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Biomedical subjects

G Williams

Publications and source records attributed to G Williams.

At least 253 records · Page 14Linked to original sources
PubMed1997

Increased feeding in fatty Zucker rats by the thiazolidinedione BRL 49653 (rosiglitazone) and the possible involvement of leptin and hypothalamic neuropeptide Y.

1. The thiazolidinedione BRL 49653 (rosiglitazone) induces hyperphagia and weight gain in obese, insulin-resistant fatty Zucker rats but not in lean insulin-sensitive rats. We investigated whether these responses might involve neuropeptide Y (NPY), leptin and insulin. 2. BRL 49653 (1 mg kg(-1) day(-1), orally) was given for 7 or 20 days to fatty and lean Zucker and Wistar rats. 3. In lean rats of either strain, BRL 49653 had no effect on food intake, body weight, plasma insulin and corticosterone, NPY or NPY mRNA levels. 4. Fatty rats given BRL 49653 showed a 30% increase in food intake and accelerated body weight gain (both P<0.01) after 7 and 20 days, but without significant changes in regional hypothalamic NPY or NPY mRNA levels. 5. Plasma leptin levels were twice as high in untreated fatty Zucker rats as in lean rats (P<0.01), but were unaffected by BRL 49653 given for 20 days. However, BRL 49653 reduced insulin levels by 42% and increased corticosterone levels by 124% in fatty rats (both P<0.01). 6. Hyperphagia induced in fatty Zucker rats by BRL 49653 does not appear to be mediated by either a fall in circulating leptin levels or increased activity of hypothalamic NPYergic neurones. The fall in plasma insulin and/or rise in corticosterone levels during BRL 49653 treatment may be involved, consistent with the postulated role of these hormones in the control of food intake.

Animals↗
PubMed1997

Insulin-induced attenuation of noradrenaline-mediated vasoconstriction in resistance arteries from Wistar rats is nitric oxide dependent.

1. We studied the mechanism of insulin-mediated attenuation of noradrenaline-induced vasoconstriction in mesenteric resistance arteries (approximately 210 microns diameter) from 10-week-old male Wistar rats (n = 10; weight 321 +/- 11 g). Exposure to physiological concentrations of insulin (50 m-units/l) significantly blunted the contractile response to noradrenaline over the concentration range 3 x 10(-6) to 3 x 10(-5) mol/l (16 vessels; 13.1 +/- 4.3% reduction in maximum tension at 3 x 10(-5) mol/l noradrenaline; P < 0.01 versus no insulin). 2. This effect of insulin was prevented by the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (10(-4) mol/l; 16 vessels; 3.3 +/- 9.1% reduction in maximum tension; P = 0.8 versus no insulin). There was no evidence of fatigue in four noradrenaline dose-response curves for 16 control vessels in the absence of insulin and NG-nitro-L-arginine methyl ester (P = 0.8; first versus second dose-response curve). With L-arginine present in the incubation medium, insulin again attenuated the noradrenaline-induced vasoconstriction (10.7 +/- 3.2% reduction in tension; P = 0.02 versus L-arginine and no insulin; P = not significant versus insulin and no L-arginine). 3. Endothelium-dependent relaxation was initially confirmed in all vessels by demonstrating normal acetylcholine- (5.4 x 10(-7) to 1.1 x 10(-4) mol/l) induced vasodilatation in vessels preconstricted with noradrenaline (6 x 10(-6) mol/l) in the absence of NG-nitro-L-arginine methyl ester, L-arginine and insulin (P = not significant between the different groups of vessels). 4. We conclude that insulin attenuates noradrenaline-induced vasoconstriction in resistance arteries by stimulation of nitric oxide release. Abnormal insulin-stimulated nitric oxide release could be of relevance in the pathogenesis of hypertension and diabetic microvascular disease.

Acetylcholine↗
PubMed1997

Impaired insulin-induced attenuation of noradrenaline-mediated vasoconstriction in insulin-resistant obese Zucker rats.

1. Insulin resistance is associated with hypertension but the underlying mechanism is unclear. We tested the hypothesis that insulin-induced vasodilatation is impaired in insulin-resistant obese Zucker rats. We studied mesenteric artery (approximately 220 microns diameter) function before the development of hypertension in 3-month old obese Zucker rats and age-matched lean rats. 2. In vessels from lean rats, insulin at concentrations of 50, 500 and 5000 m-units/l attenuated the constriction in response to noradrenaline (50 m-units/l: 8 +/- 3%, P < 0.05; 500 m-units/l: 13 +/- 3%, P < 0.02; 5000 m-units/l: 13 +/- 2%, P < 0.02). 3. Vessels from obese rats failed to show any such response to insulin (2 +/- 6% increase in maximal tension with 5000 m-units/l; not significant), both in the presence and absence of L-arginine (3 mmol/l). 4. Vessels from obese rats showed slight but significant impairment in the vasodilator response to acetylcholine (5 x 10(-8)-10(-4) mol/l) (obese: 64.1 +/- 3.7% relaxation; lean: 77.3 +/- 3.7% relaxation; P < 0.05); however, relaxation in response to A23187 was not significantly different between the phenotypes (obese: 81.3 +/- 10.6% relaxation; lean: 79.1 +/- 9.7% relaxation; not significant). 5. Systolic blood pressure was not significantly different in lean (126 +/- 8 mmHg) and obese (127 +/- 7 mmHg) rats at the time of study (not significant). 6. We conclude that insulin-induced attenuation of noradrenaline-mediated vasoconstriction is impaired in the obese Zucker rat and that this defect precedes and therefore could contribute to the development of hypertension in this insulin-resistant model. The defect in insulin action could reside in the endothelial generation of nitric oxide, as endothelial function is also abnormal.

Acetylcholine↗
PubMed1997

T-cell epitopes recognized within the 65,000 MW hsp in patients with IgA nephropathy.

IgA nephropathy (IgAN) is the commonest cause of glomerulonephritis and clinical exacerbation of IgAN is frequently associated with mucosal infection. T-cell receptor gamma delta (TCR gamma delta+) cells are increased in both the circulation and in renal biopsies of patients with progressive IgAN. We examined the hypothesis that specific peptides within the 65,000 MW heat-shock protein (hsp) might stimulate TCR gamma delta cells and play a part in the immunopathogenesis of IgAN. We studied T-cell proliferative responses stimulated by overlapping peptides derived from the sequence of mycobacterial 65,000 MW hsp. Three T-cell epitopes have been identified (peptides 51-65, 71-85 and 281-295). The three peptides have a synergistic effect and they stimulate significantly higher proliferation of T cells in patients with IgAN than in disease or healthy controls. This response was inhibited by monoclonal antibodies (mAb) to TCR gamma delta+ and human leucocyte antigen (HLA) class I, but not by mAb to HLA class II. The involvement of TCR gamma delta+ cells was confirmed by up-regulation of the proportion of TCR gamma delta+ cells when stimulated with the three specific peptides. We suggest that IgAN might be associated with mucosal infection by a variety of micro-organisms and that peptides within the microbial hsp cross-react with the homologous human hsp which may stimulate TCR gamma delta+ cells and play a part in the pathogenesis of IgAN.

Adult↗
PubMed1997

A potential autocrine loop between heregulin-alpha and erbB-3 receptor in human prostatic adenocarcinoma.

OBJECTIVE: To examine the expression of heregulin-alpha (a new member of the epidermal growth factor family) and its receptor erbB-3 in human prostate cancer by immunohistochemistry, and to analyse their implication for clinical outcome. PATIENTS AND METHODS: Using specific anti-peptide antibodies, tumour samples from 50 consecutive patients with newly diagnosed prostate cancer (18 well, 15 moderately and 17 poorly differentiated) and four patients with benign prostatic hyperplasia (BPH) were immunostained for heregulin-alpha (an isoform of heregulin) and erbB-3 proteins. Representative areas from each case were used to assess immunoreactivity. RESULTS: Heregulin-alpha was expressed (i.e. > or = 10% of tumour cells positive) in 36 (72%) and erbB-3 in 27 (54%) of the 50 cases. High levels of expression of heregulin-alpha (> 90% of tumour cells stained) appeared to be related to high-grade tumours, but the association did not reach statistical significance. There was no correlation between the levels of expression of erbB-3 and tumour grade. All four samples from BPH stained negatively for heregulin-alpha and erbB-3. Fourteen patients had bony metastases identified by bone scintigraphy and all received androgen ablation after undergoing transurethral resection of the prostate. Immunoreactivity for heregulin-alpha and erbB-3 were absent in five cases, all of whom responded to hormone manipulation and remained symptom-free at the time of review (mean follow up 3 years, range 2-4). Despite hormone manipulation, the nine patients overexpressing heregulin-alpha and/or erbB-3 died during a mean follow up of 2.5 years (range 0.5-4). CONCLUSION: The overexpression of heregulin-alpha and erbB-3 in prostate cancer is detectable by immunostaining. Activation of the type 1 growth-factor receptor system by heregulin-alpha and/or the erbB-3 receptor appears to be associated with a less favourable prognosis in advanced disease.

Adenocarcinoma↗
PubMed1997

Female urethral diverticula.

Most urethral diverticula should be diagnosed on clinical grounds alone, but investigations may be used to confirm the diagnosis in difficult cases, delineate the extent of the disease and investigate other entities such as stress incontinence. A high index of suspicion is required when assessing women with lower urinary tract symptoms to ensure that cases of urethral diverticulum are not missed. The cases presented demonstrate that greater awareness of the signs and symptoms of this not uncommon disease may facilitate early diagnosis. Our cases also show that surgical treatment is effective and worthwhile.

Journal Article↗
PubMed1997

Neurobiology.

The role of neuropeptide Y (NPY), leptin and 5-HT and other neurotransmitters implicated in the regulation of energy balance are only now being fully investigated. Little is known about how they may interact with each other in this complex process. In evolutionary terms, the availability of excess food, and the risk of obesity, is only a recent occurrence in humans. Man, and perhaps other species, may not have developed a specialised neurochemical system for adjusting food intake during obesity. Hence perturbation of a single system, such as hypothalamic NPY or leptin, is unlikely to be directly responsible for the development of most obesity. In contrast, periods of food deprivation and partial starvation have been common in the animal kingdom and the multitude of neurotransmitters implicated in energy balance are more likely to be directed towards increasing food consumption and conserving energy than reducing appetite and increasing thermogenesis in the presence of excess. The last few years have witnessed rapid advances in the understanding of the fundamental mechanisms that regulate body weight and fat content. This progress will undoubtedly continue in the future, and it is hoped that this will be rewarded with the development of new drugs to treat obesity. At present, however, it is unclear whether NPY, leptin, or other apparently strong candidates will be the winner in the lucrative race for the ideal anti-obesity drug.

Body Weight↗
PubMed1997

Effect of erionite on the pleural mesothelium of the Fischer 344 rat.

OBJECTIVE: This study sought to assess the fibrogenic and carcinogenic potential of erionite (a fibrous zeolite) on the pleural mesothelium of the Fischer 344 rat (n = 24). DESIGN: The study was designed to examine rat pleural mesothelial changes by three independent observers at timed intervals, ranging from 1 to 480 days postinoculation using erionite from the Pine Valley, Nevada (USA) area. The mean length and width of the erionite fibers were 2.29 and 0.48 microns, respectively. Only microscopic observations made by majority (2/3) or unanimity (3/3) were accepted for final diagnosis. RESULTS: Pleural and lung tissue were available for examination in 21 of the 24 rats. Fibrosis, chronic inflammation, and foreign body reaction occurred in 6 of 21 rats. Mesothelial hyperplasia and dysplasia occurred in 9 and 3 of the 21 rats, respectively. A single mesothelioma was identified at 434 days in a rat that had gross nodular pleural lesions. CONCLUSIONS: The findings reported herein confirm the strong fibrogenic potential of erionite but are at variance with previous studies reporting much higher yields of mesothelioma. The reasons for the low yield of mesothelioma in this study are not known, but may be related to the study design, the strict criteria used for histopathologic diagnosis, and/or possible differences in erionite physicochemical properties, associated with its geographic distribution, most previous animal studies having used erionite from the Rome, Oregon (USA) area.

Animals↗
PubMed1997

Inhibition of food response to intracerebroventricular injection of leptin is attenuated in rats with diet-induced obesity.

The fat-derived hormone, leptin, is thought to regulate adipose tissue mass by acting on the brain to reduce food intake and increase thermogenesis. We have produced obesity in rats more than 8 weeks old by feeding a high-calorie diet and have then examined the inhibitory effect of intracerebroventricularly injected recombinant murine leptin on their food intake versus control rats. In control rats, randomized injections of leptin (0.5, 2.0, or 10.0 microg) or sterile saline vehicle into the lateral ventricle produced a dose-dependent reduction in normal laboratory diet consumed 1, 4, and 24 h after the lights were turned off. However, in diet-induced obesity, the dose-dependent inhibition of food intake was observed at 1 h only, and the effect was attenuated. Switching the diet-induced obese rats to a normal laboratory diet 1 week before injections of leptin were commenced resulted in a reduction in the daily food consumption. These data suggest that rats made obese by feeding a high-calorie diet override the normal satiety effects of leptin since when they are returned to a normal laboratory diet, they reduce their calorie intake, possibly as a result of a restoration of the satiety effects of endogenous leptin. However, the fact that the hypophagic response to exogenous leptin is impaired in these rats at this time suggests some residual impairment of the satiety signal, perhaps caused by reduced receptor sensitivity and/or near total occupation of receptors by endogenous leptin molecules, levels of which are raised in plasma.

Adipose Tissue↗
PubMed1997

Interactions between leptin and hypothalamic neuropeptide Y neurons in the control of food intake and energy homeostasis in the rat.

Leptin acts on the brain to inhibit feeding, increase thermogenesis, and decrease body weight. Neuropeptide Y (NPY)-ergic neurons of the hypothalamic arcuate nucleus (ARC) that project to the paraventricular nuclei (PVN) and dorsomedial nuclei (DMH) are postulated to control energy balance by stimulating feeding and inhibiting thermogenesis, especially under conditions of energy deficit. We investigated whether leptin's short-term effects on energy balance are mediated by inhibition of the NPY neurons. Recombinant murine leptin (11 microg) injected into the lateral ventricle of fasted adult Wistar rats inhibited food intake by 20-25% between 2 and 6 h after administration, compared with saline-treated controls (P < 0.05). Uncoupling protein mRNA levels in brown adipose tissue (BAT) rose by 70% (P < 0.01). Leptin treatment significantly reduced NPY concentrations by 20-50% (P < 0.05) in the ARC, PVN, and DMH and significantly decreased hypothalamic NPY mRNA levels (0.61 +/- 0.02 vs. 0.78 +/- 0.03 arbitrary units; P < 0.01). A second study examined changes in leptin during 5 days' intracerebroventricular NPY administration (10 microg/day), which induced sustained hyperphagia and excessive weight gain. In NPY-treated rats, leptin mRNA levels in epididymal fat were comparable to those in saline-treated controls (0.94 +/- 0.17 vs. 1.0 +/- 0.28 arbitrary units; P > 0.1), but plasma leptin levels were significantly higher (4.88 +/- 0.66 vs. 2.85 +/- 0.20 ng/ml; P < 0.01). Leptin therefore acts centrally to decrease NPY synthesis and NPY levels in the ARC-PVN projection; reduced NPY release in the PVN may mediate leptin's hypophagic and thermogenic actions. Conversely, NPY-induced obesity results in raised circulating leptin concentrations. Leptin and the NPY-ergic ARC-PVN neurons may interact in a homeostatic loop to regulate body fat mass and energy balance.

Adipose Tissue, Brown↗
PubMed1997

P53, MDM-2, BAX and BCL-2 and drug resistance in chronic lymphocytic leukemia.

Most antitumor agents exert their cytotoxic effect through the induction of apoptosis, and this process may be mediated through an elevation in p53 protein, with a subsequent increase in bax and decrease in bcl-2. p53 also increases mdm-2 expression and mdm-2 may then bind and inactivate p53. Cells from 31 patients with chronic lymphocytic leukemia (CLL) were treated in vitro with 2-chlorodeoxyadenosine (CdA), arabinosyl-2-fluoroadenine (F-ara-A), or chlorambucil (CLB) and drug sensitivity measured using the MTT assay. The protein levels of bax and bcl-2 were measured in CLL cells from 25 patients, and were found to be higher in leukemic cells than in normal B cells. The bcl-2 levels varied three-fold, the bax levels fifteen-fold, and the bax:bcl-2 ratios ranged from 0.44 to 2.91. The expression of mdm-2 mRNA was measured in CLL cells from 28 patients and was found to vary twenty-fold. However, no correlation was observed between drug sensitivity to CdA, F-ara-A, or CLB and the cellular levels of mdm-2 mRNA, or the protein levels of bax or bcl-2, or the bax:bcl-2 ratio. Treatment of CLL cells having wild type p53 with CdA, F-ara-A or CLB produced an increase in p53 protein and mdm-2 mRNA. This was not observed in cells having a p53 mutation, and these cells were highly resistant to both CLB and the nucleoside analogs. In contrast to the nucleoside analogs and CLB, dexamethasone and vincristine had no effect on mdm-2 mRNA levels. Treatment of CLL cells containing a wild type p53 gene with CdA, F-ara-A, or CLB, did not produce any consistent changes in bax or bcl-2. Thus, CdA, F-ara-A and CLB appear to act in CLL cells through a p53-dependent pathway, whereas this does not occur with dexamethasone or vincristine. The cellular levels of mdm-2, bcl-2, bax or the bax:bcl-2 ratios are not predictive indicators of clinical sensitivity in CLL, but an increase in mdm-2 levels after drug treatment is indicative of p53 function in these cells.

Adult↗
PubMed1997

Reflections on some dynamics of eating disorders: 'no entry' defences and foreign bodies.

In the context of the treatment of eating disorders, the author describes a specific failure in the container/contained relationship (Bion, 1962) that goes beyond the experience of having projections rejected. She addresses the predicament of those patients who have not only lacked containment, but also perceived themselves as receptacles of unmetabolised phantasies and experiences projected into them by their parents. The author briefly refers to those patients who succeed in protecting themselves from this predicament by developing a 'no entry system of defences' that often includes anorexia. The main focus of the clinical exploration in this paper is the predicament of 'porous' patients, those who remain open to parental projections. The author suggests that in such cases the introjection of an object performing a function opposite to organising 'alpha function' can be hypothesised. She suggests the term 'omega function' to describe a disorganising, disrupting agent in the patient's internal world. The author makes reference to the type of countertransference experienced by the clinician working with the disorganised 'porous' patients, which is different from the type experienced in the treatment of patients prone to envious attacks and, in particular, to attacks on linking.

Adolescent↗