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Biomedical subjects

J Watson

Publications and source records attributed to J Watson.

At least 145 records · Page 8Linked to original sources
PubMed1996

Species differences in 5-HT autoreceptors.

Release of 5-HT in the CNS is under the control of autoreceptors. These autoreceptors fall into two categories: cell body autoreceptors and terminal autoreceptors. The former inhibit 5-HT release through inhibition of cell firing; the latter through direct inhibition of release at the terminal. Cell body (or somatodendritic) autoreceptors belong to the 5-HT1A receptor subtype in all species studied so far. In the rat and mouse, the terminal autoreceptor is known to be a 5-HT1B receptor, whereas in human, pig, rabbit, and guinea pig, the terminal autoreceptor is thought to belong to the 5-HT1D receptor subtype. Until recently, the absence of a potent and selective 5-HT1D receptor antagonist has hindered this classification. We now present data with the novel 5-HT1D receptor antagonist, GR 127935, which demonstrates that in guinea pig cerebral cortex the terminal autoreceptor is a 5-HT1D receptor. In vitro [3H]5-HT release studies demonstrate that 5-HT inhibition of [3H]5-HT release is attenuated by GR 127935. In vivo, using the technique of microdialysis, GR 127935 and the non-selective antagonist methiothepin, when administered down the dialysis probe, potentiate extracellular levels of 5-HT. Both the in vitro and in vivo effects of these compounds are consistent with terminal autoreceptor blockade. However, when GR 127935 and methiothepin were administered systemically, both compounds inhibit extracellular levels of 5-HT. The most plausible explanations for this effect, such as partial agonism or activation of somatodendritic 5-HT1A receptors, are discussed.

Animals↗
PubMed1996

Insulin translocates PKC-epsilon and phorbol esters induce and persistently translocate PKC-beta 2 in BC3H-1 myocytes.

Initial studies suggested that insulin increases diacylglycerol and activates protein kinase C (PKC) in BC3H-1 myocytes. In these earlier studies, insulin was found to translocate PKC-beta, but the presence of PKC-epsilon was not appreciated. More recently, the presence of PKC-epsilon was documented, but PKC-beta was not detected, and it was questioned whether insulin activates PKC in BC3H-1 myocytes [Stumpo, D.J., Haupt, D.M. and Blackshear, P.J. (1994) J. Biol. Chem. 269:21184-21190]. We questioned whether insulin translocates PKC-epsilon in BC3H-1 myocytes, and re-evaluated the question of whether myocytes truly contain a PKC-beta isoform whose existence can be verified by its response to phorbol ester treatment. We found that PKC-epsilon was acutely translocated by insulin and phorbol esters from the cytosol to the membrane fraction in BC3H-1 myocytes; in addition, PKC-epsilon, like PKC-alpha, was depleted by chronic phorbol ester treatment. We also found that BC3H-1 myocytes containing a 76,000 Mr PKC-beta isoform that is acutely translocated and subsequently depleted by phorbol esters. Moreover, chronic phorbol ester treatment induced an 84,000 Mr PKC-beta 2 isoform that appeared to be persistently translocated and activated, as suggested by studies of myristoylated arginic-rich C kinase substrate (MARCKS) phosphorylation. We conclude that: (1) insulin acutely translocates PKC-epsilon, as well as PKC-beta, in BC3H-1 myocytes; and (2) PKC-beta is not truly downregulated by phorbol esters in BC3H-1 myocytes.

Amino Acid Sequence↗
PubMed1996

Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study.

BACKGROUND/AIMS: Small, uncontrolled studies of ribavirin for patients with chronic hepatitis C have reported efficacy in chronic hepatitis C. We have evaluated the efficacy and safety of a 24-week course of oral ribavirin in patients with chronic hepatitis C, compared to placebo. METHODS: A total of 114 patients were randomised to ribavirin or placebo. Ribavirin was administered in doses of 1000 or 1200 mg/day for 24 weeks. Efficacy was determined in the intention-to-treat population: 76 received ribavirin and 38 placebo. RESULTS: Ribavirin was significantly more effective than placebo in reducing and normalising serum ALT levels: 42/76 (55%) of ribavirin-treated patients vs 2/38 (5%) placebo recipients had either normalisation of the ALT levels or a reduction from baseline of at least 50% (p < 0.001). ALT levels were normal in 22/76 (29%) of ribavirin-treated patients vs 0/38 placebo recipients (p < 0.001). Twenty-four weeks after stopping ribavirin, the majority of patients had abnormal ALT levels. There was no difference between the treatment groups in reduction or disappearance of HCV-RNA levels. HCV RNA disappeared during treatment in 3% of ribavirin-treated patients and 3% of placebo recipients. More ribavirin than placebo patients showed improvement in total Knodell score (45% vs 31%), but these differences were not statistically significant. Analysis of each component of a histology activity index revealed no statistically significant differences between treatment groups. Ribavirin patients had fewer lymphoid aggregates than did placebo recipients at the post-treatment assessment (p = 0.05). Ribavirin was associated with reversible haemolytic anaemia: a fall in haemoglobin occurred in 3% of placebo- and 32% (25/78) of ribavirin-treated patients, respectively (p < 0.001). CONCLUSIONS: These data indicate that ribavirin was no more effective than placebo in reducing or eliminating HCV-RNA levels, and was not significantly more effective than placebo in improving hepatic histology after 6 months of treatment. The role of a 6-month treatment of chronic hepatitis C with ribavirin alone, without a significant effect on HCV RNA, is therefore limited.

Administration, Oral↗
PubMed1996

Enteroaggregative Escherichia coli heat-stable enterotoxin is not restricted to enteroaggregative E. coli.

Enteroaggregative Escherichia coli (EAggEC) have been implicated as diarrheal pathogens in several settings. Some EAggEC produce a distinct heat-stable enterotoxin named EAST1. The distribution and prevalence of the EAST1 gene in selected groups of bacterial enteropathogens were determined by colony hybridization. One hundred percent of 75 O157:H7 enterohemorrhagic E. coli (EHEC), 41% of 227 EAggEC, 41% of 149 enterotoxigenic E. coli, 22% of 65 enteropathogenic E. coli (EPEC), and 38% of 47 E. coli stool isolates from asymptomatic children hybridized with an EAST1 DNA probe. None of 55 enteroinvasive E. coli, 12 Yersinia enterocolitica, or 20 Vibrio cholerae non-O1 strains were EAST1 probe-positive. Concordance between EAST1 genotype and enterotoxicity was shown in examined strains of EAggEC, EHEC, and EPEC. The gene encoding EAST1 is more broadly distributed among diarrheogenic E. coli than previously known and may represent an additional determinant in the pathogenesis of E. coli diarrhea.

Bacterial Adhesion↗
PubMed1996

Functional characterization of the 5-HT terminal autoreceptor in the guinea-pig brain cortex.

1 In guinea-pig cerebral cortical slices in vitro we have shown that the rank order of potency of 5-hydroxytrptamine (5-HT), 5-carboxamidotryptamine and sumatriptan for inhibition of electrically stimulated [3H]-5-HT release correlates well with published data on their 5-HT1D receptor binding affinities. 2 Both the non-selective 5-HT1D receptor antagonist, methiothepin and the selective 5-HT1D receptor antagonist, N-[4-methoxy-3-(4-methyl-1-piperazinyl]phenyl]-2'-methyl-4'- (5-methyl-1,2,4-oxadiazole-3-yl) [1,1-biphenyl]4-carboxamide (GR127935) increased stimulated [3H]-5-HT release per se and also attenuated agonist-induced inhibition of [3H]-5-HT release. GR127935 (10 nM-100 nM) produced a pA2 of 9.0 against 5-HT, which is consistent with its 5-HT1D receptor binding affinity. 3 From these findings we conclude that, in guinea-pig cerebral cortex, the 5-HT terminal autoreceptor is of the 5-HT1D receptor subtype. However, three observations suggest the presence of multiple terminal autoreceptors: shallow inhibition curves to the agonists; a shallow Schild slope of GR127935 antagonism and differences in the maximal responses to 5-HT between whole cortex and frontal cortex.

Animals↗
PubMed1996

Audit of the outcome of peptic ulcer disease diagnosed 10 to 20 years previously.

UNLABELLED: METHODS/AIMS: During 1993-1994 an audit of the outcomes of a consecutive series of peptic ulcer patients, first diagnosed endoscopically between 1972-1983, was carried out. Three hundred and thirty six patients fitting the entry criteria were identified, 46 had died in the interval, and 44 were lost to follow up, leaving 246 available for evaluation. All patients completed questionnaires on their current symptomatic state, drug treatment, and details of any operations they had undergone since their original diagnosis. In addition they were asked to indicate, on an analogue scale, their overall assessment of how their ulcer problem was affecting them at the time of the review. Where available hospital records were obtained and analysed for any further admissions and the results of any further endoscopies. RESULTS: Of the 246 patients, 158 were men and 88 female. Duodenal ulcers (DU) were present in 204 and gastric ulcers (GU) in 51 (nine had both a DU and GU). Since the diagnosis 65 patients had undergone surgical treatment: 44 for poor ulcer control, nine for pyloric stenosis, nine for a perforation, one for a major gastrointestinal bleed, and two for a gastric carcinoma developing within two years of the diagnosis of a GU. The overall incidence of ulcer complications during this follow up period (excluding the carcinomas) was 7.7%. Initial medical treatment was with histamine H2 blockade in 234 patients--87.4% cimetidine (C) and 11% ranitidine (R)--with other agents in the remainder. At follow up 176 patients were still receiving medical treatment (C, 71%: R, 22%, other, 7%) including 30 who had previously undergone a definitive surgical procedure. Dyspeptic symptoms were recorded in 50.4% of the patients, abdominal pain being the commonest complaint. There was a significant relation between abdominal pain and the analogue scores provided by the patients with significantly more (p = 0.02) of those who had undergone surgical treatment recording this as a continuing problem (44.6% v 36%). CONCLUSION: There is no evidence provided by this study that, in these patients, their ulcer disease is undergoing spontaneous remission with time.

Abdominal Pain↗
PubMed1996

Characterization of CP-122,721; a nonpeptide antagonist of the neurokinin NK1 receptor.

CP-122,721 [(+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2 -phenylpiperidine] interacts with high affinity (pIC50 = 9.8) at the human NK1 receptor expressed in IM-9 cells. In the presence of CP-122,721, there was a reduction in Bmax of [125I]BH-SP binding with no change in affinity suggesting that CP-122,721 does not interact with the NK1 receptor in competitive manner. In an in vitro functional assay. CP-122,721 blocked SP-induced excitation of locus ceruleus cells in guinea pig brain slices with a IC50 value of 7 nM. In vivo, CP-122,721 potently blocked plasma extravasation in guinea pig lung elicited by aerosolized capsaicin (1 mM) with an ID50 = 0.01 mg/kg, p.o. Orally administered CP-122,721 antagonized Sar9, Met (O2)11-SP-induced locomotor activity in guinea pigs with an ID50 = 0.2 mg/kg suggesting good entry into the central nervous system. In addition, consistent with insurmountable blockade observed in vitro, CP-122,721 (0.01, 0.03 0.3 mg/kg, p.o.) produced a rightward shift in the dose response curve for SP-induced hypotension in the awake dog that was accompanied by a decrease in the maximal response. Thus, in vitro and in vivo CP-122,721 appears to behave functionally as a non-competitive antagonist producing an insurmountable blockade of the actions of SP.

Animals↗
PubMed1996

Effects of heat shock on gram negative bacteria: use of lysis by sodium dodecyl sulphate as a probe for the integrity of DNA.

Rheograms of Alcaligenes eutrophus (NCIMB 40529) and Escherichia coli (C90 NCIMB 10616) cells lysed by sodium dodecyl sulphate were compared before and after a variety of heat shock regimes. It was found that unheated cells produced a very characteristic shear thickening rheogram which could be destroyed by DNase treatment. Cells which had been subjected to heat shock produced rheograms very similar to DNase digested material. We thus suggest that the rheogram is largely due to the presence of intact DNA molecules. The extent and nature of the heat shock affected the shape of the rheogram of the SDS lysed material. Heat shock of cells after SDS lysis did not appear to significantly damage the DNA. Storage of the cells at 10 degrees C before heat shock considerably reduced the shear thinning effect of subsequent heat shock at 90 degrees C. We attribute the shear thinning effect of the heat shock to the action of nucleases which are activated and then depolymerise the DNA molecules.

Alcaligenes↗
PubMed1996

The nurse's role in clinical trials.

Parkinson's disease (PD) is a chronic and progressive degenerative disorder of the central nervous system characterized by tremor, rigidity, slowness of movement (bradykinesia) and postural abnormalities. The cause is unknown, but the pathology shows that dopamine is profoundly reduced in the basal ganglia of patients with PD. When dopamine is replenished by the administration of levodopa, most of the symptoms of parkinsonism are reduced significantly. Levodopa is considered to be the most reliable and effective symptomatic drug treatment for keeping patients autonomous and functionally independent for as long as possible.

Antiparkinson Agents↗
PubMed1995

Mycobacterial infections: guidelines for reporting and revised format for presentation.

A new format for the presentation of mycobacterial infections appears in the accompanying CDR Weekly (Communicable Disease Report 1995; 5:22). To ensure accuracy and consistency in the collation of information about mycobacterial infections, the PHLS Communicable Disease Surveillance Centre has developed guidelines for reporting and has adopted definitions for the classification of sites of infection. These guidelines and definitions are published here for the first time.

Disease Notification↗
PubMed1995

Laboratory reports of opportunistic and other mycobacterial infections and their relationship to notifications of tuberculosis in England and Wales.

SETTING: England and Wales, UK. OBJECTIVE: To investigate: (1) whether misclassification of opportunistic mycobacterial disease had contributed to the failure of tuberculosis notifications to continue declining; (2) whether laboratory reports of Mycobacterium tuberculosis complex infections could be used to validate trends in the tuberculosis notification system. DESIGN: Descriptive epidemiological study using laboratory reports of infections to the Public Health Laboratory Service Communicable Disease Surveillance Centre, Medical Research Council National Surveys of Tuberculosis and tuberculosis notifications to the Office of Population Censuses and Surveys. RESULTS: Compared to 1983, an extra 1% of tuberculosis notifications in 1988 were opportunistic mycobacterial disease inappropriately notified as tuberculosis. On the basis of the expected proportion of microbiologically confirmed tuberculosis infections, laboratory reporting was incomplete: for one laboratory report there were four notifications. CONCLUSION: Misclassification of opportunistic mycobacterial infection was estimated to account for only a small proportion of the excess tuberculosis notifications since 1988. This excess of tuberculosis notifications could be due to artefact, for instance because a greater proportion of cases are being notified. Laboratory reports of tuberculosis infections are of limited use in validating the recent trends in tuberculosis notification rate. At present changes in the level of reporting of laboratory isolates are likely to obscure genuine trends.

Diagnostic Errors↗
PubMed1995

Effect of magnesium on fetal heart rate variability using computer analysis.

We studied 16 women, at 32 weeks' or more gestation who required magnesium sulfate (MgSO4) therapy for preterm labor or preeclampsia. A 60-minute Doppler fetal heart rate (FHR) tracing, analyzed by the Oxford Sonicaid System 8000, was obtained for 1 hour before and 2 hours after each patient received intravenous MgSO4 therapy. Maternal serum Mg2+ levels were obtained at the second monitoring session. Matched paired measures of FHR parameters were compared with the Student's t test. After MgSO4 administration, we noted significant falls in long-term variability, short-term variability, and total acceleration (more than 10 beats/min) counts. Reduced short-term and overall variability occurred in all cases with maternal serum Mg2+ levels more than 4.6 mg/dL. Therapeutic maternal serum Mg2+ levels are linked with decreases in long-term and short-term FHR variability and acceleration counts. These findings should be considered when evaluating resting FHR baseline of patients thus treated.

Adult↗
PubMed1995

Identification of a silencer, enhancer, and basal promoter region in the human CD95 (Fas/APO-1) gene.

Genomic clones for the human CD95 (Fas/APO-1) and CD40 genes have been isolated and 2.3 kb of the CD95 and 0.8 kb of the CD40 gene 5'-flanking regions sequenced. Comparisons of the human CD95 gene with the human CD40 and the murine CD40 and TNFR-II genes showed a low degree of sequence similarity. However, dot matrix analyses revealed conservation of two stretches between human CD95 (-387 to -362 and -288 to 261 in CD95) and murine TNFR-II genes. Additionally, TCCTCC motifs are present within 400 bp up-stream of the ATG of all genes examined. Repeated interferon-beta (IFN-beta) silencer B motifs and a lysozyme silencer 1 motif have been found in the CD95 gene at approximately -1,600 and -1,100, respectively. Sequence comparison of the 5'-flanking regions of the murine and human CD40 genes revealed the presence of a conserved AP-4 site and two SP-1 sites. CD95, CD40, and TNFR-II genes all lack classical TATA and CAAT boxes. However, a strongly increased frequency of CpG dinucleotides was found. Primer extension analysis revealed multiple transcriptional start sites in the CD95 gene, where the usage of individual start sites appeared to be cell type-specific. Functional analysis, using reporter constructs and transient transfections, identified a silencer activity residing between nucleotide positions -1,781 and -1007 and a strong enhancer region between -1,007 and -425 in the human CD95 gene. The region between -425 and -1 retained a basal promoter activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗