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Biomedical subjects

J Williams

Publications and source records attributed to J Williams.

At least 505 records · Page 28Linked to original sources
PubMed1995

No association between schizophrenia and polymorphisms within the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT).

It has been suggested that the cytochrome P450 mono-oxygenase, debrisoquine 4-hydroxylase, is involved in the catabolism and processing of neurotransmitters subsequent to their reuptake into target cells. It is also thought to be related to the dopamine transporter that acts to take released dopamine back up into presynaptic terminals. The present study used the association approach to test the hypothesis that mutations in the genes for debrisoquine 4-hydroxylase (CYP2D6) and the dopamine transporter (DAT) confer susceptibility to schizophrenia. There were no differences in allele or genotype frequencies between patients and controls in the mutations causing the poor metaboliser phenotype in CYP2D6. In addition there was no association found between schizophrenia and a 48bp repeat within the 3' untranslated region of DAT.

Adolescent↗
PubMed1995

Non-peptidic inhibitors of human leukocyte elastase. 4. Design, synthesis, and in vitro and in vivo activity of a series of beta-carbolinone-containing trifluoromethyl ketones.

A novel series of human leukocyte elastase (HLE) inhibitors containing the beta-carbolinone ring system are reported. The design of these trifluoromethyl ketone-based inhibitors used a combination of structural information obtained from X-ray crystallography and molecular modeling investigations. The beta-carbolinone ring in these compounds serves as a highly efficient peptidiomimetic for the P2-P3 region of peptidyl trifluoromethyl ketone inhibitors of HLE. Several of the beta-carbolinones exhibit significant in vitro potency, with Ki values in the nanomolar range. Using aqueous molecular dynamics simulations, realistic models for the molecular recognition of these inhibitors by HLE have been obtained and are discussed. This series of compounds are found to have excellent selectivity for HLE over a number of other proteolytic enzymes, including closely related enzymes such as porcine pancreatic elastase.

Amino Acid Sequence↗
PubMed1995

Prenatal identification of i(Yp) by molecular cytogenetic analysis.

An i(Yp) is a rare marker chromosome. We present a case of de novo 46,X,i(Yp) detected prenatally in an amniotic fluid specimen. Fluorescence in situ hybridization (FISH) studies using a panel of Y-specific biotinylated DNA probes identified the marker chromosome as i(Yp). Comparative genomic hybridization (CGH) studies further confirmed the diagnosis. Upon pregnancy termination, external examination of the fetus revealed a generally well-developed male fetus with slight facial dysmorphism and prominent rocker-bottom feet. The molecular cytogenetic data in this case proved very useful in genetic counselling and served as a good example illustrating the important role of molecular techniques for accurate identification of marker chromosomes.

Adult↗
PubMed1995

Improved viability of hepatic allografts from fasted donors is associated with decreased peripheral TNF activity.

Despite improvements in preservation solutions, hepatic allografts continue to be lost from primary nonfunction. Previous work by this group and others has established that donor fasting improves the viability of hepatic allografts. We have also established an association between viability of stored organs and serum TNF levels. The purpose of this study was to determine whether improved viability of hepatic allografts from fasted donors is associated with lower peripheral serum TNF levels. TNF was measured using a bioassay employing a WEHI cell line. Transplanted livers from fasted donors displayed gross deglycogenation had less bile flow postrevascularization and increased postoperative AST, but had significant improvement in viability and were associated with significantly less TNF recovered from the peripheral circulation. The association of improved viability and diminished serum TNF and previous work that links changes in postrevascularization TNF levels with changes in Kupffer cell activity suggest a possible cause for improved survival of recipients of fasted allografts.

Animals↗
PubMed1995

Modulation of adhesion molecules by cytokines in vivo using human/severe combined immunodeficient (SCID) mouse chimeras.

Endothelial cell-leukocyte interactions involve multiple cell adhesion molecules acting in a programmed and sequential manner to create a leukocyte-endothelial cell adhesion cascade. To understand this process fully, in vivo models are needed. To accomplish this, we have transplanted pieces of normal human tissues onto immunodeficient mice to create chimeric animals. In one model, human skin is grafted and closely resembles normal skin histologically. The grafts retain their human vasculature and show low baseline expression of E-selectin, vascular cell adhesion molecule-1, and intercellular cell adhesion molecule-1. After intradermal injection of human cytokines, these cell adhesion molecules are markedly upregulated and an active inflammatory reaction ensues, with migration of murine leukocytes. Intravenous injection of an anti-human E-selectin antibody completely inhibits leukocyte accumulation induced by tumor necrosis factor-alpha but only partially inhibits leukotriene B4-induced inflammation. In a second model, human bronchus was successfully transplanted heterotopically into severe combined immunodeficient mice. Injection of tumor necrosis factor induced upregulation of E-selectin, intercellular cell adhesion molecule-1, and vascular cell adhesion molecule-1 in the submucosal microvessels, with slightly different kinetics than in the skin. In conclusion, human-severe combined immunodeficient chimeric mice represent a useful model system to study the regulation and function of human cell adhesion molecules in an in vivo setting.

Animals↗
PubMed1995

Validation of an enzyme immunoassay for serodiagnosis of acute Q fever.

An enzyme immunoassay was validated for the serodiagnosis of acute Q fever. Minimum positive tests were determined for both serial dilutions and a single dilution of patient sera. To establish the specificity of the test, 152 serum samples were tested from individuals with no evidence of past Coxiella burnetii infection. Diagnostic titers were set at > or = 128 for the IgM and IgG responses to phase I, at > or = 512 for the IgM response to phase II and at > or = 1,024 for the IgG response to phase II Coxiella burnetii. These titers gave a false-positive rate of < or = 1%. Alternatively, testing a single dilution of sera (1:128) gave specificities ranging from 97.3 to 98.7%. Tests with the greatest sensitivities, using serially diluted early convalescent-phase sera, were the IgM (84%) and IgG (80%) responses to phase II Coxiella burnetii. At a single serum dilution, 92% of early convalescent sera had a positive IgG response to phase II Coxiella burnetii. With a high specificity and good sensitivity, the EIA can be used to diagnose acute Q fever with a single convalescent serum specimen. The duration of a positive response was greater than five years.

Coxiella burnetii↗
PubMed1995

Comparison of the effects of sumatriptan and the NK1 antagonist CP-99,994 on plasma extravasation in Dura mater and c-fos mRNA expression in trigeminal nucleus caudalis of rats.

Dural plasma extravasation produced by electrical stimulation of the trigeminal ganglion was measured in rats and the concomitant expression of c-fos mRNA produced in the trigeminal nucleus caudalis (NtV) was measured using in situ hybridization techniques. The non-peptide NK1 receptor selective antagonist CP-99,994 (1-3000 micrograms kg-1) and the 5HT1D receptor agonist sumatriptan (1-1000 micrograms kg-1) reduced dural plasma extravasation dose-dependently with ID50S of 52 micrograms kg-1 and 30 micrograms kg-1 respectively. CP-99,994 (1000 micrograms kg-1). a compound known to have good brain penetration, decreased c-fos mRNA expression in the NtV by 37 +/- 7% without disruption of the blood brain barrier (BBB). Sumatriptan (1000 micrograms kg-1), known to be poorly brain penetrant, had no significant effect on c-fos mRNA expression in the NtV unless the BBB was disrupted by infusion of a hyperosmolar mannitol solution after which sumatriptan decreased c-fos mRNA expression by 65 +/- 11%. The results suggest that brain penetrant NK1 receptor antagonists may have anti-migraine effects peripherally through blockade of dural extravasation and centrally by inhibition of nociceptive pathways. Furthermore the data indicates that the anti-migraine action of sumatriptan must be predominantly peripherally mediated, be it via inhibition of plasma extravasation or direct vasoconstriction, since it had little effect on the activation of neurones in the NtV unless the BBB was disrupted.

Animals↗
PubMed1995

Identification of genes downregulated in the thymus by cyclosporin-A: preliminary characterization of clone CSA-19.

Using a novel subtractive hybridization approach, we have identified a set of cDNA clones whose expression is downregulated in the thymus by cyclosporin-A (CsA). A number of regulated genes were identified, but the major focus of this report is the clone termed CsA-19. In the adult mouse, CsA-19 is expressed at high levels in lymphoid organs, particularly in secondary lymphoid organs such as lymph node and spleen. CsA-19 expression was also found to be regulated in the brain and liver during mouse development. The full length sequences of the murine and human CsA-19 cDNAs have been determined. Both are 700 nucleotides in length and encode a predicted product of 217 amino acids. Comparison of the full length cDNA sequences of murine and human CsA-19 reveal that they are greater than 91% conserved. At the predicted amino acid level the homology is even greater, with only two amino acid differences in 217 residues (99% identity). The high degree of homology between murine and human CsA-19 indicates that has there been strong evolutionary pressure to conserve the amino acid sequence of CsA-19, and suggests that CsA-19 may play a critical role both during embryogenesis and in mature lymphoid cells.

Amino Acid Sequence↗
PubMed1995

Krox20 may play a key role in the stabilization of long-term potentiation.

Long-term potentiation-inducing stimulation of the perforant path was followed in dentate gyrus granule cells by a dramatic increase of mRNA and protein for Krox20, a zinc-finger-containing transcription factor. Induction of Krox20 required stimulation sufficient to induce LTP and was prevented by NMDA antagonists CPP and MK-801, which block LTP induction. Krox20 protein increased within 20 min of tetanization, was maximal between 1 and 8 h, and was still significantly elevated at 24 h after LTP induction. This prolonged appearance is in striking contrast with the more transient induction of the related molecule, Krox24. The elevation in the mRNA for Krox20 and Krox24 was of similar duration, suggesting that the Krox20 protein has a greater stability and may play a key role in the stabilization of long-term potentiation.

Animals↗
PubMed1995

Analysis of the decremental nature of LTP in the dentate gyrus.

The persistence of long-term potentiation (LTP) in the dentate gyrus was compared for two tetanization protocols: 50 trains on one day, or 50 trains on 5 consecutive days. LTP induction was significantly greater in the 250 train condition, but the LTP decay rate over weeks was similar between conditions. The decay of LTP could not be accounted for by deterioration of the preparation. Successive days of stimulation caused repetitive induction of immediate early genes, but did not prolong LTP, suggesting that either the effects of gene expression on LTP stabilization had saturated, or that these genes play other roles in synaptic plasticity.

Animals↗
PubMed1995

Implementing a tuberculosis control program.

Between January 1989 and December 1990, 26 patients acquired multidrug-resistant tuberculosis at our institution. Their exposures occurred when they were admitted to a ward where a patient with acid fast bacillus smear-positive pulmonary tuberculosis was also admitted. In 20 cases, the infectious patients were not isolated until the sputum smears were positive. When the outbreak was recognized in the spring of 1990, the infection control department undertook a risk assessment and instituted measures that would become the tuberculosis control program. Since then, administrative and environmental controls have been implemented, education programs are ongoing, personal protective equipment is in use, and a more aggressive employee health testing program is underway. The steps we took and the barriers we had to overcome to implement our plan are included in this article.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Inactivation of Kupffer cells after prolonged donor fasting improves viability of transplanted hepatic allografts.

Data from recent studies suggest that donor fasting imparts a beneficial effect on the viability of transplanted hepatic allografts. Because starvation may temporarily inactivate Kupffer cells, and because these cells are the likely mediators of liver injury after prolonged preservation-reperfusion, the purpose of this study is to establish a link between improved organ viability and Kupffer cell inactivation caused by donor allograft fasting. In an in vivo rat liver transplant model, 48 hours of donor fasting (1) improved allograft viability, (2) significantly decreased Kupffer cell phagocytosis, and (3) significantly decreased cytokine (tumor necrosis factor [TNF]) production postrevascularization. These data validate work from previous studies demonstrating that donor fasting improves allograft viability and furthermore support our previous research implicating activation of Kupffer cells as a causative agent of cold ischemia-preservation injury.

Animals↗
PubMed1995

Morphogenesis in Dictyostelium: new twists to a not-so-old tale.

Prespore differentiation requires both cAMP-dependent protein kinase and the transcription factor GBF, and for one class of prespore genes the two form part of a single pathway. It seems that differentiation-inducing factor, the inducer of prestalk cell differentiation, may operate via a calcium signalling pathway, and terminal stalk cell differentiation is in part regulated by glycogen synthase kinase 3.

Animals↗
PubMed1995

Plasma erythropoietin reference ranges in children.

Plasma erythropoietin values were determined in 1122 hospitalized and outpatient children aged 1 to 18 years with a commercially available enzyme-linked immunosorbent assay. A computerized approach based on the Hoffman technique was used to establish erythropoietin reference ranges. Plasma erythropoietin values ranged from 1.0 to 21.9 mIU/ml in male subjects, and from 1.1 to 20.5 mIU/ml in female subjects (2.5th to 97.5th percentiles).

Adolescent↗