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Biomedical subjects

M Glickman

Publications and source records attributed to M Glickman.

At least 19 recordsLinked to original sources
PubMed2000

Cognitive-behavioral therapy for anxiety disorders: why and how it works.

Cognitive-behavioral therapy (CBT) has been found to be effective in the treatment of anxiety disorders such as obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD). There is a gap, however, between reports of controlled clinical trials and actual clinical use of the methods of CBT in general medical and psychiatric settings. While psychiatric medications are commonly the first line of treatment, pharmacotherapy may not completely eradicate symptomatology or may have a delayed effectiveness, during which time patients continue to suffer. Cognitive and behavioral interventions can complement, if not replace, pharmacotherapy for relief of symptoms of OCD and PTSD. This article explains how CBT works in the treatment of OCD and PTSD. Basic instructions for implementing these treatment methods are provided.

Adult↗
PubMed1999

Molecular cloning, tissue-specific expression, and chromosomal localization of a novel nerve growth factor-regulated G-protein- coupled receptor, nrg-1.

A novel and differentially expressed gene, named nrg-1, was identified by EST expression profiling and subsequently isolated as a 2.2-kb full-length clone from a rat PC12 cell cDNA library. Sequence analysis reveals that nrg-1 encodes a putative seven transmembrane spanning domain protein with structural features characteristic of receptors belonging to the G-protein-coupled receptor gene superfamily. The 400-amino-acid protein encoded by nrg-1 exhibits a high degree of sequence identity (40-44%) to the Edg receptor family; members include Edg-1, Edg-2, Edg-3, Edg-4, and H218. Both Northern analysis andEST expression profiling revealed that whole-tissue distribution of nrg-1 mRNA is restricted, found almost exclusively in brain. Transcripts of nrg-1 could be ubiquitously detected in different regions, with very prominent expression in lower brain regions such as the midbrain, pons,medulla, and spinal cord. In PC12 cells, nerve growth factor induces neuronal differentiation and repressed expression of nrg-1. Two other agents that differentiate PC12 cells, fibroblast growth factor and dibdutyryl cAMP, down-regulated nrg-1 mRNA levels. Epidermal growth factor, and agent that does not induce differentiation, did not repress nrg-1 mRNA levels. In a PC12 cell mutant that is deficient in protein kinase A activity (AB.11), all three differentiating agents were unable to down-regulate nrg-1 mRNA. Hence, protein kinase A appears to be an obligatory cellular component in nrg-1 mRNA regulation. Chromosomal mapping employing a rat somatic cell readiation hybrid panel demonstrated that nrg-1 is linked to marker D8Rat54 and tightly associated with H218 on chromosome 8.

Amino Acid Sequence↗
PubMed1999

Central corticotropin-releasing hormone receptors modulate hypothalamic-pituitary-adrenocortical and sympathoadrenal activity during stress.

The role of brain corticotropin-releasing hormone receptors in modulating hypothalamic-pituitary-adrenal and sympathoadrenal responses to acute immobilization stress was studied in conscious rats under central corticotropin-releasing hormone receptor blockade by intracerebroventricular injection of a peptide corticotropin-releasing hormone receptor antagonist. Blood for catecholamines, adrenocorticotropic hormone and corticosterone levels was collected through vascular catheters, and brains were removed at 3 h for in situ hybridization for tyrosine hydroxylase messenger RNA in the locus coeruleus, and corticotropin-releasing hormone and corticotropin-releasing hormone receptor messenger RNA in the hypothalamic paraventricular nucleus. Central corticotropin-releasing hormone receptor blockade reduced the early increases in plasma epinephrine and dopamine, but not norepinephrine, during stress. Immobilization stress increased tyrosine hydroxylase messenger RNA levels in the locus coeruleus by 36% in controls, but not in corticotropin-releasing hormone antagonist-injected rats. In control rats, corticotropin-releasing hormone messenger RNA and type 1 corticotropin-releasing hormone receptor messenger RNA in the paraventricular nucleus increased after stress (P<0.01), and these responses were attenuated by central corticotropin-releasing hormone receptor blockade. In contrast, central corticotropin-releasing hormone antagonist potentiated plasma adrenocorticotropic hormone responses, but slightly attenuated plasma corticosterone responses to stress. The inhibition of plasma catecholamine and locus coeruleus tyrosine hydroxylase messenger RNA responses to stress by central corticotropin-releasing hormone receptor blockade supports the notion that central corticotropin-releasing hormone regulates sympathoadrenal responses during stress. The attenuation of stress-induced corticotropin-releasing hormone and corticotropin-releasing hormone receptor messenger RNA responses by central corticotropin-releasing hormone receptor blockade suggests direct or indirect positive feedback effects of corticotropin-releasing hormone receptor ligands on corticotropin-releasing hormone expression, whereas additional mechanisms potentiate adrenocorticotropic hormone responses at the pituitary level. In addition, changes in neural activity by central corticotropin-releasing hormone are likely to modulate adrenocortical responsiveness during stress.

Adrenal Cortex↗
PubMed1999

The base of the proteasome regulatory particle exhibits chaperone-like activity.

Protein substrates of the proteasome must apparently be unfolded and translocated through a narrow channel to gain access to the proteolytic active sites of the enzyme. Protein folding in vivo is mediated by molecular chaperones. Here, to test for chaperone activity of the proteasome, we assay the reactivation of denatured citrate synthase. Both human and yeast proteasomes stimulate the recovery of the native structure of citrate synthase. We map this chaperone-like activity to the base of the regulatory particle of the proteasome, that is, to the ATPase-containing assembly located at the substrate-entry ports of the channel. Denatured but not native citrate synthase is bound by the base complex. Ubiquitination of citrate synthase is not required for its binding or refolding by the base complex of the proteasome. These data suggest a model in which ubiquitin-protein conjugates are initially tethered to the proteasome by specific recognition of their ubiquitin chains; this step is followed by a nonspecific interaction between the base and the target protein, which promotes substrate unfolding and translocation.

Adenosine Triphosphate↗
PubMed1998

Inadequate management of blood pressure in a hypertensive population.

BACKGROUND: Many patients with hypertension have inadequate control of their blood pressure. Improving the treatment of hypertension requires an understanding of the ways in which physicians manage this condition and a means of assessing the efficacy of this care. METHODS: We examined the care of 800 hypertensive men at five Department of Veterans Affairs sites in New England over a two-year period. Their mean (+/-SD) age was 65.5+/-9.1 years, and the average duration of hypertension was 12.6+/-5.3 years. We used recursive partitioning to assess the probability that antihypertensive therapy would be increased at a given clinic visit using several variables. We then used these predictions to define the intensity of treatment for each patient during the study period, and we examined the associations between the intensity of treatment and the degree of control of blood pressure. RESULTS: Approximately 40 percent of the patients had a blood pressure of > or =160/90 mm Hg despite an average of more than six hypertension-related visits per year. Increases in therapy occurred during 6.7 percent of visits. Characteristics associated with an increase in antihypertensive therapy included increased levels of both systolic and diastolic blood pressure at that visit (but not previous visits), a previous change in therapy, the presence of coronary artery disease, and a scheduled visit. Patients who had more intensive therapy had significantly (P<0.01) better control of blood pressure. During the two-year period, systolic blood pressure declined by 6.3 mm Hg among patients with the most intensive treatment, but increased by 4.8 mm Hg among the patients with the least intensive treatment. CONCLUSIONS: In a selected population of older men, blood pressure was poorly controlled in many. Those who received more intensive medical therapy had better control. Many physicians are not aggressive enough in their approach to hypertension.

Aged↗
PubMed1998

Multiubiquitin chain binding and protein degradation are mediated by distinct domains within the 26 S proteasome subunit Mcb1.

The 26 S proteasome is a multisubunit proteolytic complex responsible for degrading eukaryotic proteins targeted by ubiquitin modification. Substrate recognition by the complex is presumed to be mediated by one or more common receptor(s) with affinity for multiubiquitin chains, especially those internally linked through lysine 48. We have identified previously a candidate for one such receptor from diverse species, designated here as Mcb1 for Multiubiquitin chain-binding protein, based on its ability to bind Lys48-linked multiubiquitin chains and its location within the 26 S proteasome complex. Even though Mcb1 is likely not the only receptor in yeast, it is necessary for conferring resistance to amino acid analogs and for degrading a subset of ubiquitin pathway substrates such as ubiquitin-Pro-beta-galactosidase (Ub-Pro-beta-gal) (van Nocker, S., Sadis, S., Rubin, D.M., Glickman, M., Fu, H., Coux, O., Wefes, I., Finley, D., and Vierstra, R. D. (1996) Mol. Cell. Biol. 16, 6020-28). To further define the role of Mcb1 in substrate recognition by the 26 S proteasome, a structure/function analysis of various deletion and site-directed mutants of yeast and Arabidopsis Mcb1 was performed. From these studies, we identified a single stretch of conserved hydrophobic amino acids (LAM/LALRL/V (ScMcb1 228-234 and At-Mcb1 226-232)) within the C-terminal half of each polypeptide that is necessary for interaction with Lys48-linked multiubiquitin chains. Unexpectedly, this domain was not essential for either Ub-Pro-beta-gal degradation or conferring resistance to amino acid analogs. The domain responsible for these two activities was mapped to a conserved region near the N terminus. Yeast and Arabidopsis Mcb1 derivatives containing an intact multiubiquitin-binding site but missing the N-terminal region failed to promote Ub-Pro-beta-gal degradation and even accentuated the sensitivity of the yeast delta mcb1 strain to amino acid analogs. This hypersensitivity was not caused by a gross defect in 26 S proteasome assembly as mutants missing either the N-terminal domain or the multiubiquitin chain-binding site could still associate with 26 S proteasome and generate a complex indistinguishable in size from that present in wild-type yeast. Together, these data indicate that residues near the N terminus, and not the multiubiquitin chain-binding site, are most critical for Mcb1 function in vivo.

Amino Acid Sequence↗
PubMed1998

Mennen paraskeletal plate fixation for fracture of the femoral shaft in association with ipsilateral hip arthroplasty.

We reviewed the results of Mennen paraskeletal plate fixation in 14 patients with fracture of the femoral shaft in association with a previously successful ipsilateral hip arthroplasty. Overall good results were obtained with undisplaced fractures but some of the results in those individuals with widely displaced and unstable fractures were disappointing leading to some serious complications including amputation. The paraskeletal plate appears then to be no more than an internal splint and caution needs to be exercised when this device is used in this situation.

Aged↗
PubMed1997

ATPase and ubiquitin-binding proteins of the yeast proteasome.

The 26S proteasome is a 2-Megadalton proteolytic complex with over 30 distinct subunits. The 19S particle, a subcomplex of the 26S proteasome, is thought to confer ATP-dependence and ubiquitin-dependence on the proteolytic core particle of the proteasome. Given the complexity of the 19S particle, genetic approaches are likely to play an important role in its analysis. We have initiated biochemical and genetic studies of the 19S particle in Saccharomyces cerevisiae. Here we describe the localization to the proteasome of several ATPases that were previously proposed to be involved in transcription. Independent studies indicate that the mammalian 26S proteasome contains closely related ATPases. We have also found that the multiubiquitin chain binding protein Mcb1, a homolog of the mammalian S5a protein, is a subunit of the yeast proteasome. However, contrary to expectation, MCB1 is not an essential gene in yeast. The mcb1 mutant grows at a nearly wild-type rate, and the breakdown of most ubiquitin-protein conjugates is unaffected in this strain. One substrate, Ub-Proline-beta gal, was found to require MCB1 for its breakdown, but it remains unclear whether Mcb1 serves as a ubiquitin receptor in this process. Our data suggest that the recognition of ubiquitin conjugates by the proteasome is a complex process which must involve proteins other than Mcb1.

Adenosine Triphosphatases↗
PubMed1996

The multiubiquitin-chain-binding protein Mcb1 is a component of the 26S proteasome in Saccharomyces cerevisiae and plays a nonessential, substrate-specific role in protein turnover.

The 26S proteasome is an essential proteolytic complex that is responsible for degrading proteins conjugated with ubiquitin. It has been proposed that the recognition of substrates by the 26S proteasome is mediated by a multiubiquitin-chain-binding protein that has previously been characterized in both plants and animals. In this study, we identified a Saccharomyces cerevisiae homolog of this protein, designated Mcb1. Mcb1 copurified with the 26S proteasome in both conventional and nickel chelate chromatography. In addition, a significant fraction of Mcb1 in cell extracts was present in a low-molecular-mass form free of the 26S complex. Recombinant Mcb1 protein bound multiubiquitin chains in vitro and, like its plant and animal counterparts, exhibited a binding preference for longer chains. Surprisingly, (delta)mcb1 deletion mutants were viable, grew at near-wild-type rates, degraded the bulk of short-lived proteins normally, and were not sensitive to UV radiation or heat stress. These data indicate that Mcb1 is not an essential component of the ubiquitin-proteasome pathway in S.cerevisiae. However, the (delta)mcb1 mutant exhibited a modest sensitivity to amino acid analogs and had increased steady-state levels of ubiquitin-protein conjugates. Whereas the N-end rule substrate, Arg-beta-galactosidase, was degraded at the wild-type rate in the (delta)mcb1 strain, the ubiquitin fusion degradation pathway substrate, ubiquitin-Pro-beta-galactosidase, was markedly stabilized. Collectively, these data suggest that Mcb1 is not the sole factor involved in ubiquitin recognition by the 26S proteasome and that Mcb1 may interact with only a subset of ubiquitinated substrates.

Amino Acid Sequence↗
PubMed1994

What makes general practitioners do child health surveillance?

The contribution of different general practitioner characteristics, views, and experiences to the likelihood of their providing child health surveillance (CHS) was determined and their perceived training needs discovered. Family health service authority administrative data on the study population was combined with a postal questionnaire survey. Subjects were all general practitioners in three district health authorities in the North West Thames region. There were striking differences between districts in the proportion of practitioners undertaking CHS. General practitioners with paediatric training were three times more likely to do CHS. Women doctors were twice as likely to do CHS as men. The personal views of general practitioners were significantly associated with whether or not they undertook CHS. The CHS fee did not appear to be the major motivating factor. There was considerable demand for further training. The proportion of general practitioners undertaking CHS is likely to increase with the proportion of women and vocationally trained doctors. More local training is wanted, both by general practitioners already doing CHS and by those who would like to do it. Health authorities need to ensure that such training is convenient and continuing.

Adult↗
PubMed1993

Antibody-catalyzed degradation of cocaine.

Immunization with a phosphonate monoester transition-state analog of cocaine provided monoclonal antibodies capable of catalyzing the hydrolysis of the cocaine benzoyl ester group. An assay for the degradation of radiolabeled cocaine identified active enzymes. Benzoyl esterolysis yields ecgonine methyl ester and benzoic acid, fragments devoid of cocaine's stimulant activity. Passive immunization with such an artificial enzyme could provide a treatment for dependence by blunting reinforcement.

Animals↗
PubMed1993

Cooperation or conflict over child health surveillance? Views of key actors.

OBJECTIVE: To describe the views of general practitioners, health visitors, and clinical medical officers on child health surveillance, recent changes, perceptions of each other's roles, and attitudes to audit. DESIGN: Postal questionnaire survey. SETTING: Three health districts in North West Thames health region. SUBJECTS: All 602 general practitioners, 272 health visitors, and 42 clinical medical officers in these districts. MAIN MEASURES: Attitudes to and perceptions of child health surveillance and audit. Questionnaires were completed by 440 general practitioners (response rate 73%), 164 health visitors (60%), and 39 clinical medical officers (93%). RESULTS: Attitudes to child health surveillance were less positive among general practitioners than health visitors or clinical medical officers. Few respondents agreed that child health surveillance was a cost effective use of general practitioners' time (general practitioners 28%, 113/407; health visitors 28%, 40/145; clinical medical officers 39%, 15/39) and most thought that health visitors should carry out more of the doctors' examinations (68%, 262/387; 65%, 89/136; 66%, 25/38). General practitioners thought that clinical medical officers were less supportive than other relevant groups of their doing more child health surveillance. Most (72%, 105/146) health visitors thought that the 1990 contract had reduced parental choice of where to attend for child health surveillance. General practitioners were less enthusiastic than health visitors about most forms of clinical audit. CONCLUSIONS: Despite reservations about the impact of recent changes all groups were willing to explore innovative ways of delivering child health surveillance. IMPLICATIONS: There is scope for health visitors to increase their responsibilities and for more varied relationships between general practitioners and community child health doctors.

Attitude of Health Personnel↗
PubMed1991

Epidemiological use of NHS activity data.

The primary purpose of the medical record is to support clinical care of patients by keeping an accurate record of their condition and of treatment given or planned; its second role is as a source of information for management; but its uses do not end there. Both the medical record itself, and information derived from it at one or more removes, are important tools in medical research, audit and evaluation of services. This paper describes the use of routine NHS activity data in general, and the medical record in particular, in epidemiology. As the author works at the Institute of Child Health, most of the examples cited involve children.

Child↗