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Biomedical subjects

G Williams

Publications and source records attributed to G Williams.

At least 307 records · Page 17Linked to original sources
PubMed1995

Increased neuropeptide Y secretion in the hypothalamic paraventricular nucleus of obese (fa/fa) Zucker rats.

NPY is synthesized in the hypothalamic arcuate nucleus (ARC), and NPY injected into the paraventricular nucleus (PVN), the main site of NPY release, induces hyperphagia and reduces energy expenditure. Hypothalamic NPY mRNA and NPY levels are increased in fatty Zucker rats, consistent with increased NPY release. This could explain the hyperphagia and reduced energy expenditure, which lead to obesity in the fatty Zucker rat. We have therefore compared NPY secretion in the PVN of conscious fatty and lean Zucker rats using push-pull sampling. The NPY secretory profile was consistently higher in fatty Zucker rats than in lean rats throughout the 3-h study period (P < 0.01), and mean NPY secretion over the whole 3 h was increased 2-fold in the fatty rats (P < 0.001). We conclude that fatty Zucker rats have increased NPY release in the PVN. This observation further supports the hypothesis that increased activity of the NPYergic ARC-PVN pathway may contribute to obesity in the fatty Zucker syndrome.

Animals↗
PubMed1995

Malignant disease in patients with long-term renal transplants.

The incidence of de novo malignancy was analyzed in 274 renal transplant recipients whose graft had functioned for at least 3 years and who had been followed for 2622 patient-years and individually for up to 29 years. The actuarial incidence and relative risks (RR) of tumor development (compared with National statistics) were calculated. Subgroup analysis was performed according to age, sex, the number of years and type of immunosuppression, and the tumor type. Seventy one tumors occurred in 54 patients. Skin tumors were the most common, followed by lymphoma, renal, bladder, and bronchial carcinoma. The actuarial cumulative risks of tumor development were 18.4% (95% confidence interval [CI] 12.4-24.3%) at 10 years and 49.6% (95% CI 36.3-62.0%) at 20 years. The overall RR of developing a tumor was 6.2 but was higher for men (RR 7.3) than women (RR 4.9). The RR of developing skin cancers, but not other malignancies, increased from 6.6 at 5 years to 20 after > 15 years. There was no evidence that cyclosporine-treated patients had an increased incidence of tumors, indeed the risk may be less in patients treated with cyclosporine and low-dose azathioprine than in those treated with azathioprine and prednisolone alone after more than 5 years.

Adolescent↗
PubMed1995

Mutagenesis of immunoglobulin-like domains from the extracellular human interferon-gamma receptor alpha chain and their recognition by neutralizing antibodies monitored by surface plasmon resonance technology.

The extracellular portion of the human interferon-gamma receptor (IFN-gamma R) is predicted to adopt two Ig-like domains each with Ig superfamily type C2 topology. Surface plasmon resonance technology has been used here to compare the equilibrium and kinetic constants for binding reactions between these and several mutant domains, and neutralising anti-IFN-gamma R monoclonal antibodies. The biosensor measurements provide a sensitive method for monitoring the effects of mutations on the functional epitopes recognized by the neutralising antibodies. Thus, using recombinant native-like proteins made in E. coli, the ten N-terminal residues of the receptor were found not to be essential for domain folding, nor for recognition by the antibodies A6, D2 and gamma R38. In a similar way, residues in the interdomain region were found to play an important functional role in the epitope recognized by the antibody gamma R99.

Amino Acid Sequence↗
PubMed1995

Dissection of the extracellular human interferon gamma receptor alpha-chain into two immunoglobulin-like domains. Production in an Escherichia coli thioredoxin gene fusion expression system and recognition by neutralizing antibodies.

The extracellular interferon gamma receptor alpha-chain (IFN gamma R) is believed to comprise two discrete approximately 110 amino acid immunoglobulin-like domains, perhaps similar to those seen in the crystal structure of the extracellular human growth hormone receptor [De Vos, A. M., Ultsch, M., & Kossiakoff, A. (1992) Science 255, 306-312], a distant relative in the cytokine receptor superfamily. In accord with this idea, we show that these IFN gamma R immunoglobulin-like domains can be produced separately in a soluble form with a native-like fold. The N-terminal domain (residues 1-108), with a Cys105 to Ser105 mutation, was produced at a high level, in a soluble form, as a thioredoxin-interferon gamma receptor fragment fusion protein in the cytoplasm of Escherichia coli. Upon extraction, the receptor Cys60-Cys68 disulfide bond formed spontaneously, to generate a native-like structure directly without the need for refolding. Cleavage of the fusion protein by enterokinase released the receptor fragment (approximately 12 kDa), which was recognized by several neutralizing antibodies with affinities, measured using surface plasmon resonance technology, that were essentially indistinguishable from those seen with the full length extracellular IFN gamma R produced in eukaryotic cells. Circular dichroism and 1D 1H nuclear magnetic resonance spectra indicated that the receptor fragment adopts a folded state, with mainly beta-sheet and reverse turn secondary structure. The second membrane-proximal Ig-like domain of the IFN gamma R (residues 90-229) was produced, albeit less efficiently, and characterized in a similar way. The production of these two independently folded proteins provides experimental support for the two domain organization of the IFN gamma R and opens new avenues for structural studies on these Ig-like molecules by NMR and crystallographic methods.

Amino Acid Sequence↗
PubMed1995

Cytokine profile in acute myelofibrosis associated with aggressive large granular lymphocyte leukemia.

We report a patient with acute large granular lymphocyte (LGL) leukemia, presenting as acute myelofibrosis (AMF). The leukemic cells were immature T-cells (CD5+, CD7+, CD16-, CD56-, CD57-, and CD41-), had monosomy 7, and secreted large amounts of Transforming Growth Factor-beta 1(TGF-beta 1). The serum levels of interleukins (IL)-2, -2R, -6 and -8 were elevated, while the IL-1 beta, IL-4, and tumor necrosis factor-alpha were normal.

Acute Disease↗
PubMed1995

Variable region cDNA sequences and characterization of murine anti-human interferon gamma receptor monoclonal antibodies that inhibit receptor binding by interferon gamma.

Murine monoclonal antibodies (mAbs) are described that recognize the extracellular human interferon gamma receptor alpha-chain (IFN gamma R) and inhibit the binding to it of interferon gamma. The inhibitory activities (IC50s) of these mAbs, quantified by radioimmunoassay using native receptor on human Raji cells, lie in the range 0.5-24 nM, whereas their relative affinities for the immobilised recombinant extracellular receptor, determined using surface plasmon resonance technology, are in the range 0.6-40.9 nM. Nine mAbs derived from one immunization, were shown by variable region cDNA sequencing to be clonally related, with mAb A6 from this group showing the highest affinity for the receptor. Another two mAbs, gamma R38 and gamma R99, derived from a separate immunization, are clonally unrelated to each other and to those in the A6 family. From the V-region sequences, the L-chains of mAbs A6, gamma R38 and gamma R99 were shown to belong to the V kappa 34C, V kappa 34C and V kappa 1 families, whereas the H-chains belong to the 3069, J606 and J558 families, respectively. The mAbs A6 and gamma R38 recognize overlapping epitopes on the N-terminal Ig-like domain of the IFN gamma R, whereas the gamma R99 epitope is located largely in the membrane proximal Ig-like domain. Sequence comparisons with Ig structures solved by X-ray diffraction allowed deductions concerning likely CDR canonical conformations. These studies provide essential information for crystallographic and mutagenesis experiments aimed at understanding the molecular basis of the interactions of these mAbs with the extracellular IFN gamma R.

Amino Acid Sequence↗
PubMed1995

Neuropeptide Y, the hypothalamus, and diabetes: insights into the central control of metabolism.

Neuropeptide Y (NPY), a major brain neurotransmitter, is expressed in neurons of the hypothalamic arcuate nucleus (ARC) that project mainly to the paraventricular nucleus (PVN), an important site of NPY release. NPY synthesis in the ARC is thought to be regulated by several factors, notably insulin, which may exert an inhibitory action. The effects of NPY injected into the PVN and other sites include hyperphagia, reduced energy expenditure and enhanced weight gain, insulin secretion, and stimulation of corticotropin and corticosterone release. The ARC-PVN projection appears to be overactive in insulin-deficient diabetic rats, and could contribute to the compensatory hyperphagia and reduced energy expenditure, and pituitary dysfunction found in these animals; overactivity of these NPY neurons may be due to reduction of insulin's normal inhibitory effect. The ARC-PVN projection is also stimulated in rat models of obesity +/- non-insulin diabetes, possibly because the hypothalamus is resistant to inhibition by insulin; in these animals, enhanced activity of ARC NPY neurons could cause hyperphagia, reduced energy expenditure, and obesity, and perhaps contribute to hyperinsulinemia and altered pituitary secretion. Overall, these findings suggest that NPY released in the hypothalamuss, especially from the ARC-PVN projection, plays a key role in the hypothalamic regulation of energy balance and metabolism. NPY is also found in the human hypothalamus. Its roles (if any) in human homeostasis and glucoregulation remain enigmatic, but the animal studies have identified it as a potential target for new drugs to treat obesity and perhaps NIDDM.

Animals↗
PubMed1995

Psychomotor seizures of temporal lobe onset: analysis of symptom clusters and sequences.

We analyzed 91 psychomotor seizures from 31 patients seizure free at least one year after temporal lobectomy (implying temporal lobe onset). Fifty symptoms were looked for in every seizure and their time of onset and ending noted. Statistical analysis was used to define symptom clusters and the order of appearance of symptoms. Of the eighteen most common symptoms examined, all of these symptoms form a tight cluster showing a high degree of correlation. Within this cluster, there was a tendency towards the following subclusters: (a) epigastric aura, ictal vomiting, alimentary and hand automatisms; (b) behavioral arrest, complete loss of consciousness, staring and bilateral facial contraction; (c) unilateral dystonic posturing of an arm, mimetic automatisms, complex gestures, ictal speech and partial loss of consciousness; (d) looking around, agitation, vocalizations and whole body movements. We also found a strong correlation between epigastric sensation and ictal vomiting in psychomotor seizures arising from the right but not the left temporal lobe. The commonest sequence of symptoms was: behavioral arrest followed by alimentary and hand automatisms, looking around and whole body movements, in that order.

Cluster Analysis↗
PubMed1995

Flow motion in peripheral diabetic neuropathy.

1. Flow motion is the cyclical variation in blood flow owing to the rhythmical opening and closing of arterioles. Previous studies have suggested that cutaneous flow motion may be altered in diabetic neuropathy but have not been consistent in their findings. 2. In order to assess the effect of diabetic peripheral neuropathy on flow motion, we have examined the frequency and amplitude of flow motion in 12 patients with diabetic peripheral neuropathy, 10 age-matched diabetic patients without peripheral neuropathy and 10 age-matched non-diabetic controls. 3. Peripheral neuropathy was diagnosed by a history of foot ulceration or chronic painful neuropathy, clinical examination and abnormal peroneal nerve conduction velocities. Blood flow, using laser Doppler flowmetry, was measured at four sites on the dorsum of both hands and feet. Flow motion was analysed using fast Fourier transform analysis, between 0.05 and 0.2 Hz, and displayed on a power spectral density graph. Predominant frequency and relative amplitude of flow motion were calculated. 4. Relative amplitude and frequency of flow motion were similar in the hands of all three groups, as was the frequency in the feet of the three groups. Relative amplitude was significantly smaller in the feet of diabetic patients with neuropathy (median 7.2%, 95% confidence interval 4.9-9.4%) than in diabetic patients without neuropathy (median 13.5%, 95% confidence interval 6.3-21.5%, P < 0.02) or in non-diabetic control subjects (median 10.3%, 95% confidence interval 6.9-27.4%, P < 0.02). 5. Flow motion amplitude is reduced in diabetic peripheral neuropathy. The control of flow motion amplitude appears to be at least partly under neurological control.

Diabetes Mellitus↗
PubMed1995

Selective enhancement of alpha 2-adrenoceptor-mediated vasoconstriction in insulin-dependent diabetic patients with microalbuminuria.

1. Microalbuminuria, the earliest clinical marker of microvascular disease, is an important predictor of early death in insulin-dependent diabetes, and abnormal vascular reactivity may contribute to microvascular disease. We have previously found that vasoconstrictive responses to noradrenaline are exaggerated in insulin-dependent diabetic patients with microalbuminuria as compared with both normoalbuminuric insulin-dependent diabetic patients and non-diabetic control subjects. 2. To determine whether this is due to increased sensitivity at alpha 1- or alpha 2-adrenergic receptors, we compared vascular responses to the alpha 1-adrenergic agonist phenylephrine and the alpha 2-adrenergic agonist clonidine. 3. We studied 15 insulin-dependent diabetic patients with microalbuminuria, 15 insulin-dependent diabetic patients with normal urinary albumin excretion and 14 non-diabetic subjects. Vascular constrictive responses were measured in dorsal hand veins. 4. No difference in vasoreactivity to phenylephrine was demonstrated between any of the three groups. However, enhanced vascular responsitivity to clonidine at infusion rates of 16-2048 ng/min (analysis of variance, P < 0.001) was found in insulin-dependent diabetic patients with microalbuminuria as compared with both non-diabetic control subjects and normoalbuminuric insulin-dependent diabetic patients. There were no significant differences between the dose-response curves of the diabetic group with normal urinary albumin excretion and the non-diabetic group. 5. Vasoconstriction mediated by alpha 2-adrenergic receptors is therefore enhanced in normotensive insulin-dependent diabetic patients with microalbuminuria. If also present at the level of the peripheral resistance arterioles or the efferent glomerular arterioles, this could lead to systemic and intraglomerular hypertension, factors which may contribute to the development of diabetic nephropathy.

Adult↗
PubMed1995

Strategic developments in drug and alcohol policy.

This review of recent developments in drug and alcohol policy investigates the reasons behind those developments and questions some of the directions in which this policy is taking the services. There is a possibility that services may become superficial and it appears that there are clients who are effectively denied public health services.

Journal Article↗
PubMed1995

Simulation of the upper gastrointestinal fluoroscopic examination for calculation of absorbed dose in tissue.

In order to simulate the upper gastrointestinal fluoroscopic examination, modifications were made to the Monte Carlo radiation-transport code that uses the anthropomorphic, mathematical reference phantoms ADAM and EVA. A set of discrete x-ray field projections of the principal anatomy of clinical interest has been previously defined. This note describes the new features incorporated in the simulations--divergent beams in oblique irradiation geometries, an esophagus and a duodenum, a double contrast medium consisting of a BaSO4-H2O mixture and air in the esophagus, stomach, and duodenum, and clinically representative beam qualities. The absorbed doses in tissues per unit entrance exposure (free-in-air) computed with the modified code appeared in Department of Health and Human Services Publication FDA 92-8282, Handbook of Selected Tissue Doses for the Upper Gastrointestinal Fluoroscopic Examination. A minor correction is described for the previously reported results for the esophagus.

Contrast Media↗