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Biomedical subjects

J Shaw

Publications and source records attributed to J Shaw.

At least 163 records · Page 9Linked to original sources
PubMed1993

Intercellular adhesion molecule-1 and MHC antigens on human intrahepatic bile duct cells: effect of pro-inflammatory cytokines.

Human intrahepatic biliary epithelial cells were isolated from the livers of patients with primary biliary cirrhosis and from normal livers and established in primary culture. The in vitro expression of intercellular adhesion molecule-1, HLA class I, and HLA class II on biliary epithelial cells was studied in response to tumour necrosis factor-alpha (0-500 U/ml), interferon-gamma (0-500 U/ml), and interleukin-1 (0-5 U/ml) by immunohistochemical staining and a semiquantitative scoring system validated by spectrophotometry and previously validated by laser confocal microscopy. The non-stimulated expression of intercellular adhesion molecule-1 and HLA class II was higher on cells derived from the primary biliary cirrhosis liver than on cells from normal liver, a difference not seen with HLA class I expression. A statistically significant increase in intercellular adhesion molecule-1 expression was seen with all three cytokines in cells derived from both primary biliary cirrhosis and normal liver. Increase in HLA class I expression was seen only with interleukin-1 5 U/ml for cells derived from both normal and diseased liver. Increase in HLA class II expression was seen only with interferon-gamma 500 U/ml for cells derived from diseased liver and with interleukin-1 5 U/ml for cells derived from both diseased and normal liver. These data show that pro-inflammatory cytokines increase expression of intercellular adhesion molecule-1, HLA class I, and HLA class II on human intrahepatic biliary epithelial cells in vitro and are consistent with the hypothesis that these locally acting factors may play a part in the pathogenesis of immune mediated disorders such as primary biliary cirrhosis in which immune mediated bile duct damage occurs.

Bile Ducts, Intrahepatic↗
PubMed1993

Predominant alpha 1-adrenoceptor-mediated contraction in the human internal mammary artery.

alpha-Adrenoceptor agonists and antagonists are widely used perioperatively for internal mammary artery (IMA)-coronary artery bypass operations. To determine subtypes of alpha-adrenoceptors in the human IMA, we studied responses of isolated human IMA segments to alpha-adrenoceptor agonists, antagonists, and electrical stimulation in organ baths. The IMA ring segments (3 mm long) were set up at a physiologic and comparable condition according to their own length-tension curves. alpha 1-Agonist methoxamine (MO) induced 2.65 +/- 0.70 g force and alpha 1, alpha 2-agonist norepinephrine (NE) induced 4.07 +/- 0.70 g force. The contractions induced by both MO and NE were totally abolished by alpha 1-antagonist prazosin (0.1 microM) but not alpha 2-antagonist yohimbine. alpha 2-Agonist UK14304 induced only 0.39 +/- 0.17 g force, which was significantly less than that induced by MO or NE (p < 0.001). Contractions induced by electrical field stimulation (2, 10, 20 Hz) were decreased by alpha 1-antagonist prazosin 1 microM (p < 0.01) but potentiated by alpha 2-antagonist yohimbine. These results strongly suggest that in the human IMA the postjunctional alpha-adrenoceptors are predominantly of the alpha 1-subtype and therefore the alpha-adrenoceptor agonist-induced contraction and the sympathetic nerve stimulation-induced contraction is mediated mainly by activation of the alpha 1-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1993

Genetic recombination events which position the Friedreich ataxia locus proximal to the D9S15/D9S5 linkage group on chromosome 9q.

The absence of recombination between the mutation causing Friedreich ataxia and the two loci which originally assigned the disease locus to chromosome 9 has slowed attempts to isolate and characterize the genetic defect underlying this neurodegenerative disorder. A proximity of less than 1 cM to the linkage group has been proved by the generation of high maximal lod score (Z) to each of the two tightly linked markers D9S15 (Z = 96.69; recombination fraction [theta] = .01) and D9S5 (Z = 98.22; theta = .01). We report here recombination events which indicate that the FRDA locus is located centromeric to the D9S15/D9S5 linkage group, with the most probable order being cen-FRDA-D9S5-D9S15-qter. However, orientation of the markers with respect to the centromere, critical to the positional cloning strategy, remains to be resolved definitively.

Adolescent↗
PubMed1993

High blood pressure--current state of play.

Blood pressure is well recognised and well treated in Australia; nevertheless, a number of problem areas still exist. The author looks at the management of hypertension in the elderly, factors affecting choice of drug and the place of cost-benefit analysis in choosing a drug for treatment of hypertension.

Aged↗
PubMed1992

Phase I trial of an interleukin-2 (IL-2) fusion toxin (DAB486IL-2) in hematologic malignancies expressing the IL-2 receptor.

DAB486IL-2 is a recombinant fusion toxin in which the native receptor binding domain of diphtheria toxin has been replaced with human interleukin-2 (IL-2). It selectively binds and intoxicates only cells that bear the high-affinity receptor for IL-2. In the first clinical trial of a genetically engineered ligand fusion-toxin, we have treated 18 patients with chemotherapy-resistant IL-2 receptor expressing hematologic malignancies with escalating doses of DAB486IL-2. The maximal tolerated dose of a daily intravenous bolus of DAB486IL-2 was 0.1 mg/kg per day for 10 doses, established by asymptomatic, reversible elevations of hepatic transaminases without changes in other tests of liver function. Other mild reversible side effects noted were rash, nausea, elevated creatinine, chest tightness, and fever. Pharmacokinetic analysis showed a monophasic clearance of 5.8 +/- 0.7 minutes with peak levels of 3,549 +/- 1,041 mg/mL at the 0.1 mg/kg dose. Approximately 50% of patients developed an antibody response to diphtheria toxin or DAB486IL-2. The presence of such antibodies did not preclude patients from experiencing an antitumor response as four of the six patients with antitumor effect had detectable antibody titers. Although this was a phase I trial designed to define the safety of DAB486IL-2, remissions were observed in three patients lasting from 5 to over 18 months. The ability to achieve significant tumor reductions in this group of heavily treated patients is encouraging and suggests additional trials are warranted in hematologic malignancies.

Adult↗
PubMed1992

Transient accumulation and subsequent rapid loss of messenger RNA encoding high molecular mass CD45 isoforms after T cell activation.

High molecular mass isoforms of CD45 protein tyrosine phosphatase, predominantly CD45RA, are expressed on naive T cells with increasing density during the first 2 days of cellular activation, and subsequently down-regulated concurrent with increasing expression of the low Mr isoform, CD45RO. We show this to be de novo synthesis of CD45RA dependent upon both RNA and protein synthesis. Using a probe shown to detect mRNA encoding the alternatively spliced abc, ab, bc, and b exon isoforms of CD45, the expression of CD45 was analyzed. Kinetic studies of the transition from high to low Mr CD45 mRNA indicate an immediate decrease in the level of high Mr CD45 mRNA after mitogen stimulation of T cells, quickly followed at 4 h by an increase to above steady state levels. This is consistent with the transitory increase in cell-surface density of CD45RA observed at 1 to 2 days poststimulation. Within 24 h of stimulation the level of high Mr CD45 mRNA declines precipitously such that little or no mRNA encoding any of the alternatively spliced exons is detectable. High levels of CD45 mRNA are detectable at later points but this does not hybridize with the Sfa N1 probe recognizing the abc exons suggesting that only the CD45RO mRNA splicing pattern is operative. We also show that CD45 mRNA have a relatively short t1/2. In mitogen-stimulated cells the t1/2 of high and low m.w. CD45 mRNA was estimated at 2.25 h and 3.5 h, respectively. In unstimulated T cells the t1/2 of high Mr CD45 mRNA was estimated at 2.8 h. CD45 mRNA is super-induced in the presence of the protein synthesis inhibitor, cycloheximide, indicating that the degradation and/or splicing of CD45 mRNA is controlled by a labile pathway, and suggesting that mechanisms may exist in vivo to prolong synthesis of CD45RA. The kinetics of accumulation for high Mr CD45 mRNA are very similar to those of the TCR beta-chain and pp56lck suggesting that these functionally linked signaling molecules are regulated in tandem. This implicates stringent molecular control mechanisms on the production of mRNA encoding either high or low m.w. isoforms, consistent with the fundamental role of CD45 in signal transduction, and the apparent need to selectively and sequentially express functionally distinct external CD45 domains.

Antigens, CD↗
PubMed1992

The effects of cooling mouse oocytes.

The effects of cooling and warming on meiotic spindles of mouse oocytes have been assessed by transmission electron microscopy. Intact cumulus-oocyte complexes were immediately cooled from 37 to 15, 4, 0, and -7 degrees C (seeding temperature) for 15 min in a programmed biological freezer and fixed at these temperatures. Other complexes, cooled to these temperatures, were rapidly warmed to 37 degrees C and incubated for 2 hr before fixation at 37 degrees C. Of 334 oocytes assessed at various temperatures, at least 100 were examined for metaphase II spindles. Spindle microtubules completely disappear at 0 and -7 degrees C, while complete or partial depolymerization of microtubules was observed at 4 degrees C. Cooling to 15 degrees C did not cause major disruptions of spindle structure in most oocytes. Chromosomes tended to rotate or clump at lower temperatures but chromosome scatter outside the spindle zone was rarely observed. Centrosomal material was fragmented at 4 degrees C and occasionally at 15 degrees C and was not evident at the spindle poles at 0 and -7 degrees C. Kinetochores were seen at all temperatures. Spindle structure was evidently restored in the majority of oocytes on rewarming at 37 degrees C. Changes in the ooplasm induced by cooling were elongation and disruption of vesicular smooth endoplasmic reticulum, especially between lipid globules and disappearance of fibrillar inclusions. Cortical granule exocytosis was not observed on cooling, while microfilaments were intact. Swelling of membranous organelles was also observed in cumulus cells. Most of the cytoplasmic changes were also reversed on rewarming. The response of mouse oocytes to cooling is compared to that of human oocytes, reported previously.

Animals↗
PubMed1992

In vitro reactions of vacuole inheritance in Saccharomyces cerevisiae.

Vacuole inheritance is temporally coordinated with the cell cycle and is restricted spatially to an axis between the maternal vacuole and the bud. The new bud vacuole is founded by a stream of vacuole-derived membranous vesicles and tubules which are transported from the mother cell into the bud to form the daughter organelle. We now report in vitro formation of vacuole-derived tubules and vesicles. In semi-intact cells, formation of tubulovesicular structures requires ATP and the proteins encoded by VAC1 and VAC2, two genes which are required for vacuole inheritance in vivo. Isolation of vacuoles from cell lysates before in vitro incubation reveals that formation of tubulovesicular structures requires cytosol as well as ATP. After forming tubulovesicular structures, isolated vacuoles subsequently increase in size. Biochemical assays reveal that this increase results from vacuole to vacuole fusion, leading to mixing of organellar contents. Intervacuolar fusion is sensitive to the phosphatase inhibitors microcystin-LR and okadaic acid, suggesting that protein phosphorylation/dephosphorylation reactions play a role in this event.

Adenosine Triphosphate↗
PubMed1992

Inhibitory effects of glyceryl trinitrate on alpha-adrenoceptor mediated contraction in the human internal mammary artery.

1. Sympathomimetic amines have been considered to be related to vasospasm. Previous studies showed that the human internal mammary artery (IMA) was capable of weak beta-adrenoceptor mediated relaxation and that alpha-adrenoceptor agonists may induce contraction in the human IMA. 2. We investigated the effects of glyceryl trinitrate (GTN), a vasodilator agent often used perioperatively, on alpha-adrenoceptor mediated contraction in the human IMA. 3. Discarded human IMA segments were taken from 37 patients who underwent IMA--coronary artery bypass graft operations and equilibrated in an organ bath. 4. A specially designed technique was used to normalize the vessel segments under the pressure similar to the in vivo situation. Noradrenaline (NA), phenylephrine (PE), and methoxamine (MO) were used to contract the vessel segments. 5. GTN fully relaxed PE or MO (submaximal concentration) induced precontraction. Therapeutic plasma concentration of GTN relaxed 40-90% of the PE induced contraction (2.82 g, EC50 = 7.92 +/- 0.06 -log M) and 20-90% of the MO induced contraction (1.8 g, EC50 = 7.63 +/- 0.16 -log M). Pretreatment by the therapeutic plasma concentration of GTN inhibited the contraction induced by NA, PE in a different range. It reduced the NA induced contraction (6.9 g) by 14.8-38% (P greater than 0.05) and the PE induced contraction (4.3 g) by 7.9-39.3% (P greater than 0.05). The alpha 1-adrenoceptor antagonist prazosin, at the therapeutic plasma concentration, nearly totally abolished the NA or PE induced contraction (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1992

Beta 141 Leu is not deleted in the unstable haemoglobin Atlanta-Coventry but is replaced by a novel amino acid of mass 129 daltons.

Reinvestigation of the structure of the beta-chain of Hb Atlanta-Coventry (beta 75 Leu----Pro, beta 141 Leu deleted) confirmed the presence of two abnormalities; however, analysis of the aberrant beta Co14 tryptic peptide by liquid secondary ion mass spectrometry indicated that the beta 141 Leu (mass 113 daltons) was not deleted but replaced by a novel amino acid of mass 129 daltons. The new amino acid in peptide beta Co14 was uncharged at pH 6.5, more hydrophillic than leucine and susceptible to cleavage by both chymotrypsin and carboxypeptidase A. We propose that the new residue is likely to be hydroxyleucine and that it results from post-translational oxidation of beta 141 Leu as a consequence of perturbation of the haem environment caused by the beta 75 Leu----Pro mutation in the E helix (E19). This proposal is entirely consistent with recent DNA analysis which showed that beta At-Co was not the product of a third beta-globin gene and that neither of the two beta-globin genes, beta A nor beta Atlanta, contained a deletion of the beta 141 Leu codon. We have subsequently found this modified amino acid at position beta 141 in two other unstable haemoglobins, both of which involve mutations on the haem side of the E helix.

Amino Acid Sequence↗
PubMed1992

Evaluation of a heart disease survey and education program for general practitioners.

In 1989 we mailed a questionnaire to all 461 general practitioners (GPs) identified as currently practising in the Eastern Metropolitan Health Region of Sydney. This was the first phase of a program to assess, amplify and reassess GPs' knowledge of the risk factors for heart disease and measure their attitudes and beliefs about their role in the prevention of cardiovascular disease. The second phase was an education program designed to meet the needs identified by the first questionnaire. Phase three was a postintervention questionnaire. Fifty-six per cent (260/461) responded to the first questionnaire. This follow-up group were mailed the second questionnaire, to which 52 per cent (135/260) responded. Thirty per cent of the original sample (139/461) attended the education program and 30 per cent (79/260) of the follow-up group did so. At baseline, the respondents' level of risk factor knowledge was good, but after the education program there was still a large gap between what they said they knew and the amount of advice they said they would give to patients. The only significant increase in the amount of advice after the intervention was to 'control blood pressure'. This applied whether the GP had participated in the intervention or not. When GPs were asked how often in the last month they had actually given advice to reduce cardiovascular disease risk, program attenders reported offering it more frequently than nonattenders. We also attempted to determine whether any particular demographic characteristics could predict respondents to the questionnaires and/or the educational program.

Australia↗
PubMed1992

Is the intercellular adhesion molecule-1/leukocyte function associated antigen 1 pathway of leukocyte adhesion involved in the tissue damage of alcoholic hepatitis?

Alcoholic hepatitis is characterised histologically by an intense inflammatory cell infiltrate made up predominantly of neutrophils but including other cell types, particularly lymphocytes. Leukocyte cytotoxicity requires cell adhesion, which is mediated via receptors on the leukocyte surface including leukocyte function associated antigen-1 (LFA-1) which binds to the ligand intercellular adhesion molecule-1 (ICAM-1) on the target cell. The distribution of ICAM-1 and LFA-1 expression in liver biopsy specimens from patients with alcoholic liver disease was examined to ascertain whether this pathway of leukocyte adhesion is involved in the tissue damage of alcoholic hepatitis. Specimens were stained for ICAM-1 and LFA-1 by a three step immunoalkaline-phosphatase method using monoclonal antibodies against ICAM-1 and LFA-1. LFA-1 staining on portal tract inflammatory cells and parenchymal inflammatory cells and ICAM-1 staining on liver components were examined. ICAM-1 expression on hepatocytes was significantly greater in alcoholic hepatitis compared with fatty liver (p less than 0.001) and normal controls (p less than 0.01). ICAM-1 expression correlated with the histological degree of hepatocellular damage (tau = 0.79; p = 0.0005) and parenchymal inflammation (tau = 0.65; p less than 0.001, and with LFA-1 expression on parenchymal leukocytes (tau = 0.63; p = 0.01). The ICAM-1/LFA-1 pathway may therefore be involved in leukocyte mediated tissue damage during alcoholic hepatitis.

Antibodies, Monoclonal↗
PubMed1992

The renaissance of excellence: re-establishing good management in a devastated teaching hospital.

An institutional development team of four technical advisers has been working at Mulago Hospital, the 1440-bed National Teaching and Referral Hospital, since 1983 to assist the hospital to re-establish working management systems, drug and supplies procurement arrangements and an engineering maintenance service. The hospital was in poor shape at the beginning of the project, but has improved over time. The Team works with counterparts to advise, coach, train, facilitate and support their development. External factors have contributed to the progress made, but the Team's contribution included long term availability in the hospital, the sustainable nature of the counterpart relationship, practical and material assistance, and access to outside charitable funds.

Civil Disorders↗