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Biomedical subjects

J S Thompson

Publications and source records attributed to J S Thompson.

At least 127 records · Page 7Linked to original sources
PubMed1994

Neutral endopeptidase (NEP) inhibition in rats with established pulmonary hypertension secondary to chronic hypoxia.

1. Atrial natriuretic peptide (ANP) causes vasorelaxation in the pulmonary vasculature. ANP levels are elevated in conditions characterized by pulmonary hypertension and it has been hypothesized that ANP may be autoregulatory in the pulmonary circulation. 2. One route of ANP metabolism in vivo is by the action of the enzyme neutral endopeptidase (NEP). We have studied the effects of the NEP inhibitor, SCH 42495, in rats with established pulmonary hypertension secondary to chronic hypoxia. 3. Rats (n = 32) were divided into 4 groups. Normoxic controls were kept in air for 10 days (NC10) and all other animals were placed in a normobaric hypoxic chamber (F1 O2 10%). Chronic hypoxic controls were studied at 10 days (CHC10). After 10 days hypoxia the two remaining groups received oral treatment for a further 10 days, consisting of either SCH 42495 (30 mg kg-1, twice daily CHT20) or methyl cellulose vehicle (0.4%, twice daily, CHV20). 4. Animals were anaesthetized and blood collected for measurement of plasma ANP. Hearts were dissected and ventricles weighed and the histology of the pulmonary vasculature examined. 5. CHC10 rats had significant right ventricular hypertrophy (0.53 +/- 0.08) and pulmonary vascular remodelling (29.0 +/- 0.01%) and had gained significantly less body weight (33.2 +/- 5.5 g) than NC10 rats (0.31 +/- 0.04, 10.9 +/- 0.01%, and 59.2 +/- 11.9 g respectively). CHC10 rats had significantly elevated plasma ANP levels (58.4 +/- 9.9 pM) compared with NC10 rats (23.9 +/- 32 pM). Treatment with SCH 42495 caused a significant reduction in pulmonary vascular remodelling (25.0 +/- 0.01%) and right ventricular hypertrophy (0.52 +/- 0.09) in CHT20 rats compared with CHV20 controls (33.0 +/- 0.02% and 0.61 +/- 0.09 respectively). Pulmonary vascular remodelling was also significantly lower in CHT20 rats than CHC1O animals.6. Thus, short term inhibition of NEP causes regression of established pulmonary vascular remodelling and may be a useful therapeutic strategy in pulmonary hypertension.

Animals↗
PubMed1994

Specific repression of the yeast silent mating locus HMR by an adjacent telomere.

The yeast silent mating loci HML and HMR are located at opposite ends of chromosome III adjacent to the telomeres. Mutations in the N terminus of histone H4 have been previously found to derepress the yeast silent mating locus HML to a much greater extent than HMR. Although differences in the a and alpha mating-type regulatory genes and in the cis-acting silencer elements do not appear to strongly influence the level of derepression at HMR, we have found that the differential between the two silent cassettes is largely due to the position of the HMR cassette relative to the telomere on chromosome III. While HML is derepressed to roughly the same extent by mutations in histone H4 regardless of its chromosomal location, HMR is affected to different extends depending upon its chromosomal positioning. We have found that HMR is more severely derepressed by histone H4 mutations when positioned far from the telomere (cdc14 locus on chromosome VI) but is only minimally affected by the same mutations when integrated immediately adjacent to another telomere (ADH4 locus on chromosome VII). These data indicate that the degree of silencing at HMR is regulated in part by its neighboring telomere over a distance of at least 23 kb and that this form of regulation is unique for HMR and not present at HML. These data also indicate that histone H4 plays an important role in regulating the silenced state at both HML and HMR.

Binding Sites↗
PubMed1994

Management of the short bowel syndrome.

The short bowel syndrome has become an increasingly common clinical condition. Malnutrition and its complications should be avoidable with use of a combination of enteral and parenteral nutrition support. Dietary management needs to be individualized. Drugs directed against gastric hypersecretion, increased motility, intestinal secretion, unabsorbed bile salts, and bacterial overgrowth improve intestinal function. Complications specific to the short bowel syndrome (gastric hypersecretion, cholelithiasis, nephrolithiasis) can be minimized and diagnosed early. Surgical management includes preserving intestinal remnant length and improving its function. Intestinal transplantation is evolving as a promising therapeutic alternative for patients with complications of long-term parenteral nutrition support.

Humans↗
PubMed1993

Somatostatin analogue inhibits intestinal regeneration.

Somatostatin analogue octreotide inhibits intestinal absorption and motility but its effect on epithelial cell migration and proliferation remains unclear. Our aim was to determine the effect of octreotide on parameters of intestinal regeneration, including epidermal growth factor (EGF)-induced changes. Thirty rabbits had full-thickness ileal defects patched with cecal serosa surface. Group 1 were controls. Groups 2 and 3 received 100 micrograms and 1000 micrograms, respectively, of subcutaneous octreotide daily. Group 4 received EGF at 1.5 micrograms/kg per hour via subcutaneous miniosmotic pump, and group 5 received both octreotide (1000 micrograms/d) and EGF (1.5 micrograms/kg per hour). Octreotide at 100 micrograms/d did not inhibit epithelial cell migration or proliferation at 7 days. Octreotide at 1000 micrograms/d inhibited normal but not EGF-stimulated cell migration. Octreotide decreased EGF-stimulated but not normal proliferation. Octreotide impairs epithelial cell migration in a dose-dependent manner. Octreotide inhibits EGF-stimulated proliferative activity but not EGF-stimulated migration. Prolonged administration of octreotide may adversely affect normal and adaptive intestinal regeneration by both direct and indirect effects.

Animals↗
PubMed1993

Activation of human monocytes and granulocytes by monoclonal antibodies to glycosylphosphatidylinositol-anchored antigens.

The present study investigated possible receptor-like characteristics of glycosylphosphatidylinositol (GPI)-linked antigens on human monocytes and granulocytes by measuring cytoplasmic calcium fluxes and the oxidative burst in cells following cross-linking of GPI-linked antigens. Cross-linking of cell-bound anti-CD14, -CDw52 and -CD55 induced cytoplasmic calcium fluxes and oxidative bursts in unprimed human monocytes similar to those observed following Fc gamma R cross-linking. In granulocytes primed with 200 mM N-formyl-Met-Leu-Phe (FMLP), cross-linking of cell-bound anti-CD16, -CD24, -CD59 and -CD67 led to calcium fluxes and activation of the oxidative burst. The oxidative bursts mediated by GPI-linked antigens were stronger than those induced by 200 nM FMLP, even though FMLP induced a larger increase in cytoplasmic calcium concentration. The responses were likely to be independent of Fc gamma R interactions as F(ab')2 fragments of IgG or IgM antibodies were used in the experiments. Activating effects of monoclonal antibody to GPI-linked antigens were not observed in cells from patients with paroxysmal nocturnal hemoglobinuria, which are deficient in GPI-linked antigens. In addition, treatment with GPI-specific phospholipase C led to inhibition of cell activation through GPI-linked antigens but not through transmembrane receptors. Cross-linking of a number of non-GPI-linked antigens (CD11a, CD18, CD31, CD35, CD43, and CD45) neither induced calcium fluxes, nor activated the oxidative burst. The results indicate that most, if not all, GPI-linked surface glycoproteins on myeloid cells are capable of mediating cell activation and suggest that the GPI anchor is a structure facilitating signal transduction.

Adult↗
PubMed1993

A review of the use of antioxidant supplements in the treatment of human oral leukoplakia.

Over the past twenty years, research into the role of antioxidants in the prevention of cancer has increased dramatically. The use of antioxidant supplements to treat oral leukoplakia has gained acceptance due to the success demonstrated in several clinical trials. This review discusses the role of antioxidants in the development of cancer and their possible use in the treatment of oral leukoplakia.

Animals↗
PubMed1993

Comparison of techniques for harvesting enterocytes for transplantation.

Selective enterocyte transplantation is a potential alternative to small intestinal transplantation for treatment of the short bowel syndrome. Our aim was to compare chelation and enzymatic methods of isolating enterocytes with respect to initial cell yield and characteristics and in vitro growth. Enterocytes were harvested from adjacent ileal segments in 35 rabbits using chelation with EDTA and warm trypsinization. Determinations were made of initial viability by trypan blue exclusion, cell yield, and proportion of intact crypts. Cells (5 x 10(6)) were seeded in growth media into culture vessels. Cell attachment was estimated by measuring cells liberated by Dispase at 24 hr. In vitro growth was assessed at 14 and 28 days. Although total cell yield (15.0 +/- 9.9 vs 12.5 +/- 8.3 x 10(6) cells/cm) and intact crypts were similar, the trypsin technique resulted in cells with higher initial viability (86 +/- 7 vs 71 +/- 18%, P < 0.05). Cell attachment (7 +/- 8 vs 8 +/- 4%) and enterocyte disaccharidase activity were similar using both techniques. While the number of epithelial cell growth foci was not significantly different at 14 days, there was significantly greater surface coverage on both plain (44 +/- 20% vs 1 +/- 0%, P < 0.05) and Matrigel-coated (80 +/- 14 vs 16 +/- 25%, P < .05) vessels at 28 days with trypsin-isolated cells. Trypsinization resulted in a cell population which had a higher percentage of viable cells but a similar proportion of intact crypts and differentiated cells compared to those resulting from the chelation technique. Trypsin-liberated cells had greater capacity for in vitro growth particularly on Matrigel-coated surfaces.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The motor response to intestinal resection: motor activity in the canine small intestine following distal resection.

BACKGROUND: The mucosal response to intestinal resection has been extensively studied; little is known of the motor response. Our aim was to evaluate motility in the intestinal remnant following distal resection. METHODS: Motor activity, duodenocecal transit, nutrition, and absorption were studied over a 3-month period in control animals (n = 9) and in groups of dogs who had undergone 25% (n = 6), 50% (n = 5), and 75% (n = 5) distal resection. RESULTS: Diarrhea and steatorrhea developed in each resection group, and the 75% group alone developed true short bowel syndrome. Resection did not affect migrating motor complex frequency or periodicity; phase 1 duration was shorter in the 75% group (control vs. 75%: 22 +/- 4 vs. 6 +/- 2 minutes, P < 0.03). The most striking motor effect was the development of prominent cluster activity in the distal part of the remnant in 25% and 50% resection animals and throughout the remaining intestine in the 75% group. Duodenocecal transit slowed during the study period from 13 +/- 1 to 20 +/- 2 minutes in the 50% and from 10 +/- 2 to 14 +/- 2 minutes in the 75% group (P < 0.05). CONCLUSIONS: The initial motor response to major resections of the distal small intestine is dominated by the development of abnormal patterns. This motor disruption may contribute to the symptomatology and clinical features of the short bowel syndrome.

Animals↗
PubMed1993

Characterization of new monoclonal antibodies directed against normal human exocrine pancreas and pancreatic adenocarcinomas.

A series of 12 cell fusions of BALB/c mice spleen cells with the SP2/O-Ag14 mouse myeloma cell line were performed after immunizations with normal human pancreas to generate monoclonal antibodies (mAbs) with high affinity against antigens of the exocrine pancreas. The immunohistologic tissue screening resulted in the selection of 14 clones that were further characterized on frozen tissues, tumor cell lines, and lectin binding assays. Four mAbs reacting with pancreatic acini detected granular antigens and three mAbs reacted with acinar cell membrane antigens. Six other clones reacted with pancreatic ducts; among these were three clones positive with antigens in both acini and ducts. Among the clones reactive with secretory products, there was one pair of mAbs identified as pancreas specific (P78C9/P79D4); the other secretory antigens (identified by P97F3 and P109H1) were also detectable in other exocrine organs, but were absent from the gastrointestinal mucosa. Two clones reactive with acinar cell membranes (P96H2 and P100H1) were also positive with hepatocytes. All but four antigens were detectable in pancreatic cancer cell lines Capan-1, Capan-2, and DAN-G. On the whole, immunizations were more effective using whole pancreatic tissues (eight clones selected) compared with single-cell suspensions as immunogen (four clones) or cell membrane preparations (two clones). Therefore, the immunization and screening strategies used in this study resulted in the generation of new mAbs against specific substructures of the exocrine pancreas. The shared expression of some of these antigens with other exocrine organs and pancreatic adenocarcinoma cell lines suggests that these mAbs detect antigens that are characteristic for the exocrine system and could therefore be useful for the study of the exocrine pancreas and pancreatic adenocarcinomas.

Adenocarcinoma↗
PubMed1993

Role of natural killer cells in the pathogenesis of human acute graft-versus-host disease.

Clinical acute graft-versus-host disease (aGVHD) was correlated with alterations in PBL phenotype and skin immunohistology in 52 patients transplanted with HLA-identical bone marrow. Concurrent with the emergence of aGVHD, there was a profound decrease in absolute number of CD3- T cells and an increase in CD3-CD16+, CD56+ (a subset of which coexpress CD8+ "dim") NK cells in the PBL. CD4+ T and CD20+ B lymphocytes failed to recover within 90 days in the patients with grades II-IV aGVHD. Ex vivo partial T cell depletion, in itself, did not significantly impair T cell recovery as compared to that in non-T-depleted recipients unless aGVHD occurred. Although leukocytic cellular infiltration in the skin was generally sparse, CD16+ NK lymphocytes were significantly increased in grades II-IV aGVHD. By contrast, there was no significant increase in CD3+, CD4+, or CD8+ lymphocytes in these lesions as compared to skin biopsies obtained from BMT patients without aGVHD or from normal skin. Taken together, these findings suggest that NK cells may be important in the pathogenesis of human aGVHD.

Acute Disease↗
PubMed1993

Acute graft-versus-host-like disease induced by transplantation of human activated natural killer cells into SCID mice.

Whereas T lymphocytes are essential for the initiation of acute graft-versus-host disease (aGVHD), it is not at all clear whether they or other cells or noncellular factors actually mediate the characteristic lesions. This report describes the in vivo effects of human NK cells, T cells, and cytokines on the induction of aGVHD in 4 Gy sublethally irradiated C.B-17 scid/scid (SCID) mice. Human NK and T lymphocytes were obtained separately by antibody- and complement-mediated negative selection from the peripheral blood of normal donors and expanded in medium containing rIL-2 and irradiated autologous feeder cells. The characteristics of the two groups of cells were analyzed before injection into SCID mice. Cytofluorometric phenotyping demonstrated that 70-95% of NK-enriched cells expressed CD3-, CD16+, CD56+, and CD8-dim+; ninety-seven per cent of T cells expressed CD3+, TCR-alpha/beta+, CD4+, or CD8-bright+. Analysis of K562 and Daudi cultured target cell lines demonstrated 40-50% higher cytotoxicity by NK-enriched cells as compared with activated T lymphocytes. TNF-alpha cytokine production was greatly increased in activated NK cells (250 pg/ml) as compared with T cells (25 pg/ml) and fresh PBMC (12.5 pg/ml). IFN-gamma was increased in both NK and T cells. After i.v. injection of 1-5 x 10(7) cells into irradiated SCID mice, minor to severe skin lesions, diarrhea, and weight loss occurred in NK- but not the T cell-injected animals. In NK-injected animals, thinning and focal loss of epithelium with pyknotic nuclear change and degeneration and loss of skin appendages were observed. Single cell necrosis, crypt abscess formation, and loss of glandular epithelium developed in the colon of NK but not in T cell-injected animals. These findings are very similar to allogeneic aGVHD in SCID mice injected with C57BL/6 mouse splenocytes. Immunohistological staining with anti-human CD56, CD3, TNF-alpha, and IFN-gamma antibodies demonstrated CD56+ cells in association with TNF-alpha and IFN-gamma secretion in the bowel of NK-injected animals. CD3+ cells were not found in the same tissues. These findings were not observed in T cell-injected and control mice. In summary, aGVHD-like lesions were induced by transplantation of xenogeneic human activated NK cells into SCID mice. We hypothesize that cytokines released from human NK cells play a central role in the pathogenesis of clinical aGVHD.

Acute Disease↗
PubMed1993

Effects of atrial natriuretic peptide and nitroprusside on isolated pulmonary resistance and conduit arteries from rats with pulmonary hypertension.

1. The relaxant effects of atrial natriuretic peptide (ANP) and nitroprusside were studied on prostaglandin F2 alpha (PGF2 alpha)-contracted preparations of pulmonary resistance vessels (internal diameter 200-500 microns) and main pulmonary arteries taken from rats with pulmonary hypertension induced by monocrotaline (105 mg kg-1, s.c., 4 weeks previously). Control rats received saline. 2. In preparations from monocrotaline-treated rats, the potencies (negative log EC50) of ANP on resistance vessels (8.45) and main pulmonary arteries (8.25) were similar to those obtained in vessels from control rats (8.78 and 8.53 respectively), whereas those of nitroprusside were significantly less than in controls in both resistance vessels (7.13 compared with 7.63 in controls; three fold decrease in potency) and main pulmonary arteries (6.92 compared with 8.17 in controls; 18 fold decrease in potency). 3. On pulmonary resistance vessels from monocrotaline-treated rats, the maximum relaxant responses to ANP and nitroprusside, and also to pinacidil, were increased compared with controls, and reversal of the PGF2 alpha-induced contraction by these drugs was greater than 100%. In contrast, on main pulmonary arteries from monocrotaline-treated rats, the maximum relaxations to ANP and nitroprusside were not increased relative to controls, and reversal of PGF2 alpha was not greater than 100%. 4. Since the high potency of ANP on pulmonary resistance and conduit arteries is retained in vessels from rats with pulmonary hypertension, whether induced by monocrotaline (this study) or by chronic hypoxia (previous findings), it is postulated that elevation of plasma levels of ANP by use of drugs that inhibit the breakdown of this endogenous peptide, may be one approach to the pharmacological treatment of pulmonary hypertension.

Animals↗