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Biomedical subjects

N Hayes

Publications and source records attributed to N Hayes.

At least 37 records · Page 2Linked to original sources
PubMed1999

Placental Fas ligand expression is a mechanism for maternal immune tolerance to the fetus.

Fas ligand (FasL) is a peptide that plays an important immunoregulatory role in limiting the host immune response. Several studies have shown that the expression of FasL in the anterior chamber of the eye and the testis allows these tissues to be immunoprivileged sites. Immunotolerance is achieved by binding of FasL to its receptor (Fas) on activated immune cells, which results in cell apoptosis. To determine whether FasL has a role in maternal immune tolerance to the fetus, we looked for the expression of FasL in the human placenta. Immunoperoxidase staining localized FasL to both syncytiotrophoblast and cytotrophoblast in placental villi and chorionic extravillous trophoblast. Western analysis demonstrated FasL in placental villi and a human first-trimester trophoblast cell line (ED27). In contrast, Fas was colocalized to CD45 (leukocyte common antigen) positive cells found in maternal decidua. When isolated peripheral blood lymphocytes were induced to express Fas with phytohemagglutinin (PHA) and interleukin-2 (IL-2) and then cocultured with trophoblast, 30% of the lymphocytes underwent apoptosis, as determined by the in situ death (TUNEL) assay. Neutralizing antibodies to FasL inhibited apoptosis by 40% in these studies. In contrast, activated lymphocytes cocultured with non-FasL-expressing fibroblasts or unactivated non-Fas-expressing lymphocytes cocultured with ED27 trophoblast showed little evidence of apoptosis. These findings suggest that FasL expressed by fetal trophoblast cells can induce apoptosis in activated lymphocytes there by providing a mechanism for maternal immune tolerance to the fetus.

Apoptosis↗
PubMed1997

The differential expression of hepatocyte growth factor and met in human placenta.

Met is the tyrosine kinase receptor for the ligand hepatocyte growth factor (HGF). Met/HGF plays an important role in epithelial cell proliferation, migration, and morphogenesis. HGF also plays a crucial role in placental development in the mouse. To determine whether HGF potentially has a similar role in human placental development, the production and localization of Met and HGF were determined in early second trimester and term placentas. Reverse transcription-PCR using specific primers demonstrated the expression of Met and HGF messenger ribonucleic acid in placental villi. HGF production was determined by enzyme-linked immunosorbent assay. HGF production over 48 h by second trimester placental villous explants in culture (810 pg/mg total protein x h) was 2.1-fold greater than that in term placental villous explants (380 pg/mg total protein x h; P < 0.01). Isolated trophoblast did not produce HGF, whereas isolated villous core tissues and villous core mesenchymal cells did produce HGF. Interleukin-1 beta treatment of placental villi or coculture of villous core mesenchymal cells with isolated trophoblast cells did not stimulate HGF production. Using immunohistochemistry, HGF localized to the villous core compartment with no localization to the trophoblast. In contrast, Met localized mainly to cytotrophoblast. These findings suggest that HGF produced by the villous core may act in a paracrine fashion to regulate trophoblast development or function through the HGF receptor, Met.

Adult↗
PubMed1997

Fibrinogen levels correlate with stage of disease in patients with oesophageal cancer.

BACKGROUND: A hypercoagulable state is well recognized in association with cancer and results in a greatly increased risk of thromboembolic disease during surgery in these patients. This study examines routine laboratory measurements of coagulation and attempts to correlate these with disease stage in patients with oesophageal cancer. METHODS: Fibrinogen concentration, platelet count and routine coagulation tests were examined before operation in a consecutive group of 73 patients with oesophageal carcinoma. All patients were staged according to standard Union Internacional Contra la Cancrum criteria. RESULTS: The fibrinogen concentration was significantly higher in patients with oesophageal carcinoma than in age- and sex-matched control patients with benign disease (P < 0.005). Fibrinogen concentration was higher in patients with greater depth of invasion (P < 0.005) and those with metastatic disease (P < 0.01). CONCLUSION: This study demonstrates a stage-dependent phenomenon of hyperfibrinogenaemia in association with oesophageal carcinoma.

Aged↗
PubMed1996

Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors gamma 1 and gamma 2.

We describe the molecular cloning and expression of cDNAs encoding human PPAR gamma 1 and PPAR gamma 2. Our sequences are distinct from the published sequence at 3 positions, resulting in nonconservative amino acid substitutions. In humans, PPAR gamma mRNA is expressed in spleen, bone marrow, liver, testis, skeletal muscle and brain, in addition to fat. Three thiazolidinediones were found to 1) displace a radiolabeled thiazolidinedione from both receptors with essentially the same IC50s and 2) to transactivate both PPAR gamma isoforms with similar EC50s in transient cotransfection assays utilizing the adipocyte-specific aP2 promoter. Saturating concentrations of these 3 thiazolidinediones altered the conformation of in vitro synthesized PPAR gamma protein producing a 27 kDa protease-resistant fragment. These results indicate that the antidiabetic effects of thiazolidinediones in humans are likely to be mediated via binding to and transactivation of PPAR gamma 1 and gamma 2.

Amino Acid Sequence↗
PubMed1996

Radical lymphadenectomy in the management of early gastric cancer.

Lymph node metastasis in patients with early gastric cancer was evaluated prospectively to determine whether radical (D2) lymphadenectomy is appropriate in such cases. Twenty-eight (18 per cent) of 156 patients having surgery for gastric cancer had early disease. Lymph node metastasis was found in 12 of the 28 patients. Metastasis was more likely in submucosal than mucosal early gastric cancer (nine of 14 versus three of 14; P = 0.024, Fisher's exact test). In two of three patients with metastasis at the N2 level, the N1 nodes were entirely clear. This study shows a higher incidence of lymph node metastasis than has been reported previously in both the UK and Japan. The high incidence of lymph node metastasis in early gastric cancer supports the continuing use of radical lymphadenectomy in patients who are fit for such major surgery.

Adenocarcinoma↗
PubMed1996

An antidiabetic thiazolidinedione potentiates insulin stimulation of glycogen synthase in rat adipose tissues.

Thiazolidinedione derivatives are a novel class of insulin-sensitizing agents that have demonstrated effective antidiabetic activity in vivo. Here, the effects of the potent thiazolidinedione derivative, AD-5075, on the rate-limiting enzyme of glycogen synthesis, glycogen synthase, were investigated in cultured rat adipose tissue. Short term preincubation of adipose tissue with AD-5075 potentiated acute insulin stimulation of I-form glycogen synthase activity in a concentration-dependent (EC50 approximately, 61nM) and time-dependent (t1/2 approximately, 2.3 h) manner. The thiazolidinedione derivative increased the responsiveness of I-form glycogen synthase activity to insulin stimulation at both maximal and submaximal insulin concentrations. In contrast, it had no effect on total glycogen synthase activity. Isoproterenol inhibited acute insulin activation of I-form glycogen synthase activity in a dose-dependent manner; maximal inhibition was attained at a concentration of 3 nM. AD-5075 antagonized isoproterenol inhibition of insulin's action. The concentration of glycogenolytic agent required to attain maximal inhibition was increased an order of magnitude in tissue treated with the antidiabetic agent. Short term preincubation of adipose tissue under hyperglycemic conditions (15 or 25 mM glucose) decreased insulin-stimulated I-form glycogen synthase activity. Concurrent treatment of the tissue with AD-5075 abrogated this glucose toxicity-induced inhibition of insulin action. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, blocked insulin activation of glycogen synthase in a dose-dependent manner. Half-maximal inhibition was observed at approximately 0.3 microM, and maximal inhibition occurred at 1.0 microM. AD-5075 did not antagonize wortmannin's inhibitory action. These results indicate that thiazolidinediones can act directly on adipose tissues to augment an important metabolic effect of insulin and counteract the inhibitory effects of catecholamines or hyperglycemia. As insulin stimulation of glycogen synthase remains wortmannin inhibitable in the presence of AD-5075, the effects of thiazolidinediones on insulin signal transduction may be phosphatidylinositol 3-kinase-dependent.

Adipose Tissue↗
PubMed1996

Calcitonin gene-related peptide, endothelin-1, the cutaneous microvasculature and Raynaud's phenomenon.

It has been argued that the digital cutaneous microvasculature is the site of the anomaly which causes Raynaud's phenomenon (RP). Both endothelin-1 (ET-1), a potent vasoconstrictor peptide present in the digital cutaneous microvasculature, and calcitonin gene-related peptide (CGRP), a powerful vasodilator present in digital cutaneous perivascular nerves, have been implicated in the pathogenesis of RP. Circulating ET-1 levels are raised, and there is a diminution of CGRP-containing perivascular nerves in finger skin in RP. We undertook a pharmacological study to investigate the sensitivity of the digital cutaneous microvasculature to intradermal ET-1 and CGRP. Differences were found in RP compared with normal digital skin, supporting the idea that the digital cutaneous microvasculature is actively involved in the pathogenesis of RP. In RP, the erythematous response to ET-1 was diminished at both 20 and 5 degrees C (a low temperature at which RP classically occurs) providing pharmacological support for the morphological evidence that in RP there is a deficiency of CGRP-containing nerves in the distal digital skin.

Adult↗
PubMed1995

Comparison of conventional Lewis-Tanner two-stage oesophagectomy with the synchronous two-team approach.

Twenty-seven patients with oesophageal carcinoma had subtotal oesophagectomy by the Lewis-Tanner operation (group 1, n = 14) or a synchronous modification (group 2, n = 13). Synchronous operations were completed more quickly (230 versus 305 min, P < 0.01), but with more time spent under single-lung anaesthesia (160 versus 120 min, P < 0.01) and a greater fall in systolic blood pressure during hiatal manipulation (60 versus 30 mmHg, P < 0.01). Operative blood loss was not significantly greater in group 2, but the total volume of blood transfused in the perioperative period was greater in this group (5 versus 3 units, P < 0.01). Four patients in group 1 suffered significant postoperative complications, compared with seven in group 2; three postoperative deaths occurred in group 2. This study suggests that the synchronous two-team oesophagectomy produces a higher incidence of complications than the conventional operation. Continued use of the Lewis-Tanner two-stage oesophagectomy is recommended for patients with carcinoma of the oesophagus.

Adenocarcinoma↗
PubMed1995

Comparison of conventional Lewis-Tanner two-stage oesophagectomy with the synchronous two-team approach.

Twenty-seven patients with oesophageal carcinoma had subtotal oesophagectomy by the Lewis-Tanner operation (group 1, n = 14) or a synchronous modification (group 2, n = 13). Synchronous operations were completed more quickly (230 versus 305 min, P < 0.01), but with more time spent under single-lung anaesthesia (160 versus 120 min, P < 0.01) and a greater fall in systolic blood pressure during hiatal manipulation (60 versus 30 mmHg, P < 0.01). Operative blood loss was not significantly greater in group 2, but the total volume of blood transfused in the peri-operative period was greater in this group (5 versus 3 units, P < 0.01). Four patients in group 1 suffered significant postoperative complications, compared with seven in group 2; three postoperative deaths occurred in group 2. This study suggests that the synchronous two-team oesophagectomy produces a higher incidence of complications than the conventional operation. Continued use of the Lewis-Tanner two-stage oesophagectomy is recommended for patients with carcinoma of the oesophagus.

Adenocarcinoma↗
PubMed1995

Quality-of-life assessment in patients undergoing treatment for oesophageal carcinoma.

In a prospective study of 69 patients being treated for oesophageal carcinoma, quality of life was assessed with the Rotterdam Symptom Checklist, a dysphagia score and an activities of daily living questionnaire. Significant correlations were found between the results of the Rotterdam Symptom Checklist, the dysphagia score and most aspects of the activities of daily living questionnaire. Eighteen patients underwent surgery, 43 radiotherapy or intubation, and eight a combination of surgery and other therapy. Patients undergoing surgery were significantly younger and had better scores in all parameters examined before operation, including significantly better scores in 'knowledge and communication' and 'mobility and fatigue'. The dysphagia score fell significantly after intervention both in patients undergoing surgery alone and in those receiving palliative therapy. The activities of daily living questionnaire showed significant improvements in two parameters in the surgical group ('self-care' and 'eating and drinking') and in none of the parameters assessed in the palliation group in 16 weeks. Quality-of-life assessment is useful in assessing quality of care and patient well-being after the diagnosis and treatment of oesophageal carcinoma.

Activities of Daily Living↗
PubMed1994

PI 3-kinase activation is required for insulin stimulation of glucose transport into L6 myotubes.

Phosphatidylinositol 3-kinase (PI 3-kinase) is acutely stimulated by insulin but its role in regulating glucose metabolism is still not fully understood. Insulin acutely stimulates glucose transport into L6 myotubes approximately 2-fold, and activates PI 3-kinase activity 2 to 3-fold. Wortmannin, an inhibitor of PI 3-kinase, blocked insulin stimulation of 2-deoxyglucose transport into the myotubes in a time and dose-dependent manner. Inhibition was observed within 5 minutes and was complete by 30 minutes. The IC50 for this inhibition was approximately 10 nM; almost complete inhibition was observed at 100 nM. Similarly, insulin stimulation of PI 3-kinase activity was inhibited by wortmannin in a dose-dependent manner. The insulinmimetic vanadate activated hexose transport into the myotubes to more than 50% of the maximal level attained with insulin. Only approximately 60% of vanadate-activated glucose transport was inhibited by maximal wortmannin concentrations. It is concluded that insulin activation of PI 3-kinase is necessary for stimulation of glucose transport into L6 muscle cells. In contrast, vanadate appears to augment transport by acting upon PI 3-kinase-dependent and independent pathways.

Androstadienes↗
PubMed1994

Potentiation of insulin stimulation of phosphatidylinositol 3-kinase by thiazolidinedione-derived antidiabetic agents in Chinese hamster ovary cells expressing human insulin receptors and L6 myotubes.

Thiazolidinedione derivatives are insulin-sensitizing agents with proven antidiabetic activities in vivo. To explore the mechanism of action of this class of compounds, the effects of pioglitazone, CP-86,325, and AD-5075 on elements of the insulin signal transduction pathways were studied in Chinese hamster ovary cells overexpressing human insulin receptor (CHO.T) and L6 myotubes. In CHO.T cells, the binding of insulin to its receptor and the insulin-stimulated tyrosine kinase activity of the receptor were not altered by pioglitazone or CP-86,325. In contrast, treatment of CHO.T cells with the compounds resulted in significant increases in insulin-stimulated phosphatidylinositol (PI) 3-kinase activity. This insulin-enhancing effect was also observed in L6 myotubes treated with CP-86,325. The augmentations in kinase activity observed in CHO.T cells correlated with increases in the amount of PI 3-kinase (p85 subunit) in anti-phosphotyrosine immunoprecipitates of cell lysates. No gross changes in the tyrosine phosphorylation state of the insulin receptor substrate-1 were detected in insulin-stimulated CHO.T cells following treatment with the compounds. Furthermore, the compounds did not enhance insulin stimulation of mitogen-activated protein kinase or DNA synthesis in CHO.T cells. Thus, thiazolidinedione-derived antidiabetic agents may act as insulin sensitizers by augmenting insulin stimulation of PI 3-kinase activity in a rather specific manner.

Animals↗