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Biomedical subjects

G Williams

Publications and source records attributed to G Williams.

At least 289 records · Page 16Linked to original sources
PubMed1996

Dissociation of body-temperature and melatonin secretion circadian rhythms in patients with chronic fatigue syndrome.

Many patients with chronic fatigue syndrome (CFS) display features of hypothalamic dysfunction. We have investigated aspects of circadian rhythmicity, an important hypothalamic function, in 20 CFS patients and in 17 age- and sex-matched healthy control subjects. There were no differences between the two groups in the amplitude, mesor (mean value) or timing of the peak (acrophase) of the circadian rhythm of core temperature, or in the timing of the onset of melatonin secretion. However, the CFS patients showed no significant correlation between the timing of the temperature acrophase and the melatonin onset (P < 0.5), whereas the normal significant correlation was observed in the controls (P < 0.05). Dissociation of circadian rhythms could be due to the sleep deprivation and social disruption, and/or the reduction in physical activity which typically accompany CFS. By analogy with jet-lag and shift-working, circadian dysrhythmia could be an important factor in initiating and perpetuating the cardinal symptoms of CFS, notably tiredness, impaired concentration and intellectual impairment.

Adult↗
PubMed1996

Isolation and characterization of the cDNA encoding BKLF/TEF-2, a major CACCC-box-binding protein in erythroid cells and selected other cells.

CACCC boxes are among the critical sequences present in regulatory elements of genes expressed in erythroid cells, as well as in selected other cell types. While an erythroid cell-specific CACCC-box-binding protein, EKLF, has been shown to be required in vivo for proper expression of the adult beta-globin gene, it is dispensable for the regulation of several other globin and nonglobin erythroid cell-expressed genes. In the work described here, we searched for additional CACCC-box transcription factors that might be active in murine erythroid cells. We identified a major gel shift activity (termed BKLF), present in yolk sac and fetal liver erythroid cells, that could be distinguished from EKLF by specific antisera. Through relaxed-stringency hybridization, we obtained the cDNA encoding BKLF, a highly basic, novel zinc finger protein that is related to EKLF and other Krüppel-like members in its DNA-binding domain but unrelated elsewhere. BKLF, which is widely but not ubiquitously expressed in cell lines, is highly expressed in the midbrain region of embryonic mice and appears to correspond to the gel shift activity TEF-2, a transcriptional activator implicated in regulation of the simian virus 40 enhancer and other CACCC-box-containing regulatory elements. Because BKLF binds with high affinity and preferentially over Sp1 to many CACCC sequences of erythroid cell expressed genes, it is likely to participate in the control of many genes whose expression appears independent of the action of EKLF.

Amino Acid Sequence↗
PubMed1996

Microsatellite instability in early onset and familial colorectal cancer.

Hereditary non-polyposis colorectal cancer syndrome (HNPCC) is often considered to be the most common form of inherited colorectal cancer, although its precise incidence is unknown. The clinical diagnosis of HNPCC relies on a combination of family history and young age of onset of colorectal cancer, but as many familial aggregations of colorectal cancer do not fulfil the strict diagnostic criteria, HNPCC might be underdiagnosed. The majority of HNPCC families have germline mutations in mismatch repair (MMR) genes, such as MSH2 or MLH1, so that HNPCC cancers characteristically exhibit DNA replication errors (RERs) at microsatellite loci. Although an RER positive phenotype in tumours can also result from somatic mutations in an MMR gene, the prevalence of RER + tumours should provide a maximum estimate of the incidence of germline MMR gene mutations in patients with early onset and familial colorectal cancer. We investigated colorectal cancers for RERs from (1) a population based study of 33 patients with colorectal cancer aged 45 years or less, (2) 65 kindreds with familial colorectal cancer which only partially fulfilled the criteria for the diagnosis of HNPCC, and (3) 18 cancers from 12 HNPCC kindreds. Seven of 33 patients (21%) with colorectal cancer aged 45 years or less had an RER + cancer, with only two of these having a clear family history of HNPCC. A greater proportion of RER + tumours (5/7) occurred proximal to the splenic flexure than RER - tumours (4/26; chi2 = 6.14, p < 0.025). RERs were detected in all 18 cancers from HNPCC patients but in only six of 65 non-HNPCC familial colorectal cancer kindreds (9%; chi2 = 52.2, p < 0.0005). These findings suggest that most cancers in patients diagnosed at 45 years of age or less and familial aggregations of colorectal cancer which do not fulfil HNPCC diagnostic criteria do not have germline mutations in MSH2 and MLH1. Hence population screening for germline mutations in these genes is unlikely to be an efficient strategy for identifying people at high risk of developing colorectal cancer.

Adult↗
PubMed1996

Dissociation of hypothalamic NPY from BAT uncoupling protein mRNA in rats exposed to 24 h thermoneutrality.

Neuropeptide Y (NPY) is increasingly considered to be involved in the central regulation of energy balance. Our previous studies suggest that hypothalamic NPY neurons of the arcuatoparaventricular (ARC-PVN) projection are inhibited in association with the marked increases in brown adipose tissue (BAT) thermogenesis and uncoupling protein (UCP) gene expression in rats exposed to cold. We therefore hypothesized that the NPYergic ARC-PVN system would be activated in a thermoneutral environment, when energy expenditure falls to a minimum, and that this activation could mediate the fall in BAT activity. We measured regional hypothalamic NPY concentrations, hypothalamic NPY receptor binding, and NPY mRNA together with UCP mRNA levels in rats exposed to thermoneutrality (29 degrees C) for 24 h. At thermoneutrality, UCP mRNA levels fell to 42% of those in controls maintained at 22 degrees C, but there were no significant changes in hypothalamic NPY or NPY mRNA levels or in NPY receptor binding. We conclude that the fall in UCP mRNA expression occurring under short-term thermoneutral condition is mediated by neuroendocrine mechanisms other than increased activity of hypothalamic NPY neurons.

Adipose Tissue, Brown↗
PubMed1996

Effects of transforming growth factor-beta 1 on nitric oxide synthesis by C2C12 skeletal myocytes.

The production of nitric oxide (NO) via the inducible form of NO synthase (iNOS) is regulated by a complex network of cytokines and endogenous hormones. Among these, transforming growth factor-beta (TGF-beta 1) is known to suppress iNOS expression and NO production by many cell types. To determine the effect of TGF-beta 1 on NO production by skeletal muscle cells, we stimulated C2C12 myocytes with interferon-gamma (IFN) and interleukin-1 (IL-1) in the presence or absence of TGF-beta 1. In contrast to findings in macrophages, TGF-beta 1 markedly enhanced NO production by skeletal muscle cells. Increases in NO production reflected significant increases in iNOS immunoreactive protein and iNOS mRNA. Elevated iNOS mRNA levels associated with TGF-beta 1 treatment were not due to an alteration in mRNA stability, but rather reflected a significantly increased transcriptional rate of the iNOS gene. These findings indicate that TGF-beta 1 enhances iNOS expression in skeletal muscle cells and suggest that the regulation of NO production by TGF-beta 1 may depend on the cell type studied.

Animals↗
PubMed1996

Expression of the inducible nitric oxide synthase gene in diaphragm and skeletal muscle.

Nitric oxide (NO) is a pluripotent molecule that can be secreted by skeletal muscle through the activity of the neuronal constitutive isoform of NO synthase. To determine whether skeletal muscle and diaphragm might also express the macrophage-inducible form of NO synthase (iNOS) during provocative states, we examined tissue from mice at serial times after intravenous administration of Escherichia coli endotoxin. In these studies, iNOS mRNA was strongly expressed in the diaphragm and skeletal muscle of mice 4 h after intravenous endotoxin and was significantly diminished by 8 h after challenge. Induction of iNOS mRNA was followed by expression of iNOS immunoreactive protein on Western immunoblots. Increased iNOS activity was demonstrated by conversion of arginine to citrulline. Immunochemical analysis of diaphragmatic explants exposed to endotoxin in vitro revealed specific iNOS staining in myocytes, in addition to macrophages and endothelium. These results may be important in understanding the pathogenesis of respiratory pump failure during septic shock, as well as skeletal muscle injury during inflammation or metabolic stress.

Animals↗
PubMed1996

Neuropeptide Y, the hypothalamus and the regulation of energy homeostasis.

Neuropeptide Y (NPY) neurones in the arcuate nucleus of the rodent hypothalamus may play a key role in responding to reductions in body energy stores with appropriate changes in energy homeostasis, namely an increase in food-seeking behaviour and hyperphagia, together with a reduction in heat production by brown adipose tissue. These adaptive responses are mimicked by the injection of NPY into the main sites of projection of the NPY neurones, and animals that are threatened by energy deficits (e.g. through starvation or insulin-deficient diabetes) show increased activity of these neurones. Genetically obese rodents also show hyperactivity of the NPY neurones, which is inappropriate to their energy needs and may contribute to their hyperphagia, reduced energy expenditure and excessive weight gain. The NPY neurones may be inhibited by insulin and leptin, which may both serve as signals of peripheral fat mass. Ultimately, characterization of the specific "feeding' receptors which mediate NPY's central effects on energy homeostasis may provide opportunities for designing drugs to manipulate and appetite and energy balance in man, notably obesity and the cachexia commonly associated with malignancy and chronic infection.

Animals↗
PubMed1996

Dual immunodetection and hybridisation in situ of opsin mRNA and rhodopsin protein in retinal sections.

We describe a simple method for combining in situ hybridisation and immunohistochemistry on the same retinal section. The technique was developed using a radiolabelled cDNA probe for opsin and an antibody (ROS1F4) against rhodopsin. This method retains the antigenic sites if immunocytochemistry is performed prior to in situ hybridisation. Opsin mRNA was found in the photoreceptor inner segment with rhodopsin immunolocalised to the photoreceptor outer segments. The technique should be applicable to numerous situations including analysis of the sequence of events in the expression and synthesis of the various opsins during retinal development and degeneration.

Antibodies, Monoclonal↗
PubMed1996

Short-term night-shift working mimics the pituitary-adrenocortical dysfunction in chronic fatigue syndrome.

The purpose of this study was to determine whether a short period (5 days) of night-shift work affected the pituitary-adrenal responses to CRH. Ten nurses (8 female and 2 male; age 28.1 +/- 1.7 yr: mean +/- SEM) working at the Royal Liverpool University Hospital, and who regularly undertook periods of night and day shift work were enrolled. Measurements were made of basal ACTH and cortisol concentrations, and their responses to iv ovine CRH (1 microgram.kg-1). Basal ACTH concentrations were higher during the night shift than during the day shift (12.9 +/- 5.1 pmol.L-1 vs. 4.7 +/- 1.2 pmol.L-1, P < 0.01) whereas cortisol concentrations were lower (551 +/- 48 nmol.L - 1 vs. 871 +/- 132 nmol.L - 1, P < 0.01). After CRH injection, ACTH concentrations remained consistently higher during the night shift, but the integrated increase in ACTH concentration was lower (P < 0.05) than during the day shift. Conversely, the increase in cortisol concentration was greater during the night shift than the day shift (283 +/- 53 nmol.L-1 vs. 134 +/- 41 nmol.L-1, P < 0.05). We conclude that the pituitary-adrenal responses to CRH are markedly disrupted after only 5 days of nighttime work. These abnormalities mimic those previously observed in patients with chronic fatigue syndrome. Neuroendocrine abnormalities reported to be characteristic of chronic fatigue syndrome may be merely the consequence of disrupted sleep and social routine.

Adrenal Cortex↗
PubMed1996

Do cyclosporin profiles provide useful information in the management of renal transplant recipients?

BACKGROUND: This study investigated the relationships between cyclosporin A (CsA) blood levels and episodes of renal allograft rejection and nephrotoxicity following renal transplantation, with the aim of establishing whether CsA profiles provided more useful information than single CsA blood levels in respect of these relationships. METHODS: One hundred and sixty-two profiles were performed over 16 months in 40 patients and analysed retrospectively. Blood samples were taken at 0, 2, 4, 6 and 8 h after the morning CsA dose. Rejection episodes were diagnosed by renal biopsy and CsA nephrotoxicity by a fall in serum creatinine 1 week after a cut in CsA dose. RESULTS: The mean area under the curve (AUC) was lower for profiles performed at the time of rejection (3821 h.ng/ml) than that of a matched group of non-rejecting profiles (5479 h.ng/ml; P < 0.02). An AUC above 6400 h.ng/ml significantly discriminated rejection from non-rejection, whereas pre-dose and peak CsA concentrations did not have such discriminating cut-off values. A comparison of CsA-toxic and non-toxic profiles showed that there were no significant differences between mean CsA concentrations nor between the mean AUCs of these groups. CONCLUSION: We conclude that basing CsA dosing on CsA profiles could help to avoid some early episodes of rejection without increasing the risk of nephrotoxicity.

Adult↗
PubMed1995

The serotonin (5-HT) antagonist methysergide increases neuropeptide Y (NPY) synthesis and secretion in the hypothalamus of the rat.

NPY is synthesized in neurons of the hypothalamic arcuate nucleus (ARC) which project to the paraventricular nucleus (PVN), an important site of NPY release. Serotonin (5-HT) has been suggested to induce satiety and 5-HT fibers contact NPY neurons in the ARC and PVN, suggesting that 5-HT could inhibit the ARC-PVN projection. Methysergide is a 5-HT antagonist which stimulates feeding in rats and increases NPY levels in the hypothalamus. To clarify the effects of methysergide on NPY, we examined its effects on NPY synthesis and on NPY secretion in the PVN using push-pull sampling. Hypothalamic NPY mRNA levels were measured in rats (n = 8/group) given either saline or methysergide (10 mg/kg) and killed after 4 h or after 7 days. Food intake was increased by 33% in the acute study and by 9% in the 7-day study (both P < 0.01). NPY mRNA levels were 80% higher in the 7-day study (P < 0.05) and unchanged in the acute study. NPY secretion was measured over a 3-h period after an i.p. injection of methysergide or saline (10 mg/kg, n = 12) with a flow rate of 15 microliters/min. Mean NPY secretion in the methysergide-injected rats was increased by 34% (P < 0.01). We conclude that methysergide induced feeding is associated with increased activity of the NPY neurons in the ARC-PVN projection. This is consistent with our previous findings suggesting that the NPYergic ARC-PVN projection may mediate, at least in part the effects of 5-HT on feeding and energy balance.

Animals↗
PubMed1995

Nicotine administration reduces neuropeptide Y and neuropeptide Y mRNA concentrations in the rat hypothalamus: NPY may mediate nicotine's effects on energy balance.

Neuropeptide Y (NPY) is synthesized in arcuate (ARC) neurons which project principally to the paraventricular nucleus (PVN). NPY injected into the PVN causes hyperphagia, reduced energy expenditure and eventually obesity, effects which are opposed by nicotine. We aimed to investigate whether nicotine's effects on energy balance might be mediated by inhibition of hypothalamic NPYergic neurons. Nicotine or saline was given for 1 or 12 days using osmotic minipumps, and additional groups of rats were food-restricted to the intake of the nicotine-treated groups to allow for the effects of hypophagia on hypothalamic NPY. One day's nicotine treatment (12 mg/kg/day) reduced food intake by 30% (P < 0.001) and body weight by 2% (P < 0.01 vs. controls). NPY mRNA levels were significantly reduced by 40% (P < 0.05) and NPY concentrations fell significantly by 33% in the ARC and PVN (both P < 0.01). Matched food restriction also reduced NPY levels significantly in the ARC and PVN (P < 0.02 vs. controls) but had no effect on NPY mRNA. 12 days' nicotine treatment (12 mg/kg/day) lowered cumulative food intake by 8% (P = 0.02) and body weight by 10% (P < 0.05). NPY mRNA levels rose by 40% (P < 0.05), while NPY levels again fell in the ARC and PVN (both P < 0.05). Food restriction, which induced weight loss comparable with that during nicotine treatment, increased NPY mRNA to levels that were 100% above controls (P < 0.01) and also significantly higher than in the nicotine-treated group (P < 0.05). Food restriction also reduced NPY peptide levels in the PVN (P < 0.02), but did not affect those in the ARC. In addition, 12 days' nicotine treatment significantly reduced plasma insulin levels compared with controls (P < 0.05). We suggest that nicotine may inhibit NPY synthesis in the hypothalamus, independently of any effects due to altered energy balance. Reduced activity of NPYergic neurons in the ARC-PVN projection may mediate the effects of nicotine on energy balance.

Animals↗