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Biomedical subjects

G Williams

Publications and source records attributed to G Williams.

At least 271 records · Page 15Linked to original sources
PubMed1996

Increased feeding and neuropeptide Y (NPY) but not NPY mRNA levels in the hypothalamus of the rat following central administration of the serotonin synthesis inhibitor p-chlorophenylalanine.

Neurons containing serotonin (5-HT), a potent anorexic agent, come into contact with neuropeptide Y-ergic neurons, that project from the arcuate nucleus (ARC) to the paraventricular nucleus (PVN). NPY powerfully stimulates feeding and induces obesity when injected repeatedly into PVN. We hypothesize that 5-HT tonically inhibits the ARC-PVN neurons and that balance between the two systems determines feeding and energy homeostasis. This study aimed to determine whether central injection of the 5-HT synthesis inhibitor p-chlorophenylalanine (pCPA), which increases feeding, increased hypothalamic NPY and NPY mRNA levels. pCPA (10 mg/kg in 3 microliters) was administered into the third ventricle either as a single injection (n = 8) or daily for 7 days (n = 8). Control rats received a similar injection of saline. pCPA significantly increased food intake compared with controls after both single and repeated injections (P < 0.05). NPY levels were measured by radioimmunoassay in microdissected hypothalamic extracts. NPY levels in the acutely treated group were significantly increased in the paraventricular nucleus (PVN; by 41%, P = 0.01), anterior hypothalamic area (AHA; by 34%, P < 0.01) and lateral hypothalamic area (LHA; by 41%, P < 0.02). In the 7-day-treated group, NPY levels were also increased in the same areas, i.e. PVN (by 24%, P < 0.01), AHA (by 30%, P < 0.01) and LHA (by 38%, P = 0.01). There were no significant changes in the ARC or any other region or in hypothalamic NPY mRNA levels. pCPA administration increased NPY levels in several regions notably the PVN. This is a major site of NPY release, where NPY injection induces feeding. We suggest that the hyperphagia induced by pCPA is mediated by increased NPY levels and secretion in the PVN. This is further evidence for interactions between NPY and 5-HT in the control of energy homeostasis.

Animals↗
PubMed1996

Mutagenesis studies of interleukin-8. Identification of a second epitope involved in receptor binding.

Interleukin-8 (IL-8) is a dimeric, C-X-C chemokine, produced by a variety of cells and which elicits proinflammatory responses from the neutrophil. As a prelude to drug design, we have investigated the interactions between IL-8 and its receptor by preparing a number of single-site mutants of IL-8 and determining their activity in receptor-binding and functional assays. In order to define the binding surface as precisely as possible, we have used chemical shifts obtained from nuclear magnetic resonance spectroscopy to screen mutant proteins for structural changes which affect regions of the IL-8 surface remote from the site of mutation. In addition to a previously recognized sequence, Glu4-Leu5-Arg6 in the N-terminal peptide, we have identified a second epitope comprising a contiguous group of non-sequential, solvent-exposed, hydrophobic residues, Phe17, Phe2l, Ile22, and Leu43. These two receptor-binding regions are separated by over 20 A in the IL-8 structure and are important both for receptor binding and function. In addition, we have shown through the production of a covalently linked IL-8 dimer, that subunit dissociation is not necessary for biological activity.

Amino Acid Sequence↗
PubMed1996

MMPI-2 patterns in African-American females.

Researchers have reported conflicting conclusions about the relation of the MMPI (MMPI-2) clinical scale elevations and race. Consequently, this study examined the concurrent validity of the MMPI-2 in evaluating African-American females. Seventy-eight (78) African American college student volunteers were administered the MMPI-2, along with other measures of personality, achievement, and coping style. Scores revealed 76% of the sample had elevated profiles. Subjects were divided into three groups based on frequency of clinical scale code type. Subjects with the 5/9 profile elevations functioned as well as normals on measures of coping skills and mood disorders. Discussion emphasizes the importance of clinical interpretation of MMPI data in research programs and the relationship of the data to coping style.

Adaptation, Psychological↗
PubMed1996

Deletion mapping of the short arm of chromosome 3 in Merkel cell carcinoma.

Little is known about the biology of Merkel cell carcinoma (MCC), also called small cell carcinoma of the skin. MCC has similarities with small cell lung cancer (SCLC): both are neuroendocrine malignancies with early metastasis to distant sites and a poor prognosis. Small cell lung cancer biopsies are known to have frequent losses on chromosome 3 in the region 3p21, yet MCCs have not been reported to have 3p deletions by karyotypic analysis. Considering the similarities between SCLC and MCC, we investigated 26 MCC tumours for loss of heterozygosity (LOH) on 3p. First, RFLP analysis was performed using PCR with nine primer sets from six loci. Second, 25 tumours were examined by microsatellite analysis for 3p markers D3S1289 and D3S1285 and SST on 3q. All 26 tumours were informative at one or more loci; of these, 18 (69%) demonstrated LOH for at least one marker on the short arm. For all informative loci the frequency of LOH was greater than 30% (range 33-75%). In a cell line derived from one tumour, it was possible to demonstrate rearrangement of chromosome 3 by in situ hybridisation. No LOH was seen in 15 informative cases for the 3q locus SST. A region 3p13-p21.1, centered on the marker D3S2, was deleted in all tumours demonstrating LOH, with a secondary deletion involving D3S30 detected in some tumours at 3p13. Our results indicate that LOH on 3p is a common occurrence in MCC; however, three tumours for which DNA was also available from a corresponding cell line suggest there may be a subset of MCC whose genesis is independent of deletions of 3p.

Carcinoma, Merkel Cell↗
PubMed1996

Interferon beta-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9.

In multiple sclerosis (MS), the influx of activated T lymphocytes into the brain parenchyma leads to the subsequent damage of oligodendrocytes, the cells that produce central nervous system (CNS) myelin. We report here that interferon beta-1b (IFNbeta-1b), a drug shown to be efficacious in the treatment of patients with MS, decreases the in vitro migration of activated T lymphocytes through fibronectin (FN), a major component of the basement membrane that surrounds cerebral endothelium. At 1,000 IU/ml, IFNbeta-1b reduced the migratory rate to that of unactivated T cells. In contrast, IFNgamma at 1,000 IU/ml, which caused a similar decrease (25%) in the proliferation rate of T lymphocytes as IFNbeta-1b, did not affect migration. All T-lymphocyte subsets and natural killer (NK) cells were demonstrated by flow cytometry to be equally affected by IFNbeta-1b treatment. 125I-Western blot analyses revealed that IFNbeta-1b treatment resulted in a marked reduction of the ability of T cells to cleave FN. The substrate-degrading capability of T lymphocytes was shown to be due predominantly to the activity of a 92-kd matrix metalloproteinase, MMP-9, whose levels were decreased by IFNbeta-1b. We suggest that the clinical benefits of IFNbeta-1b treatment in MS patients may be in part a result of the ability of this drug to significantly decrease MMP-9 activity, leading to a reduction of T-lymphocyte infiltration into the CNS.

Adjuvants, Immunologic↗
PubMed1996

Acute leukaemia following renal transplantation.

Four renal transplant patients on immunosuppressive therapy who presented with acute myeloid leukaemia are described. In two cases, azathioprine may have played an important role as a cofactor in leukaemogenesis. In a third case, the alkylating agent cyclophosphamide may have contributed. All patients were treated for leukaemia with full doses of cytotoxic chemotherapy and, in each case, a functioning renal allograft was preserved throughout the treatment despite attenuation of immunosuppressive therapy. Three patients achieved complete remission. Of the three, one is surviving at 2 years and two expired during the pancytopenic phase of their treatment with no active leukaemia present, and with intact renal function. As increasing expertise in the field of organ transplantation allows patients to survive longer, such patients' exposure to immunosuppressive and potentially leukaemogenic drugs is prolonged. The risk of secondary neoplasia has been previously documented in this population. Two of the four cases reported here suffered from polycystic kidney disease as their underlying condition. While this report suggests that the leukaemias are related to renal transplantation, we cannot rule out an association with the underlying disease which led to the transplant. This report further suggests that the leukaemia that develops in such patients may respond to standard therapy, and that such treatment does not compromise the transplanted kidney.

Acute Disease↗
PubMed1996

Relationships between hypothalamic neuropeptide Y and food intake in the lactating rat.

NPYergic neurons in the hypothalamic arcuate nucleus (ARC) that project to the paraventricular nucleus (PVN) are postulated to regulate food intake and energy balance. This projection is overactive in lactation and is thought to drive hyperphagia in this condition. We have explored further the relationship between hypothalamic NPY and food intake in lactation and tested the hypothesis that hypoinsulinemia is the stimulus to NPY neuronal activity. Compared with nonlactating controls (n = 10), freely fed lactating rats (n = 9) showed significantly increased (p < 0.05) NPY levels in the ARC and medial preoptic area (MPO), but there was no significant increase in whole hypothalamic NPY mRNA levels. Lactating rats (n = 8) that were restricted to control rats' food intake for 3 days showed generally higher hypothalamic NPY levels, with significantly higher concentrations than controls (p < 0.05) in the ARC, MPO, PVN, and lateral hypothalamic area (LHA); NPY mRNA levels were also significantly increased (p < 0.05). Across all three experimental groups, there was a significant inverse correlation between plasma insulin concentration and hypothalamic NPY mRNA levels (r = -0.39, p < 0.01). We conclude that the ARC-PVN projection is overactive in lactation and that this is not a consequence of hyperphagia. Hypoinsulinemia may stimulate these neurons, as it is thought to do in other conditions of energy deficit.

Animals↗
PubMed1996

Differential effects of the 5-HT 1B/2C receptor agonist mCPP and the 5-HT1A agonist flesinoxan on hypothalamic neuropeptide Y in the rat: evidence that NPY may mediate serotonin's effects on food intake.

To determine whether NPY and 5-HT interact, we studied the effects on hypothalamic NPY and NPY mRNA levels of acute (10 mg/kg) and 7-day administration (10 mg/kg/day) of mCPP (a 5-HT 1B/2C agonist) and flesinoxan (a 5-HT 1A agonist). After both treatments, mCPP reduced food intake and NPY levels in the PVN (p < 0.01). NPY mRNA levels were only increased by comparable food restriction (p < 0.05). Acute flesinoxan injection increased food intake and NPY levels in the PVN and ARC (p < 0.01). This suggests that food intake changes induced by mCPP and flesinoxan are associated with altered NPYergic activity. Stimulation of different hypothalamic 5-HT1 receptors may alter NPY levels available for release in the PVN, possibly by altering transport along the ARC-PVN projection. Therefore, inhibition of the ARC-PVN projection may at least partly mediate the hypophagic effects of serotonin.

Animals↗
PubMed1996

Public health research and lay knowledge.

Social science research into the social patterning of health and illness is extensive. One important aspect of this has been work on lay knowledge about health and illness. In this paper we develop three main arguments. First, we suggest that recent developments in social science understanding of the nature and significance of lay knowledge should be more widely recognized within the social sciences themselves. Second, we argue that if public health research, whatever the disciplinary perspective, is to provide an understanding of contemporary health problems that is simultaneously more robust and more holistic, it must incorporate and develop the theoretical and conceptual insights offered by this recent work on lay knowledge and with lay people. Finally, we argue that in order to accomplish this it will be necessary to construct research questions in such a way that the conventional distinctions between science and non-science, and the methodological wrangles associated with this distinction, become marginal to the research process. This will inevitably involve conflicts between members of different professional groups. These conflicts provide the opportunity for open debate on the science and politics of public health research and represent a challenge for the many disciplines involved in this field.

Forecasting↗
PubMed1996

The serotonergic agent fluoxetine reduces neuropeptide Y levels and neuropeptide Y secretion in the hypothalamus of lean and obese rats.

Evidence suggests that serotonin and neuropeptide Y neurons in the hypothalamus, which respectively inhibit and stimulate food intake, may interact to control energy homoeostasis. We therefore investigated the effects of fluoxetine, which inhibits serotonin reuptake, on food intake and the activity of the neuropeptide Yergic arcuato-paraventricular projection in lean Wistar and Zucker rats. We also studied its effects in obese Zucker rats, in which obesity is postulated to be due to overactivity of the arcuato-paraventricular projection. Fluoxetine significantly reduced food intake in lean and obese rats, both during continuous subcutaneous infusion and (10 mg/kg/day for seven days) and acutely after a single injection (10 mg/kg). Fluoxetine also significantly reduced neuropeptide Y levels in the paraventricular nucleus, a major site of neuropeptide Y release which is highly sensitive to the appetite-stimulating actions of neuropeptide Y. Push-pull sampling in lean and fatty Zucker rats showed that neuropeptide Y secretion in the paraventricular nucleus was significantly reduced after acute fluoxetine treatment. Furthermore, seven days fluoxetine treatment prevented the significant increases in hypothalamic neuropeptide Y messenger RNA which were induced in lean rats by food restriction which precisely matched the hypophagia induced by the drug. We conclude that fluoxetine inhibits various aspects of the activity of the neuropeptide Yergic arcuato-paraventricular neurons, and suggest that reduced neuropeptide Y release in the paraventricular nucleus may mediate, at least in part, the drug's hypophagic action. We further suggest that serotonin may influence food intake and energy balance by inhibiting the arcuato-paraventricular projection, and that the two neurotransmitters may act together to regulate feeding and energy homoeostasis.

Animals↗
PubMed1996

Selective renal transplantation in primary hyperoxaluria type 1.

Primary hyperoxaluria type I (PHI) is a cause of end-stage renal disease in young people. It is caused by deficient activity of hepatic peroxisomal alanine:glyoxylate aminotransferase (AGT), which results in hyperoxalemia and hyperoxaluria. The consequent urolithiasis and nephrocalcinosis result in renal impairment, with further reduction in oxalate excretion and eventual systemic oxalosis. Historically, renal transplantation has yielded very poor results in these patients because of recurrent oxalosis of the graft. Within the last 10 years, combined hepatorenal transplantation has been successfully applied, simultaneously correcting the metabolic lesion in the liver and replacing the damaged kidneys. It has, however, become apparent that medical therapy with vigorous hydration, inhibitors of stone formation and pyridoxine (AGT co-factor), may be successful at delaying, and occasionally in preventing, urolithiasis in some hyperoxaluric patients, particularly those whose hyperoxaluria is reduced by pyridoxine. This, together with intensive perioperative management and modern surgical methods of stone management such as lithotripsy, laser or ultrasound stone fragmentation, and percutaneous nephrolithotomy, means that renal transplantation alone may be feasible in selected patients. We describe a patient with PHI with clinical and biochemical evidence of significant residual AGT activity who underwent a successful live-related renal transplantation with excellent renal function and no stone recurrence 1 year posttransplantation. The appropriate transplantation strategies for these complex patients are discussed and include isolated renal transplantation for those patients who are without significant systemic oxalosis and have evidence of residual AGT activity.

Adult↗
PubMed1996

Long-term follow-up of patients with erectile dysfunction commenced on self injection with intracavernosal papaverine with or without phentolamine.

OBJECTIVES: To determine the usage, complications and satisfaction with intracavernosal agents in patients with erectile dysfunction commenced on self-injection treatment at home. PATIENTS AND METHODS: A total of 344 patients who had commenced intracavernosal treatment before December 1992 and had requested a repeat prescription were sent a questionnaire to determine the usage, complications, satisfaction and reasons for discontinuing treatment. RESULTS: Replies were received from 216 patients; of those who replied, only 126 were still using the treatment. The mean duration of treatment was 3.9 years in those continuing treatment. Whilst satisfaction ratings were high in those continuing therapy, most patients had experienced some side-effects. CONCLUSION: The long-term follow-up revealed a high attrition rate and a significant number of complications. Patients receiving auto-injection therapy should be offered regular long-term follow-up.

Adult↗
PubMed1996

Endoscopic laser ablation of the prostate (ELAP): changes in magnetic resonance imaging and clinical outcome at 1 year.

OBJECTIVE: To assess the ability of magnetic resonance imaging (MRI) to detect tissue changes immediately after laser ablation of the prostate and to correlate these changes with clinical outcome by detecting changes that may improve the outcome by allowing the laser dosimetry to be adjusted during therapy by monitoring effects on gland morphology. PATIENTS AND METHODS: Eight men with proven bladder outlet obstruction had a standard four-quadrant laser ablation of the prostate with a side-firing non-contact fibre. MRI scans were performed before, during and immediately after treatment and again after one week, 3 months and one year. RESULTS: The clinical outcome was a decrease in the American Urological Association (AUA)-7 symptom score from a pre-operative mean of 21.3-12.0 1 year after treatment and a corresponding increase in peak urinary flow rates from a mean of 8.9 mL/s to 12.3 mL/s. Immediately after treatment, MRI showed marked swelling of the gland (mean increase in volume 34%, range 12-75) with the loss of internal architecture. A low-signal thin periurethral band was present in six of the eight patients after 1 week and was replaced by a wider periurethral ring at 3 months in four of the six patients. No patient had evidence of prostatic cavitation after treatment or a significant reduction in prostate volume at 1 year. CONCLUSION: MRI can detect tissue changes after laser ablation of the prostate. The marked swelling seen on MRI immediately after laser prostatectomy may explain the delayed improvement in symptoms. The periurethral ring may indicate the depth to which laser energy has an effect on the tissue and could delineate an area of necrosis. The lack of cavitation at one year questions the durability of the effect of laser treatment delivered in this way.

Aged↗