Showing papers by "University of California, San Francisco published in 1990"

Grounded Theory Research: Procedures, Canons and Evaluative Criteria

Abstract: Using grounded theory as an example, this paper examines three methodological questions that are generally applicable to all qualitative methods. How should the usual scientific canons be reinterpreted for qualitative research? How should researchers report the procedures and canons used in their research? What evaluative criteria should be used in judging the research products? We propose that the criteria should be adapted to fit the procedures of the method. We demonstrate how this can be done for grounded theory and suggest criteria for evaluating studies following this approach. We argue that other qualitative researchers might be similarly specific about their procedures and evaluative criteria.

Caregiving and the Stress Process: An Overview of Concepts and Their Measures

Abstract: This paper views caregiver stress as a consequence of a process comprising a number of interrelated conditions, including the socioeconomic characteristics and resources of caregivers and the primary and secondary stressors to which they are exposed. Primary stressors are hardships and problems anchored directly in caregiving. Secondary stressors fall into two categories: the strains experienced in roles and activities outside of caregiving, and intrapsychic strains, involving the diminishment of self-concepts. Coping and social support can potentially intervene at multiple points along the stress process.

Dominant forces in protein folding

Abstract: T e purpose of this review is to assess the nature and magnitudes of the dominant forces in protein folding. Since proteins are only marginally stable at room temperature,’ no type of molecular interaction is unimportant, and even small interactions can contribute significantly (positively or negatively) to stability (Alber, 1989a,b; Matthews, 1987a,b). However, the present review aims to identify only the largest forces that lead to the structural features of globular proteins: their extraordinary compactness, their core of nonpolar residues, and their considerable amounts of internal architecture. This review explores contributions to the free energy of folding arising from electrostatics (classical charge repulsions and ion pairing), hydrogen-bonding and van der Waals interactions, intrinsic propensities, and hydrophobic interactions. An earlier review by Kauzmann (1959) introduced the importance of hydrophobic interactions. His insights were particularly remarkable considering that he did not have the benefit of known protein structures, model studies, high-resolution calorimetry, mutational methods, or force-field or statistical mechanical results. The present review aims to provide a reassessment of the factors important for folding in light of current knowledge. Also considered here are the opposing forces, conformational entropy and electrostatics. The process of protein folding has been known for about 60 years. In 1902, Emil Fischer and Franz Hofmeister independently concluded that proteins were chains of covalently linked amino acids (Haschemeyer & Haschemeyer, 1973) but deeper understanding of protein structure and conformational change was hindered because of the difficulty in finding conditions for solubilization. Chick and Martin (191 1) were the first to discover the process of denaturation and to distinguish it from the process of aggregation. By 1925, the denaturation process was considered to be either hydrolysis of the peptide bond (Wu & Wu, 1925; Anson & Mirsky, 1925) or dehydration of the protein (Robertson, 1918). The view that protein denaturation was an unfolding process was

Atomic charges derived from semiempirical methods

Abstract: It is demonstrated that semiempirical methods give electrostatic potential (ESP) derived atomic point charges that are in reasonable agreement with ab initio ESP charges. Furthermore, we find that MNDO ESP charges are superior to AM1 ESP charges in correlating with ESP charges derived from the 6-31G* basis set. Thus, it is possible to obtain 6-31G* quality point charges by simply scaling MNDO ESP charges. The charges are scaled in a linear (y = Mx) manner to conserve charge. In this way researchers desiring to carry out force field simulations or minimizations can obtain charges by using MNDO, which requires much less computer time than the corresponding 6-31G* calculation.

The GTPase superfamily: a conserved switch for diverse cell functions

Abstract: Proteins that bind and hydrolyse GTP are being discovered at a rapidly increasing rate. Each of these many GTPases acts as a molecular switch whose 'on' and 'off' states are triggered by binding and hydrolysis of GTP. Conserved structure and mechanism in myriad versions of the switch--in bacteria, yeast, flies and vertebrates--suggest that all derive from a single primordial protein, repeatedly modified in the course of evolution to perform a dazzling variety of functions.

Structural design and molecular evolution of a cytokine receptor superfamily.

Abstract: A family of cytokine receptors comprising molecules specific for a diverse group of hematopoietic factors and growth hormones has been principally defined by a striking homology of binding domains. This work proposes that the approximately 200-residue binding segment of the canonical cytokine receptor is composed of two discrete folding domains that share a significant sequence and structural resemblance. Analogous motifs are found in tandem approximately 100-amino acid domains in the extracellular segments of a receptor family formed by the interferon-alpha/beta and -gamma receptors and tissue factor, a membrane tether for a coagulation protease. Domains from the receptor supergroup reveal clear evolutionary links to fibronectin type III structures, approximately 90-amino acid modules that are typically found in cell surface molecules with adhesive functions. Predictive structural analysis of the shared receptor and fibronectin domains locates seven beta-strands in conserved regions of the chain; these strands are modeled to fold into antiparallel beta-sandwiches with a topology that is similar to immunoglobulin constant domains. These findings have strong implications for understanding the evolutionary emergence of an important class of regulatory molecules from primitive adhesive modules. In addition, the resulting double-barrel design of the receptors and the spatial clustering of conserved residues suggest a likely binding site for cytokine ligands.

Early detection of regional cerebral ischemia in cats: comparison of diffusion- and T2-weighted MRI and spectroscopy.

Abstract: Diffusion-weighted MR images were compared with T2-weighted MR images and correlated with 1H spin-echo and 31P MR Spectroscopy for 6-8 h following a unilateral middle cerebral and bilateral carotid artery occlusion in eight cats. Diffusion-weighted images using strong gradient strengths (b values of 1413 s/mm2) displayed a significant relative hyperintensity in ischemic regions as early as 45 min after onset of ischemia whereas T2-weighted spin-echo images failed to clearly demonstrate brain injury up to 2-3 h postocclusion. Signal intensity ratios (SIR) of ischemic to normal tissues were greater in the diffusion-weighted images at all times than in either TE 80 or TE 160 ms T2-weighted MR images. Diffusion- and T2-weighted SIR did not correlate for the first 1-2 h postocclusion. Good correlation was found between diffusion-weighted SIR and ischemic disturbances of energy metabolism as detected by 31P and 1H MR Spectroscopy. Diffusion-weighted hyperintensity in ischemic tissues may be temperature-related, due to rapid accumulation of diffusion-restricted water in the intracellular space (cytotoxic edema) resulting from the breakdown of the transmembrane pump and/or to microscopic brain pulsations. © 1990 Academic Press, Inc.

Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase.

Abstract: The pancreatic islet β-cell autoantigen of relative molecular mass 64,000 (64K), which is a major target of autoantibodies associated with the development of insulin-dependent diabetes mel-litus (IDDM) has been identified as glutamic acid decarboxylase, the biosynthesizing enzyme of the inhibitory neurotransmitter GABA (γ-aminobutyric acid). Pancreatic β cells and a subpopulation of central nervous system neurons express high levels of this enzyme. Autoantibodies against glutamic acid decarboxylase with a higher titre and increased epitope recognition compared with those usually associated with IDDM are found in stiff-man syndrome, a rare neurological disorder characterized by a high coincidence with IDDM.

A class I antigen, HLA-G, expressed in human trophoblasts.

Abstract: The alpha chain of the human histocompatibility antigen HLA-G was identified as an array of five 37- to 39-kilodalton isoforms by the use of two-dimensional gel electrophoresis. Both cell-associated and secreted HLA-G antigens are prominent in first trimester villous cytotrophoblasts and are greatly reduced in third trimester cytotrophoblasts. Allelic variation was not detected, an indication that HLA-G is not obviously polymorphic in cytotrophoblasts. Among the following choriocarcinoma cell lines studied, HLA-G is expressed in JEG but not in Jar or BeWo. Expression of endogenous HLA-G genes has not been found in normal lymphoid cells. Thus, HLA-G is subject to both cell type-specific and developmental regulation and is expressed in early gestation human cytotrophoblasts.

Interaction of Hsp 70 with newly synthesized proteins: implications for protein folding and assembly

Abstract: The 70-kilodalton family of heat shock proteins (Hsp 70) has been implicated in posttranslational protein assembly and translocation. Binding of cytosolic forms of Hsp 70 (Hsp 72,73) with nascent proteins in the normal cell was investigated and found to be transient and adenosine triphosphate (ATP)-dependent. Interaction of Hsp 72,73 with newly synthesized proteins appeared to occur cotranslationally, because nascent polypeptides released prematurely from polysomes in vivo can be isolated in a complex with Hsp 72,73. Moreover, isolation of polysomes from short-term [35S]Met-labeled cells (pulsed) revealed that Hsp 72,73 associated with nascent polypeptide chains. In cells experiencing stress, newly synthesized proteins coimmunoprecipitated with Hsp 72,73; however, in contrast to normal cells, interaction with Hsp 72,73 was not transient. A model consistent with these data suggests that under normal growth conditions, cytosolic Hsp 72,73 interact transiently with nascent polypeptides to facilitate proper folding, and that metabolic stress interferes with these events.

Transcription factor interactions: selectors of positive or negative regulation from a single DNA element.

Abstract: The mechanism by which a single factor evokes opposite regulatory effects from a specific DNA sequence is not well understood. In this study, a 25-base pair element that resides upstream of the mouse proliferin gene was examined; it conferred on linked promoters either positive or negative glucocorticoid regulation, depending upon physiological context. This sequence, denoted a "composite" glucocorticoid response element (GRE), was bound selectively in vitro both by the glucocorticoid receptor and by c-Jun and c-Fos, components of the phorbol ester-activated AP-1 transcription factor. Indeed, c-Jun and c-Fos served as selectors of hormone responsiveness: the composite GRE was inactive in the absence of c-Jun, whereas it conferred a positive glucocorticoid effect in the presence of c-Jun, and a negative glucocorticoid effect in the presence of c-Jun and relatively high levels of c-Fos. The receptor also interacted selectively with c-Jun in vitro. A general model for composite GRE action is proposed that invokes both DNA binding and protein-protein interactions by receptor and nonreceptor factors.

Diffusion-weighted MR imaging of anisotropic water diffusion in cat central nervous system.

Abstract: The diffusion behavior of intracranial water in the cat brain and spine was examined with the use of diffusion-weighted magnetic resonance (MR) imaging, in which the direction of the diffusion-sensitizing gradient was varied between the x, y, and z axes of the magnet. At very high diffusion-sensitizing gradient strengths, no clear evidence of anisotropic water diffusion was found in either cortical or subcortical (basal ganglia) gray matter. Signal intensities clearly dependent on orientation were observed in the cortical and deep white matter of the brain and in the white matter of the spinal cord. Greater signal attenuation (faster diffusion) was observed when the relative orientation of white matter tracts to the diffusion-sensitizing gradient was parallel as compared to that obtained with a perpendicular alignment. These effects were seen on both premortem and immediate postmortem images obtained in all axial, sagittal, and coronal views. Potential applications of this MR imaging technique included the stereospecific evaluation of white matter in the brain and spinal cord and in the characterization of demyelinating and dysmyelinating diseases.

Zidovudine in Asymptomatic Human Immunodeficiency Virus Infection: A Controlled Trial in Persons with Fewer Than 500 CD4-Positive Cells per Cubic Millimeter

Abstract: Zidovudine (AZT) is a potent inhibitor of the replication of the human immunodeficiency virus (HIV), and it has been shown to improve survival in advanced HIV disease. We conducted a randomized, double-blind trial in adults with asymptomatic HIV infection who had CD4+ cell counts of fewer than 500 per cubic millimeter on entry into the study. The subjects (92 percent male) were randomly assigned to one of three treatment groups: placebo (428 subjects); zidovudine, 500 mg per day (453); or zidovudine, 1500 mg per day (457). After a mean follow-up of 55 weeks (range, 19 to 107), 33 of the subjects assigned to placebo had the acquired immunodeficiency syndrome (AIDS), as compared with 11 of those assigned to receive 500 mg of zidovudine (P = 0.002; relative risk, 2.8; 95 percent confidence interval, 1.4 to 5.6) and 14 of those assigned to receive 1500 mg of zidovudine (P = 0.05; relative risk, 1.9; 95 percent confidence interval, 1.0 to 3.5). In the three treatment groups, the rates of progression (per 100 person-years) to either AIDS or advanced AIDS-related complex were 7.6, 3.6, and 4.3, respectively. As compared with those assigned to placebo, the subjects in the zidovudine groups had significant increases in the number of CD4+ cells and significant declines in p24 antigen levels. In the 1500-mg zidovudine group, severe hematologic toxicity (anemia or neutropenia) was more frequent than in the other groups (P less than 0.0001). In the 500-mg zidovudine group, nausea was the only toxicity that was significantly more frequent (in 3.3 percent) than in the placebo group (P = 0.001). We conclude that zidovudine is safe and effective in persons with asymptomatic HIV infection and fewer than 500 CD4+ cells per cubic millimeter. Additional study will be required to determine whether such treatment will ultimately improve survival for persons infected with HIV.

Voluntary facial action generates emotion-specific autonomic nervous system activity.

Abstract: Four experiments were conducted to determine whether voluntarily produced emotional facial configurations are associated with differentiated patterns of autonomic activity, and if so, how this might be mediated. Subjects received muscle-by-muscle instructions and coaching to produce facial configurations for anger, disgust, fear, happiness, sadness, and surprise while heart rate, skin conductance, finger temperature, and somatic activity were monitored. Results indicated that voluntary facial activity produced significant levels of subjective experience of the associated emotion, and that autonomic distinctions among emotions: (a) were found both between negative and positive emotions and among negative emotions, (b) were consistent between group and individual subjects' data, (c) were found in both male and female subjects, (d) were found in both specialized (actors, scientists) and nonspecialized populations, (e) were stronger when the voluntary facial configurations most closely resembled actual emotional expressions, and (f) were stronger when experience of the associated emotion was reported. The capacity of voluntary facial activity to generate emotion-specific autonomic activity: (a) did not require subjects to see facial expressions (either in a mirror or on an experimenter's face), and (b) could not be explained by differences in the difficulty of making the expressions or by differences in concomitant somatic activity.

Perioperative Cardiac Morbidity

Abstract: Ischemic heart disease (IHD) can be complex in its clinical presentation. The patient with IHD usually has one of the many symptom complexes associated with varying degrees of ventricular dysfunction. As anesthesiologists, our assessment of a patient with IHD presenting for surgery is usually conducted over a very brief period of time and, therefore, requires a rather intense assessment of the patient’s cardiac status. Several other factors add to the difficulties involved in this assessment: 1) The age of the population presenting for surgery is increasing; 2) surgical procedures are becoming more complex; and 3) cost containment procedures will limit the number and type of preoperative tests used to assess risk in patients with IHD, and there will be increasing pressure on us to expedite such an assessment (e.g., come-and-go, come-and-stay surgery). Thus, more than ever, we must know what specific tests are available for assessment of these patients and what information we can obtain from these tests to determine perioperative risk, preoperative therapeutics, intraoperative monitoring, choice of anesthetic, and postoperative care.

Two G protein oncogenes in human endocrine tumors

Abstract: Somatic mutations in a subset of growth hormone (GH)-secreting pituitary tumors convert the gene for the alpha polypeptide chain (alpha s) of Gs into a putative oncogene, termed gsp. These mutations, which activate alpha s by inhibiting its guanosine triphosphatase (GTPase) activity, are found in codons for either of two amino acids, each of which is completely conserved in all known G protein alpha chains. The likelihood that similar mutations would activate other G proteins prompted a survey of human tumors for mutations that replace either of these two amino acids in other G protein alpha chain genes. The first gene so far tested, which encodes the alpha chain of Gi2, showed mutations that replaced arginine-179 with either cysteine or histidine in 3 of 11 tumors of the adrenal cortex and 3 of 10 endocrine tumors of the ovary. The mutant alpha i2 gene is a putative oncogene, referred to as gip2. In addition, gsp mutations were found in 18 of 42 GH-secreting pituitary tumors and in an autonomously functioning thyroid adenoma. These findings suggest that human tumors may harbor oncogenic mutations in various G protein alpha chain genes.

Towards an Understanding of Risk Behavior: An AIDS Risk Reduction Model (ARRM)

Abstract: This report presents a three-stage model (ARRM) that characterize people's efforts to change sexual behaviors related to HIV transmission. ARRM focuses on social and psychological factors hypothesized to influence (1) labeling of high risk behaviors as problematic, (2) making a commitment to changing high risk behaviors, and (3) seeking and enacting solutions directed at reducing high risk activities. The proposed model integrates important concepts from prior behavioral medicine and human sexuality studies, specifies their differential import to achieving the goals associated with each stage of the model, and denotes factors hypothesized to influence people's motivation to continue the change process over time. Current findings are discussed within this three-stage model and directions for further research are suggested. Recent findings from our ongoing studies of gays and heterosexuals in San Francisco are presented.

Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. The Study of Perioperative Ischemia Research Group

Abstract: Background. Adverse cardiac events are a major cause of morbidity and mortality after noncardiac surgery. It is necessary to determine the predictors of these outcomes in order to focus efforts on prevention and treatment. Patients undergoing noncardiac surgery sometimes have postoperative cardiac events. It would be helpful to know which patients are at highest risk. Methods. We prospectively studied 474 men with coronary artery disease (243) or at high risk for it (231) who were undergoing elective noncardiac surgery. We gathered historical, clinical, laboratory, and physiologic data during hospitalization and for 6 to 24 months after surgery. Myocardial ischemia was assessed by continuous electrocardiographic monitoring, beginning two days before surgery and continuing for two days after. Results. Eighty-three patients (18 percent) had postoperative cardiac events in the hospital that were classified as ischemic events (cardiac death, myocardial infarction, or unstable angina) (15 patients), c...

Appendicular bone density and age predict hip fracture in women. The Study of Osteoporotic Fractures Research Group.

Abstract: To determine whether measurement of bone density predicts hip fracture in women, we prospectively studied 9703 nonblack women aged 65 years and older who had measurements of bone mineral density using single-photon absorptiometry in the calcaneus, distal radius, and proximal radius. During an average of 1.6 years of follow-up, 53 hip fractures occurred. The risk of hip fracture was inversely related to bone density at all three measurement sites. After adjusting for age, the relative risk of hip fracture was 1.66 for a decrease of 1 SD in the bone density at the calcaneus (95% confidence interval, 1.22 to 2.26), 1.55 (95% confidence interval, 1.13 to 2.11) at the distal radius, and 1.41 (95% confidence interval, 1.06 to 1.88) at the proximal radius. None of the three measurements was a significantly better predictor of hip fracture than the others. After adjusting for bone mineral density, the risk of hip fracture doubled for each 10-year increase in age (relative risk, 2.09; 95% confidence interval, 1.31 to 3.33). We conclude that decreased bone density in the appendicular skeleton is associated with an increased risk of hip fracture, but this accounts for only part of the age-related increase in risk of hip fracture among older women. ( JAMA . 1990;263:665-668)

Noninvasive estimation of right atrial pressure from the inspiratory collapse of the inferior vena cava.

Abstract: To evaluate a simple noninvasive means of estimating right atrial (RA) pressure, the respiratory motion of the inferior vena cava (IVC) was analyzed by 2-dimensional echocardiography in 83 patients. Expiratory and inspiratory IVC diameters and percent collapse (caval index) were measured in subcostal views within 2 cm of the right atrium. Parameters were correlated with RA pressure by flotation catheter within 24 hours of the echocardiogram (38 were simultaneous). Correlations between RA pressure (range 0 to 28 mm Hg), expiratory and inspiratory diameters and caval index were 0.48, 0.71 and 0.75, respectively. Of 48 patients with caval indexes less than 50%, 41 (89%) had RA pressure greater than or equal to 10 mm Hg (mean +/- standard deviation, 15 +/- 6), while 30 of 35 patients (86%) with caval indexes greater than or equal to 50% had RA pressure less than 10 mm Hg (mean 6 +/- 5). Sensitivity and specificity for discrimination of RA pressure greater than or equal to or less than 10 mm Hg were maximized at the 50% level of collapse. Thus, IVC respiratory collapse on echocardiography is easily imaged and can be used to estimate RA pressure. A caval index greater than or equal to 50% indicates RA pressure less than 10 mm Hg, and caval indexes less than 50% indicate RA pressure greater than or equal to 10 Hg.

Diffusion-weighted MR imaging of acute stroke: correlation with T2-weighted and magnetic susceptibility-enhanced MR imaging in cats.

Abstract: We evaluated the temporal and anatomic relationships between changes in diffusion-weighted MR image signal intensity, induced by unilateral occlusion of the middle cerebral artery in cats, and tissue perfusion deficits observed in the same animals on T2-weighted MR images after administration of a nonionic intravascular T2 shortening agent. Diffusion-weighted images obtained with strong diffusion-sensitizing gradient strengths (5.6 gauss/cm, corresponding to gradient attenuation factor, b, values of 1413 sec/mm2) displayed increased signal intensity in the ischemic middle cerebral artery territory less than 1 hr after occlusion, whereas T2-weighted images without contrast usually failed to detect injury for 2-3 hr after stroke. After contrast administration (0.5-1.0 mmol/kg by Dy-DTPA-BMA, IV), however, T2-weighted images revealed perfusion deficits (relative hyperintensity) within 1 hr after middle cerebral artery occlusion that corresponded closely to the anatomic regions of ischemic injury shown on diffusion-weighted MR images. Close correlations were also found between early increases in diffusion-weighted MR image signal intensity and disrupted phosphorus-31 and proton metabolite levels evaluated with surface coil MR spectroscopy, as well as with postmortem histopathology. These data indicate that diffusion-weighted MR images more accurately reflect early-onset pathophysiologic changes induced by acute cerebral ischemia than do T2-weighted spin-echo images.

Functional reorganization of primary somatosensory cortex in adult owl monkeys after behaviorally controlled tactile stimulation

Abstract: 1. Multiple microelectrode maps of the hand representation within and across the borders of cortical area 3b were obtained before, immediately after, or several weeks after a period of behaviorally controlled hand use. Owl monkeys were conditioned in a task that produced cutaneous stimulation of a limited sector of skin on the distal phalanges of one or more fingers. 2. Analysis of microelectrode mapping experiment data revealed that 1) stimulated skin surfaces were represented over expanded cortical areas. 2) Most of the cutaneous receptive fields recorded within these expanded cortical representational zones were unusually small. 3) The internal topography of representation of the stimulated and immediately surrounding skin surfaces differed greatly from that recorded in control experiments. Representational discontinuities emerged in this map region, and "hypercolumn" distances in this map sector were grossly abnormal. 4) Borders between the representations of individual digits and digit segments commonly shifted. 5) The functionally defined rostral border of area 3b shifted farther rostralward, manifesting either an expansion of the cutaneous area 3b fingertip representation into cortical field 3a or an emergence of a cutaneous input zone in the caudal aspect of this normally predominantly deep-receptor representational field. 6) Significant lateralward translocations of the borders between the representations of the hand and face were recorded in all cases. 7) The absolute locations--and in some cases the areas or magnifications--of representations of many skin surfaces not directly involved in the trained behavior also changed significantly. However, the most striking areal, positional, and topographic changes were related to the representations of the behaviorally stimulated skin in every studied monkey. 3. These experiments demonstrate that functional cortical remodeling of the S1 koniocortical field, area 3b, results from behavioral manipulations in normal adult owl monkeys. We hypothesize that these studies manifest operation of the basic adaptive cortical process(es) underlying cortical contributions to perception and learning.

Structure and variability of human chromosome ends.

Abstract: Mammalian telomeres are thought to be composed of a tandem array of TTAGGG repeats. To further define the type and arrangement of sequences at the ends of human chromosomes, we developed a direct cloning strategy for telomere-associated DNA. The method involves a telomere enrichment procedure based on the relative lack of restriction endonuclease cutting sites near the ends of human chromosomes. Nineteen (TTAGGG)n-bearing plasmids were isolated, two of which contain additional human sequences proximal to the telomeric repeats. These telomere-flanking sequences detect BAL 31-sensitive loci and thus are located close to chromosome ends. One of the flanking regions is part of a subtelomeric repeat that is present at 10 to 25% of the chromosome ends in the human genome. This sequence is not conserved in rodent DNA and therefore should be a helpful tool for physical characterization of human chromosomes in human-rodent hybrid cell lines; some of the chromosomes that may be analyzed in this manner have been identified, i.e., 7, 16, 17, and 21. The minimal size of the subtelomeric repeat is 4 kilobases (kb); it shows a high frequency of restriction fragment length polymorphisms and undergoes extensive de novo methylation in somatic cells. Distal to the subtelomeric repeat, the chromosomes terminate in a long region (up to 14 kb) that may be entirely composed of TTAGGG repeats. This terminal segment is unusually variable. Although sperm telomeres are 10 to 14 kb long, telomeres in somatic cells are several kilobase pairs shorter and very heterogeneous in length. Additional telomere reduction occurs in primary tumors, indicating that somatic telomeres are unstable and may continuously lose sequences from their termini.

Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens.

Abstract: We conducted a randomized, controlled trial in 72 patients with heterozygous familial hypercholesterolemia to test whether reducing plasma low-density lipoprotein levels by diet and combined drug regimens can induce regression of coronary lesions. Four hundred fifty-seven lesions were measured before and after a 26-month interval by computer-based quantitative angiography. The primary outcome variable was within-patient mean change in percent area stenosis. Mean low-density lipoprotein cholesterol levels decreased from 7.32 +/- 1.5 to 4.45 +/- 1.6 mmol/L. The mean change in percent area stenosis among controls was +0.80, indicating progression, while the mean change for the treatment group was -1.53, indicating regression (P = .039 by two-tailed t test for the difference between groups). Regression among women, analyzed separately, was also significant. The change in percent area stenosis was correlated with low-density lipoprotein levels on trial. We conclude that reduction of low-density lipoprotein cholesterol levels can induce regression of atherosclerotic lesions of the coronary arteries in patients with familial hypercholesterolemia. The anticipation of benefit from treatment applies to women and men alike.

Functional comparison of neurotransmitter receptor subtypes in mammalian central nervous system

Abstract: Nos connaissances actuelles concernant les effets physiologiques des neurotransmetteurs au niveau du systeme nerveux central sont le resultat des etudes in vitro realisees sur des coupes de cerveau et sur des cultures cellulaires. Ce travail resume et analyse ces investigations

Reduced levels of hsp90 compromise steroid receptor action in vivo

Abstract: Signalling by steroid hormones is mediated by receptor proteins that bind hormonal ligands and regulate the transcription of specific genes. The heat-shock protein hsp90 seems to associate selectively with unliganded receptors (aporeceptors), but it has not been determined whether this interaction affects receptor function in vivo. To address the role of hsp90, we have taken advantage of the capacity of mammalian steroid receptors to function in yeast. We constructed a strain of Saccharomyces cerevisiae in which hsp90 expression was regulatable and could be reduced more than 20-fold relative to wild type. At low levels of hsp90, aporeceptors seem to be mostly hsp90-free, yet fail to enhance transcription; on hormone addition, the receptors are activated but with markedly reduced efficiency. Thus hsp90 does not inhibit receptor function solely by steric interference; rather, hsp90 seems to facilitate the subsequent response of the aporeceptor to the hormonal signal. This is the first biological evidence that hsp90 acts in the signal transduction pathway for steroid receptors.