The purpose of this study was to determine the effects of a resistive training program on the time course of changes in strength, body mass index, lipids, lipoproteins, and apolipoproteins in sedentary obese women. Sixteen sedentary obese women strength trained 3 times . wk-1 for 12 wk performing three sets of six to eight repetitions per set with sets 1 and 2 at 60-70% of one-repetition maximum. During set 3, the subjects used the greatest weight possible so that failure occurred between six to eight repetitions. Six sedentary obese women served as controls. Blood samples for serum total cholesterol (TC), high-density lipoproteins (HDL-C), low-density lipoproteins (LDL-C), triglycerides (TG), TC/HDL-C ratio, apolipoprotein A-I (apo A-I), and apolipoprotein B-100 (apo B-100) were obtained pre, and after 4, 8, and 12 wk of training and approximately 3-4 d following the last training session. A 3-d dietary record was obtained on all subjects pre and post, and subjects were instructed not to alter their diet. The 12 wk of resistive training did not result in a significant change in body weight, BMI, or total kilocalories consumed per day but did show a mean improvement of 58% in muscular strength (P less than 0.05). The training program did not significantly alter the TC, HDL-C, LDL-C, TG, TC/HDL-C ratio, apo A-I, or apo B-100 levels, which suggests that this increase in strength owing to resistive training in the absence of body weight loss did not alter the lipid profiles in these sedentary obese women.
The T cell antigen receptor complex (TCR) and the interleukin 2 (IL-2) receptor are responsible for signal transduction that results in T lymphocyte activation and proliferation. Stimulation of either the TCR or the IL-2 receptor induces an increase in tyrosine phosphorylation of several cellular proteins indicating that signal transduction by both of these receptors involves the activation of a tyrosine protein kinase. Although the tyrosine protein kinases activated by these receptors have not yet been characterized the receptors themselves are known not to contain a tyrosine protein kinase domain. To determine if these receptors are coupled to the activation of similar or distinct tyrosine protein kinases we examined the patterns and kinetics of tyrosine phosphorylation induced by stimulation of these receptors on a cloned cell line. Hut 78.3 cells co-express the TCR and the p75 IL-2 receptor. These cells were stimulated with either OKT3 antibodies, specific for the TCR, or with IL-2. Signal transduction by these receptors was found to increase the tyrosine phosphorylation of a set of proteins unique to each stimulus. The kinetics of the tyrosine phosphorylation induced by OKT3 antibodies also differed from that induced by IL-2. The OKT3-dependent tyrosine phosphorylation reached maximal levels within 2.5 min and began to decline by 5 min after stimulation. In contrast, the IL-2-induced tyrosine phosphorylation did not achieve maximal levels until 15 min after the addition of IL-2 and the proteins remained phosphorylated even after 60 min of incubation. In addition the tyrosine phosphorylations induced by OKT3 and IL-2 were not affected by prior stimulation with the other agent. These results demonstrate that the TCR and IL-2 receptor are coupled to different signal transduction pathways responsible for the independent activation of distinct tyrosine protein kinases.
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A pilot survey of one third-year medical school class was carried out to explore student perceptions of mistreatment and professional misconduct in medical school training. Students were asked to rate the frequency and cite sources of mistreatment and misconduct among classmates, faculty, residents, and interns. They were also asked to assess the effects of such episodes on their physical health, emotional well-being, social and family life, and attitudes toward becoming a physician. The results indicate that students perceive mistreatment (particularly verbal abuse and unfair tactics) to be pervasive and professional misconduct all too common. As many as three fourths of the students report having become more cynical about academic life and the medical profession as a result of these episodes. Two thirds feel they are worse off than their peers in other professions. More than a third have considered dropping out of medical school and one fourth report they would have chosen a different profession had they known in advance about the extent of mistreatment they would experience. Rather than dismiss these problems as isolated events, we need to examine this issue more closely.
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We have molecularly delineated a Drosophila beta-amyloid protein precursor-like (Appl) gene and analyzed its pattern of expression. Appl defines a new locus within the 1B division of the X-chromosome, a region previously shown to be important for neural development. The genomic limits of the Appl gene were defined by mapping of the Appl cDNAs. The Appl transcript spans approximately 38 kb (1 kb = 10(3) base-pairs) of genomic DNA. Genomic regions surrounding the first two exons were sequenced. The first exon contains 78 nucleotides of the coding sequence and is separated from the second exon by a approximately 21 kb intron. The second exon is 171 nucleotides long and is separated from the third exon by a approximately 7 kb intron. We present in situ RNA localization data that demonstrate that the Appl transcript is found in post-mitotic neurons in all developmental stages, in the central and peripheral nervous systems. Within the nervous system transcripts are not observed in neuroblasts, newly generated neurons and at least one class of presumed glial cells. The temporal and spatial specificity of Appl expression suggests that the gene product has a function that is common to most neurons. Appl cDNA predicts an 886-amino acid polypeptide that exhibits strong sequence similarity to the human beta-amyloid protein precursor (APP) (Rosen et al. 1989). In this paper, we compare the Appl gene expression with the pattern of expression of the beta-amyloid protein precursor (APP) gene in mammals. Furthermore, we suggest that during evolution, a neural-specific function encoded by the APP gene has been selectively maintained.