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Biomedical subjects

M Marshall

Publications and source records attributed to M Marshall.

At least 109 records · Page 6Linked to original sources
PubMed1996

Insulin like growth factor-binding protein-1 as a marker for hyperinsulinemia in obese menopausal women.

Hyperinsulinemia, a manifestation of insulin resistance, precursor of non-insulin dependent diabetes mellitus (NIDDM) and the hallmark of Syndrome X was assessed in 27 obese post-menopausal women. Insulin-like growth factor binding protein-1 (IGFBP-1), which had been shown previously to correlate inversely with insulin in animal and human studies, was evaluated as a diagnostic marker for abnormal glucose stimulated area under the curve (AUC) insulin (defined a priori as > or = 100 microU/ml). We performed analysis of variance and logistic regression to assess IGFBP-1 and other study covariates, including body mass index, blood pressure, lipids and measures of glucose and insulin in hyperinsulinemic vs. normal women and evaluated performance characteristics (sensitivity, specificity, positive and negative predictive values and accuracy rates). The mean IGFBP-1 was 6.1 ng/ml (95% confidence interval (CI) 3.1 to 8.9) for the hyper-insulinemic women compared to 33.5 ng/ml (CI 15.8 to 51.2) for normal women (P = .0027). At a cutoff point of 15ng/ml, which was selected to correspond to the lower 95% confidence limit for the normal study population, IGFBP-1 was abnormal in all 13 women with hyperinsulinemia and 4 women with normal insulin levels (sensitivity 100%, specificity 69%; positive predictive value 76%, negative predictive value 100%, diagnostic accuracy rate 85%). Logistic regression models indicated that, of all study covariates, IGFBP-1 was the best predictor variable for AUC-insulin as a binary dependent variable. These results suggest that IGFBP-1 may be a simple serum marker for hyperinsulinemia in a subpopulation of obese menopausal women.

Biomarkers↗
PubMed1995

Identification of the sites of interaction between c-Raf-1 and Ras-GTP.

Specific sites of protein-protein interaction were identified in the 51-149 region of c-Raf-1 using contact epitope scanning and site-directed mutagenesis. Nineteen overlapping peptides based upon the primary sequence of the Ras binding domain of c-Raf-1 were tested for the ability to competitively inhibit complex formation between Ras-GTP and the c-Raf-1 N-terminus. A peptide containing c-Raf-1 residues 91-105 as well as five overlapping peptides covering a region extending from residues 118 to 143 interfered with Ras association, defining these sites as potential contact surfaces with Ras. Alanine scanning mutagenesis was used as a second probe for sites of Ras interaction with the c-Raf-1 N-terminus. Raf residues 64-67 and 80-103 were demonstrated as important for association with Ras-GTP with residues 66, 67, 84, 87, 89 and 91 identified as the most critical individual points of contact with the Ras protein. Alanine substitution of residues between 118-143 suggested only one potentially weak site of interaction defined by residues 120-125. The combined results of both peptide and mutagenic analyses suggest that the primary site of c-Raf-1 interaction with Ras maps to Raf residues 80-103, with secondary interactions occurring with residues 66 and 67 and possibly 120-125. Contact epitope scanning of the Ras effector region found maximum inhibition of Ras/Raf association with a peptide corresponding to Ras amino acids 37-51. A model is proposed for the GTP-dependent association of Ras and Raf.

Amino Acid Sequence↗
PubMed1995

Social services case-management for long-term mental disorders: a randomised controlled trial.

Case management arose in the USA as a solution to the difficulties of providing community care to people with severe mental disorders. The basic principle of the approach is that a case manager takes responsibility for a client; arranges an assessment of need, a comprehensive service plan, delivery of suitable services, and monitoring and assessment of services delivered. The case-management approach has been widely accepted, to the extent that recent legislation has made case-management the cornerstone of community care in the UK. We did a randomised controlled trial to evaluate a social services case-management team for people with long-term mental disorders. Subjects were referred from hostels for the homeless, night shelters, a general-practitioner clinic for the homeless, the Oxford City Council homelessness unit, and local voluntary-sector group homes. Of 103 subjects referred, 80 consented to be randomised to treatment or control groups. At 14-month follow-up, as assessed by standardised interviews, there were no significant differences between groups in number of needs, quality of life, employment status, quality of accommodation, social behaviour, or severity of psychiatric symptoms. In the case-management group there was a significant reduction in deviant behaviour on a standardised behaviour rating scale (REHAB) (mean = 0.79; 95% CI 0.26-1.32). It is unfortunate, in view of the limited effectiveness we have shown, that social services case-management was not evaluated in randomised controlled trials before its implementation in the UK.

Adult↗
PubMed1995

Why do so few patients appeal against detention under Section 2 of the Mental Health Act?

OBJECTIVE: To determine why most patients do not exercise their right of appeal against detention under section 2 of the Mental Health Act 1983. DESIGN: Part one--retrospective analysis of the clinical notes of patients detained under section 2 of the Mental Health Act. Part two-interviews with patients on the penultimate day before the deadline for lodging an appeal. SETTING: In part one, five districts in the Oxfordshire Regional Health Authority. In part two, six hospitals from three districts in the region. SUBJECTS: In part one all patients detained under section 2 in the five districts in 1993 (n = 418). In part two interviews with 40 patients detained under section 2 in the six hospitals. RESULTS: Patients were more likely to appeal if they were educated to A level standard (odds = 2.26; P = 0.0014) or had had a previous admission (2.19, P = 0.0029). Patients with a diagnosis of depression (0.31; P = 0.0.15) or dementia (0.0003, P = 0.0001) were less likely to appeal. Compared with those who appealed (n = 12) those who did not (n = 28) showed less understanding of their rights (P = 0.034) and poorer comprehension of sentences from the booklet describing patients' rights (P = 0.057). The main reasons given for not appealing were not being aware of the appeals process and being deterred by having to appeal in writing. After they received a full explanation of their rights 12 of those who did not appeal said that they wished to appeal and four did so within the time remaining before the deadline. Of 40 patients, 39 said there should be an automatic right of appeal. CONCLUSIONS: The appeals procedure against detention under section 2 of the Mental Health Act is not a satisfactory way of protecting the civil liberties of patients. If patients were fully informed of their rights they would probably be much more likely to appeal.

Adult↗
PubMed1995

Interactions between Ras and Raf: key regulatory proteins in cellular transformation.

Ras proteins function during cell growth and development as essential, plasma membrane-bound signaling proteins. Current evidence suggests that Ras is part of a signal transduction chain extending from extracellular signals to transcriptional regulation in the nucleus. Growth factor and cytokine activation of many tyrosine kinase and kinase-linked receptors recruits many proteins to the plasma membrane including Ras-specific guanine nucleotide releasing proteins (GNRP). Under the influence of a GNRP, Ras proteins bind GTP, resulting in activation of the Ras signal. The GTP-bound form of Ras is capable of interacting directly with RasGAP, neurofibromin, and the Raf kinases. Although believed to be endowed with some signaling capacity, RasGAP and neurofibromin act primarily to negatively regulate Ras. Based upon genetic and biochemical studies in a variety of diverse organisms, the Raf kinases are considered the primary targets of Ras signaling. Activation of the Raf kinases is the first step in a cascade of multiple protein kinases, including Mek, Erk1, and Erk2. We are attempting to understand structurally how activated Ras proteins interact specifically with Raf kinases to induce the downstream signals necessary for cell division. Using mutagenesis, peptide epitope scanning, and in vitro reconstitution of protein interactions, we have identified specific sites of association between the Ras-GTP and c-Raf-1 proteins. The interaction between these contact points is essential for the plasma membrane localization of Raf, which ultimately leads to kinase activation. The formation of this protein complex is negatively regulated by protein kinase A (PKA) through phosphorylation of the c-Raf-1 N-terminus. Phosphorylation of c-Raf-1 serine 43 is believed to cause an N-terminal cap structure to cover the Ras docking site.

Amino Acid Sequence↗
PubMed1995

Evidence for a high molecular weight pre-robustoxin molecule in the venom of the male Sydney funnel-web spider (Atrax robustus).

Robustoxin is the lethal polypeptide toxin in Atrax robustus venom. A monoclonal antibody was produced using synthetic, unfolded robustoxin conjugated to keyhole limpet haemocyanin as the immunogen. This monoclonal antibody did not protect newborn mice against challenge with the crude venom of the male Sydney funnel-web spider, but did slightly prolong their survival time. Western blotted crude venom of the male Sydney funnel-web spider showed two monoclonal antibody binding bands. One band at low M(r) corresponded to robustoxin (M(r) 4854), while the other higher M(r) band (approximately 37,000) may be due to a pre-robustoxin molecule.

Adjuvants, Immunologic↗
PubMed1995

The Cardinal Needs Schedule--a modified version of the MRC Needs for Care Assessment Schedule.

This paper describes a modified version of the MRC Needs for Care Schedule (the Cardinal Needs Schedule), for measuring needs for psychiatric and social care amongst patients with severe psychiatric disorders. The modified schedule has three new features: (i) it is quick and easy to use; (ii) it takes systematic account of the views of patients and their carers; (iii) it defines and identifies need in a way that is concise and easy to interpret. The paper describes why the three new features were considered necessary, and then gives an overview of the structure of the Cardinal Needs Schedule, together with a description of how the three new features were developed. During a study of social services care management the practicality of the modified schedule was investigated and further data were obtained on the reliability and validity of the standardized approach to measuring need, in domains not previously investigated. Because of its speed and simplicity, the Cardinal Needs Schedule offers a new choice to researchers who wish to use a standardized and practical assessment of need in evaluative studies of community care. Examples of the usage of the modified schedule are given in an Appendix.

Activities of Daily Living↗
PubMed1994

Structural analysis of the Ras GTPase activating protein catalytic domain by semirandom mutagenesis: implications for a mechanism of interaction with Ras-GTP.

The bovine complementary DNA encoding the catalytic domain of Ras GTPase activating protein was mutagenized semirandomly using a variation of the polymerase chain reaction. Sixty-four mutated codons were identified with seventeen of the mutations deleterious to Ras GTPase activating function. All of the inactivating single mutations affected the structure of the catalytic fragment as assessed by large decreases in soluble protein when expressed in Escherichia coli. Upon examination of the Ras binding properties of 10 of the mutants, only 1 was measurably impaired for Ras binding and 4 appeared to have increased affinity for Ras. These results demonstrate that Ras binding and GTPase activation are two distinct properties of GTPase activating protein. Additionally, the catalytic mechanism of GTPase activating protein is much more sensitive to structural perturbation than is Ras binding.

Amino Acid Sequence↗
PubMed1994

Bacterial expression of Chinese hamster regulatory type-I and catalytic subunits of cyclic AMP-dependent protein kinase and mutational analysis of the type-I regulatory subunit.

The type-I regulatory subunit (RI) of the cyclic AMP-dependent protein kinase (PKA) from Chinese hamster ovary (CHO) cells has been cloned and expressed in a strain of BL21(DE3) Escherichia coli lacking adenylate cyclase [BL21(DE3)/delta cya]. RI expressed in this bacterial system free of cyclic AMP is soluble and can reconstitute functional PKA. Recombinant CHO C alpha is predominantly insoluble with some active soluble protein. C beta is entirely insoluble and inactive. Soluble recombinant RI and soluble recombinant C alpha can associate in vitro and be activated by cyclic AMP. Six site-directed mutations of RI were generated to study the interaction of cyclic AMP with RI and RI-C alpha subunit interactions. Four cyclic AMP-binding-site point mutants were generated [W261R (tryptophan to arginine at position 261), a novel mutation in site A; V376G, a novel mutation in site B; G200E (site A), and Y370F (site B), previously described in bovine RI were introduced into the CHO RI for comparison purposes]. Mutants W261R, Y370F, and G200E demonstrated decreased 8-N3-[3H]cyclic AMP binding as well as 5-fold reduced affinity for [3H]cyclic AMP, with threefold increased EC50 values for cyclic AMP activation of kinase activity from reconstituted mutant holoenzymes. The mutation at V376G did not alter cyclic AMP binding or activation by cyclic AMP of mutant holoenzyme. A truncation mutant, G200Stop, which lacks both cyclic AMP-binding sites, did not bind cyclic AMP but can inhibit C alpha subunit activity. A novel mutation outside the cyclic AMP-binding regions of RI (V89A) weakened the interaction with C alpha indicated by a 7-fold lower EC50 for mutant holoenzyme activation by cyclic AMP.

Amino Acid Sequence↗
PubMed1994

Evaluation of chemical releases and worker exposures from filter press operations.

The exposures (inhalation and dermal) and releases (air, water, solids, and process streams) associated with the filtration of industrial wastewater sludge from an electronics manufacturing plant were characterized. Chemical releases and worker exposures for a target chemical (total copper) were measured over four operational cycles. Various aspects of the filtration operation believed to influence the measurement values were documented. Worker exposures associated with the discreet stages of the filter operation were measured. Ventilation patterns around the filter press were also monitored. The workers' time-weighted average exposures to total copper during the 113-minute operational cycle ranged from 3.1 to 25 micrograms/m3 (2.2 geometric standard deviation, 6.4 micrograms/m3 geometric mean concentration). The manual removal of filter cake comprised only 15% of the time in an average filtration cycle, but produced 72% of the workers' inhalation exposure. During this cake-removal stage, inhalation exposures ranged from 11 micrograms/m3 to 130 micrograms/m3 (2.5 geometric standard deviation, 30 micrograms/m3 geometric mean concentration). Differences in worker technique may account for the large range of inhalation exposures during the cake-removal stage. Exposures and releases were successfully determined for a single unit operation, as well as for the discreet stages of operation. The data generated will enable EPA to more accurately estimate worker exposures and chemical releases for new chemicals as required by the Toxic Substances Control Act. The approach utilized will benefit industrial hygienists in providing estimates of worker exposures and aid in the targeting of survey sampling.

Air Pollution↗
PubMed1994

Effect of endotoxin and cytokines on lipoprotein lipase activity in mice.

Endotoxin (lipopolysaccharide [LPS]) stimulates the production of cytokines, which mediate many of the metabolic effects associated with infection. In LPS-sensitive C57B1/6 mice, LPS doses as low as 0.01 micrograms per mouse decreased adipose tissue lipoprotein lipase (LPL) activity by greater than 50%. In LPS-resistant C3H/HeJ mice, which do not produce cytokines in response to LPS, doses of LPS as high as 10 micrograms per mouse did not affect LPL activity in adipose tissue. In muscle of C57Bl/6 mice, LPL activity was decreased by 27% after 10 micrograms of LPS, whereas in C3H/HeJ mice there was no effect. These results indicate that the LPS-induced decrease in both adipose and muscle LPL activity is mediated by cytokines. Tumor necrosis factor (TNF), interleukin (IL)-1, leukemia-inhibiting factor (LIF), interferon alfa, and interferon gamma all decreased adipose tissue LPL activity in intact mice. In skeletal and cardiac muscle, only IL-1 and interferon gamma decreased LPL activity, whereas TNF, LIF, and interferon alfa had no effect. Inhibition of TNF activity blocked the increase in serum triglycerides that is characteristically observed after LPS but did not affect the ability of LPS to decrease adipose tissue LPL activity. Inhibition of IL-1 activity with IL-1 receptor antagonist partially inhibited the increase in serum triglycerides; however, the ability of LPS to decrease LPL activity in either adipose or muscle tissue was not affected. These data indicate that although TNF and IL-1 play a role in mediating the increase in serum triglyceride levels, these cytokines do not play a crucial role in the inhibition of either adipose or muscle LPL activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Speech-language patterns in a child with moya moya disease.

Moya Moya disease is a cerebrovascular condition associated with occlusion of the terminal portion of the internal carotid artery along with the appearance of an abnormal net-like system of collateral blood vessels. This paper presents a description beginning in 1973 over a 6-yr. period of the speech-language performance of a Caucasian female diagnosed with the disease.

Child↗