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Biomedical subjects

G Williams

Publications and source records attributed to G Williams.

At least 235 records · Page 13Linked to original sources
PubMed1997

NSF and SNAP are present on adrenal chromaffin granules.

N-ethylmaleimide sensitive fusion protein (NSF) and soluble NSF attachment proteins (SNAPs) are involved in many vesicular transport steps. It has been proposed that SNAPs and NSF associate with their membrane receptors only when vesicles dock on the target membrane. Analysis of NSF and alpha-SNAP distribution in fractionation of organelles from adrenal medulla indicated that a substantial amount of both proteins distributed with chromaffin granules. Further fractionation of intact granules and lysed granule membranes showed exact overlap of NSF and alpha-SNAP distribution with chromaffin granules. These results suggest that NSF and alpha-SNAP are associated with chromaffin granules and support the idea that they function prior to docking of the granules on the plasma membrane.

Adrenal Medulla↗
PubMed1997

Microglial production of TNF-alpha is induced by activated T lymphocytes. Involvement of VLA-4 and inhibition by interferonbeta-1b.

TNF-alpha is a proinflammatory cytokine involved in many inflammatory conditions such as Crohn's disease, rheumatoid arthritis, cachexia, AIDS, and multiple sclerosis (MS). TNF-alpha is produced mainly by cells of the macrophage lineage, which includes microglia in the central nervous system. Here, we describe a mechanism through which TNF-alpha is generated by microglia. We show that activated human T lymphocytes induce the microglial production of TNF-alpha, and that is attenuated by a functional blocking antibody to CD49d, the alpha chain of the VLA-4 integrin on T cells. We also report that interferonbeta-1b (IFNbeta-1b), a drug that alleviates symptoms in MS, downregulates the expression of CD49d and reduces TNF-alpha production, mechanisms which can help account for its efficacy in MS.

Cells, Cultured↗
PubMed1997

Identification of critical residues in the colicin E9 DNase binding region of the Im9 protein.

1H-15N NMR studies, in conjunction with mutagenesis experiments, have been used to delineate the DNase-binding surface of the colicin E9 inhibitor protein Im9 (where Im stands for immunity protein). Complexes were formed between the 15 kDa unlabelled E9 DNase domain and the 9.5 kDa Im9 protein uniformly labelled with 15N. Approx. 90% of the amide resonances of the bound Im9 were assigned and spectral parameters obtained from 1H-15N heteronuclear single quantum coherence (HSQC) spectra were compared with those for the free Im9 assigned previously. Many of the amide resonances were shifted on complex formation, some by more than 2 p.p.m. in the 15N dimension and more than 0.5 p.p.m. in the 1H dimension. Most of the strongly shifted amides are located on the surfaces of two of the four helices, helix II and helix III. Whereas helix II had already been identified through genetic and biochemical investigations as an important determinant of biological specificity, helix III had not previously been implicated in binding to the DNase. To test the robustness of the NMR-delineated DNase-binding site, a selection of Im9 alanine mutants were constructed and their dissociation rate constants from E9 DNase-immunity protein complexes quantified by radioactive subunit exchange kinetics. Their off-rates correlated well with the NMR perturbation analysis; for example, residues that were highly perturbed in HSQC experiments, such as residues 34 (helix II) and 54 (helix III), had a marked effect on the DNase-immunity protein dissociation rate when replaced by alanine. The NMR and mutagenesis data are consistent with a DNase-binding region on Im9 composed of invariant residues in helix III and variable residues in helix II. The relationship of this binding site model to the wide range of affinities (Kd values in the range 10(-4) to 10(-16)M) that have been measured for cognate and non-cognate colicin DNase-immunity protein interactions is discussed.

Bacterial Proteins↗
PubMed1997

Insulin receptors are widely distributed in human brain and bind human and porcine insulin with equal affinity.

Insulin receptors differing structurally from those in other tissues have been demonstrated in brain from many species. Subtle differences in binding properties have been reported between insulin receptors in brain and other tissues, including differences in affinity of pig brain receptors for human and porcine insulin. Insulin binding has been demonstrated in human cerebral cortex, but insulin binding has not been characterized in other areas of human brain. We have studied the binding of 125I labelled human insulin, and its displacement by unlabelled human and porcine insulin, in homogenates prepared from human hypothalamus, cerebral cortex and cerebellum obtained post-mortem from eight non-diabetic subjects. Specific binding was demonstrated in all brain regions studied, and displacement curves obtained with unlabelled human and porcine insulin were identical. By contrast, unlabelled insulin-like growth factor-1 did not significantly displace 125I labelled human insulin over the same concentration range. We therefore conclude that insulin receptors are widely distributed in human brain and do not differ in their affinity for human and porcine insulin.

Aged↗
PubMed1997

Factors influencing MAC reduction after cardiopulmonary bypass in dogs.

BACKGROUND: Anaesthetic requirements may be reduced following surgery employing cardiopulmonary bypass (CPB). This study, in dogs, determined the role of a) volatile agents (enflurane [E] vs isoflurane [I]), b) oxygenator (bubble [B] vs membrane [M]), and c) presence [FL] vs absence [NoFL] of an in-line arterial filter in the bypass circuit in altering anaesthetic requirements following CPB. METHODS: Male mongrel dogs were anaesthetized with either enflurane (n = 24) or isoflurane (n = 24). They were randomly assigned to one of eight groups (n = 6 per group); Group 1 (E/B/FL), Group 2 (E/M/FL), Group 3 (E/M/NoFL), Group 4 (E/B/NoFL), Group 5 (I/M/FL), Group 6 (I/B/FL), Group 7 (I/M/NoFL) or Group 8 (I/B/NoFL). MAC was determined using the tail-clamp method at hourly intervals, twice before and three times after a one hour normothermic perfusion using aortoatrial cannulation and CPB. RESULTS: Prior to CPB, MAC was reproducible (enflurane: MAC1 2.17 +/- 0.29 vs MAC2 2.14 +/- 0.28%; isoflurane: MAC1 1.42 +/- 0.31 vs MAC2 1.41 +/- 0.33%) and differed among groups only for the volatile agent employed. Following CPB, MAC was reduced in all groups (P < 0.05 vs pre-CPB measurements) except Group 1 (E/B/FL). The degree of MAC reduction in other groups ranged from 39-64% and was not different based on type of agent employed, use of a membrane or bubble oxygenator, or presence or absence of an in-line arterial filter. CONCLUSION: In dogs, MAC reduction following CPB was variable, not related to type of volatile agent employed, use of a membrane or bubble oxygenator, or presence or absence of an in-line arterial filter. The explanation for reductions in anaesthetic requirements following CPB in this model remains speculative.

Anesthetics↗
PubMed1997

Intermittent androgen deprivation after PSA-complete response as a strategy to reduce induction of hormone-resistant prostate cancer.

OBJECTIVES: The increasing interest in exploring the use of intermittent androgen deprivation in prostate cancer has prompted a retrospective review of patients who elected to stop treatment. METHODS: Case records were reviewed. RESULTS: Twenty patients after 3 to 48 months (median 12) of endocrine therapy elected to stop therapy. Thirteen subsequently relapsed after a median observation of 9 months. Seven of 20 patients continue progression-free for 9 to 42 months (median 33). After second-line therapy, 75% of patients with a relapse remain progression-free at 2 years. Progression-free survival was higher in patients at Stage M0 (82% at 1 year) versus M+ (29% at 1 year). CONCLUSIONS: With 10 of 13 patients demonstrating an ongoing second PSA response, 45% of patients showing no progression, and 85% alive at 3 years, these results support findings from previous publications that suggest that there are no major risks with use of intermittent hormone therapy. However, in the future, there is an urgent need that such studies should be randomized and done in the context of audit-based research and development programs. The resources released could then be invested with respect to further improvements in treatment of prostate cancer, possibly considering such a combined approach with immunotherapy as an alternative to surgery or radiotherapy for early disease in elderly patients with long PSA-doubling time.

Aged↗
PubMed1997

Chemokine-enhanced migration of human peripheral blood mononuclear cells is antagonized by interferon beta-1b through an effect on matrix metalloproteinase-9.

The increased migration of peripheral blood mononuclear cells (PBMNCs) across a fibronectin (FN) matrix in response to the chemokines RANTES, MIP-1 alpha and MCP-1 is antagonized by interferon-beta-1b (IFN beta-1b). MCP-1 treatment of PBMNCs elevates their mRNA level and secretion of a matrix degrading enzyme, matrix metalloproteinase (MMP)-9, which is abrogated by IFN beta-1b. The clinical benefits of IFN beta-1b treatment in multiple sclerosis patients may in part be a result of this drug's ability to decrease the migration of PBMNCs in spite of a chemotactic gradient. Furthermore, the elevation of MMP-9 production by PBMNCs may be an important mechanism of action of chemokines.

Cell Migration Inhibition↗
PubMed1997

Paradoxes of GP fundholding: contracting for community health services in the British National Health Service.

The expansion of GP fundholding (GPFH) is central to the British government's attempt to maintain the revolution under way in the National Health Service (NHS). Evaluations of the NHS reforms have portrayed GPFH as an important mechanism for competition, and GPFH's bargaining power is reported to have secured significant changes in health service provision. However, these developments have been acknowledged to be less applicable in relation to community health services (CHS) than acute hospital services. On the basis of case studies of the process of contracting for CHS, GPFHs are shown to display ambivalent and sometimes contradictory views which have to be related to broader policy developments in general practice and primary care. Although this paper focuses on the British situation, many of the issues raised by reforms in primary and community health services have implications for developments in other Western health care systems.

Attitude of Health Personnel↗
PubMed1997

Role of hypothalamic neuropeptide Y neurons in the defective thermogenic response to acute cold exposure in fatty Zucker rats.

The fatty Zucker rat has impaired heat production and fails to mount an adequate thermogenic response to cold exposure, partly because of decreased sympathetic drive to thermogenesis in brown adipose tissue. Neuropeptide Y, synthesized in neurons of the hypothalamic arcuate nucleus and released in the paraventricular nucleus, stimulates feeding and inhibits brown adipose tissue activity. The neuropeptide Y neurons are overactive in fatty Zucker rats and are thought to contribute to hyperphagia, reduced energy expenditure and obesity. We have examined the relationship between thermogenic activity in brown adipose tissue (measured as uncoupling protein messenger RNA levels) and hypothalamic neuropeptide Y and neuropeptide Y messenger RNA levels in response to cold exposure (4 degrees C) for 2.5 and 18 h, in fatty and lean Zucker rats. In lean Zucker rats, cold exposure at 4 degrees C for 2.5 and 18 h significantly increased uncoupling protein messenger RNA levels by 3.5-fold (P<0.01) and 3.3-fold (P<0.01), respectively, compared with warm-maintained controls. Exposure to cold for 18 h also increased neuropeptide Y concentrations in the paraventricular nucleus (P<0.01) and ventromedial nucleus (P<0.001) in lean rats, with no change in neuropeptide Y messenger RNA after either 2.5 or 18 h. By contrast, fatty Zucker rats showed no significant changes in uncoupling protein messenger RNA (P>0.05) at either duration of cold exposure. There were also no significant changes in neuropeptide Y levels in any region nor in neuropeptide Y messenger RNA, with cold exposure for either period (P>0.05). In lean rats, cold exposure therefore stimulates brown fat uncoupling protein messenger RNA and also increases neuropeptide Y concentrations in its hypothalamic sites of release. We suggest that increased brown fat thermogenic capacity induced by cold in lean rats may be mediated, at least in part, by decreased neuropeptide Y release in the paraventricular nucleus, resulting in its accumulation in this site. Defective thermogenic responses in fatty rats may result from central dysregulation of brown adipose tissue due to sustained and non-suppressible overactivity of hypothalamic neuropeptide Y neurons.

Animals↗
PubMed1997

Issues of death and dying: the perspective of critical care nurses.

A major shift in the care of terminally ill people, due to advances in technology, and the development of legislation regarding patient self-determination and autonomy, has occurred over recent years. Critical care nurses (CCNs) are involved daily in issues of death and dying and are very aware of the needs, fears and psychosocial issues of patients and their families. Professional associations see a legitimate role for nurses in assisting the dying to achieve a dignified death. For legislation, policies and guidelines surrounding end-of-life issues to be effective, and to assist nursing staff with these sensitive, often difficult concerns, it is important that data on the opinions and perspectives of CCNs be objectively obtained. In a study by the Department of Social and Preventive Medicine at the University of Queensland, questionnaires were sent to 1100 randomly sampled community members and almost 1200 health professionals (nurses, general practitioners and specialists), including 299 CCNs. The response rate of CCNs to a 30-page postal questionnaire was 79 per cent (n = 231), indicating those nurses' high levels of interest in and/or concern regarding this area. CCNs supported the use of advance directives, the appointment of proxies and the need for doctors and nurses to give sufficient medication to relieve pain, even if this hastened the death of the patient. In addition, CCNs, more than any other professional group, supported the right of the terminally ill patient to physician-assisted suicide or euthanasia, their responses being very similar to those of community members. CCNs clearly face issues which, from legal, medical and ethical viewpoints, cause them concern. In sharing their personal experiences, CCNs stressed the need for more communication between doctors and patients, as well as between doctors and nurses. In addition, CCNs saw a clear role for themselves as advocates for patients/families in the decision-making process.

Adult↗
PubMed1997

Synthesis of glycosides in which the aglycon is an N-(hydroxymethyl)amino-1,3,5-triazine derivative.

The synthesis of analogues of the anti-tumour drug 2-[N-(hydroxymethyl)methylamino]-4,6-bis(dimethylamino)-1,3,5-triazine (HMPMM) in which the OH or a dimethylamino group is replaced by a carbohydrate has been explored. Triazinyl beta-glycosides were readily prepared by reaction of sugars with trimethyl-triazinylammonium salts. These were made with one or two methylamino groups on the triazine for reaction with formaldehyde to give the cytotoxic NMeCH2OH group. However, reaction of the triazinyl glycosides with formaldehyde gave complex intractable mixtures. When the carbohydrate portion was changed to the fully protected 2,3,4,6-tetra-O-acetyl glucose a good yield of the 2-[N-(hydroxymethyl)methylamino]-4-(dimethylamino)-1,3,5-triazin-2 -yl tetra-O-acetyl beta-glucoside was obtained. However, de-acetylation using sodium methoxide also removed the N-CH2OH group. We are investigating protection of the base-sensitive N-CH2OH group as trialkylsilyl and benzyl ethers and are looking at de-acetylation methods that are more selective. We have prepared glycosides in which the sugar is joined through the oxygen of the NMeCH2OH group. Coupling of acetobromoglucose with HMPMM catalysed by silver salts was not successful. Although methyl and cyclohexyl derivatives of HMPMM may be produced in high yields by reaction of HMPMM with methyl and cyclohexyl alcohols under acidic catalysis, production of glycosides in this way gave poor yields. MNDO calculations on reactions of HMPMM helped us devise improved reaction conditions for the condensation of 2,3,4,6-tetra-O-acetyl glucose with HMPMM and its derivatives. The best procedure to generate one of the target glycosides is to react 2,3,4,6-tetra-O-acetyl glucose and formaldehyde with 2-methylamino-4,6-bis(dimethylamino)-1,3,5-triazine. The beta-glycoside product was de-acetylated using potassium carbonate in dry methanol.

Acetylation↗