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Biomedical subjects

I Perry

Publications and source records attributed to I Perry.

At least 19 recordsLinked to original sources
PubMed2000

Aberrant P-cadherin expression is a feature of clonal expansion in the gastrointestinal tract associated with repair and neoplasia.

The recognition of key roles for cadherins in the determination of epithelial cell phenotype, migration, differentiation, and tumour dissemination have stimulated much interest in this family of adhesion molecules. In the gastrointestinal tract, alteration of the expression of classical cadherins with aberrant P-cadherin up-regulation, associated with co-expression or loss of E-cadherin expression, is seen in neoplastic transformation of oral and oesophageal squamous mucosa and in lesions representing early neoplastic transformation of glandular mucosa, such as aberrant crypt foci and metaplastic and adenomatous polyps. This same phenotype is seen in enterocytes adjacent to foci of ulceration in the intestine in colitis, including inflammatory bowel disease, and in colitis-associated dysplasia. In coeliac disease, reversible E-cadherin down-regulation correlates with the degree of villous atrophy, but in contrast with colitis, aberrant P-cadherin expression is not a feature. Aberrant epithelial P-cadherin expression is thus associated with a proliferative phenotype related to ulceration and neoplastic transformation in the gastrointestinal tract, which may confer a survival advantage on these cells, but the relative functional roles of P-cadherin and E-cadherin and the molecular mechanisms underlyingP-cadherin/catenin interactions have yet to be elucidated.

Cadherins↗
PubMed2000

Barrett's mucosa: remodelling by the microenvironment.

Barrett's metaplasia and the associated adenocarcinoma are composed not only of epithelial cells, but also of inflammatory cells and endothelial cells in the lamina propria and around the tumour, respectively. The early incidence of vascular invasion and metastasis is a feature of Barrett's adenocarcinomas. A paper in this issue of The Journal of Pathology shows that vascular endothelial growth factor (VEGF) is expressed in both metaplastic cells and endothelial cells of pre-neoplastic Barrett's epithelium early in the development of neoplasia. It is becoming clearer that the harmful insults of acid and bile reflux alter not only the epithelium, but also the lamina propria. Cytokines such as tumour necrosis factor alpha (TNFalpha) or transforming growth factor (TGFalpha) are implicated in the formation of early Barrett's adenocarcinomas. From current knowledge it is possible to hypothesize that metaplastic cells, perhaps as a consequence of either TNFalpha or TGFalpha stimulation, secrete VEGF. VEGF can promote adjacent endothelial cell growth through phosphorylation of beta-catenin and vascular endothelial cadherin (VE-cadherin) in endothelial cells. In this de novo microenvironment, angiogenesis is therefore accelerated, enhancing the chance of microvascular invasion.

Barrett Esophagus↗
PubMed2000

Barrett's esophagus: disregulation of cell cycling and intercellular adhesion in the metaplasia-dysplasia-carcinoma sequence.

The incidence of both esophageal adenocarcinoma and Barrett's esophagus, a premalignant condition predisposing to this cancer, is rising rapidly. There is growing evidence that both of these conditions are related to the reflux of acid and bile into the esophagus. This results in inflammation and cell damage which initiates a sequence of events termed the metaplasia-dysplasia-carcinoma sequence in which the squamous epithelium is replaced by columnar epithelium exhibiting increasing degrees of dysplasia and overt malignancy. This sequence of events is underpinned by changes in cell cycling, such as accumulation of p16 and p53 mutations and increased cyclin D1 activity. Progression along this pathway is characterized by changes in intercellular adhesion, in particular, loss of adenomatous polyposis coli, reduced cadherin expression and increased catenin phosphorylation resulting in its nuclear translocation. Herein, we detail these molecular defects and propose how they may interrelate in an ordered progression in the development of esophageal adenocarcinoma.

Adenocarcinoma↗
PubMed1999

Magnesium in drinking water supplies and mortality from acute myocardial infarction in north west England.

OBJECTIVES: To examine whether higher concentrations of magnesium in drinking water supplies are associated with lower mortality from acute myocardial infarction at a small area geographical level; to examine if the association is modified by age, sex, and socioeconomic deprivation. DESIGN: Small area geographical study using 13,794 census enumeration districts. Water constituent concentrations (magnesium, calcium, fluoride, lead) measured at water supply zone and assigned to enumeration districts. SETTING: 305 water supply zones in north west England. SUBJECTS: Resident population of 1,124,623 men and 1,372,036 women (1991 census) aged 45 years or more. MAIN OUTCOME MEASURE: Mortality from acute myocardial infarction, International Classification of Diseases, ninth revision (ICD-9) 410. Subsidiary analysis examined deaths from ischaemic heart disease, ICD 410-414. RESULTS: There were 21,339 male and 17,883 female deaths from acute myocardial infarction in 1990-92. Drinking water magnesium concentrations in water zones ranged from 2 mg/l to 111 mg/l (mean (SD) 19 (20) mg/l, median 12 mg/l); 24% of variation in magnesium concentrations was within zone and 76% was between zone. The relative risk of mortality from acute myocardial infarction (standardised for age, sex, and Carstairs deprivation quintile) for a quadrupling of magnesium concentrations in drinking water (for example, 20 mg/l v 5 mg/l) was 1.01 (95% confidence interval (CI) 0.99 to 1.03). When adjusted for north-south and east-west trends in mortality from acute myocardial infarction and for drinking water calcium, fluoride, and lead concentrations, this relative risk was 1.01 (95% CI 0.96 to 1.06). There was no evidence of a protective effect for acute myocardial infarction even among age, sex, and deprivation groups that were likely to be relatively magnesium deficient. For ischaemic heart disease mortality there was an apparent protective effect of magnesium and calcium (with calcium predominating in the joint model), but these were no longer significant when the geographical trends were incorporated. CONCLUSIONS: No evidence was found of an association between magnesium concentrations in drinking water supplies and mortality from acute myocardial infarction. These results do not support the hypothesis that magnesium is the key water factor in relation to mortality from heart disease.

Age Factors↗
PubMed1999

Cadherin adhesion in the intestinal crypt regulates morphogenesis, mitogenesis, motogenesis, and metaplasia formation.

The topographical organisation of the epithelium lining mucous membranes has been an intense point of research. One of the fundamental biological issues underpinning this and associated issues relates to the role and regulation of epithelial adhesion molecules. Adhesion between individual cells allows an intact layer to be formed, which is selectively permeable. In addition, the orchestrated regulation of multiple adhesion molecules allows the gradual transition from basal secretory cells to apical absorptive cells in the crypt-villus gradient. Moreover, it is becoming clear that no one class of adhesion molecule can sufficiently govern crypt architecture; however, the main cell-cell adhesion molecules are the cadherins and the related desmosomal cadherins. These latter molecules interact with the catenins, which bind directly or indirectly with cytoskeletal molecules such as Rho and Rac. In addition, other complex glycoproteins, such as the carcinoembryonic antigens, might contribute to adhesion, although their mechanisms of function are distinctly different. Integrins on the basal aspect of the cells also signal important morphoregulatory signals as a result of their binding to the extracellular maxtrix. The disruption of these physiological processes also provides a necessary and, in some cases, sufficient molecular mechanism for cancer invasion and metastasis, such as occurs in E-cadherin mutation positive familial gastric cancer.

Cadherins↗
PubMed1999

A colorectal cell line with alterations in E-cadherin and epithelial biology may be an in vitro model of colitis.

BACKGROUND: It has been shown previously in ulcerative colitis tissue that E-cadherin can occasionally be mutated in the extracellular domain early in neoplastic progression. E-cadherin is known to maintain differentiation and inhibits invasion in vivo. AIMS: To assess the mechanisms by which such dysfunction occurs. METHODS: Four human colorectal cancer cell lines, HCA-7 colonies 1, 3, 6, and 30, derived from a single heterogeneous colorectal cancer were studied. The HCA-7 cell line has p53 mutations and a random errors of replication "positive" phenotype, as is seen in early colitis associated cancers or hereditary nonpolyposis coli cancer (HNPCC). RESULTS: Cell lines 6 and 30 expressed E-cadherin abundantly and this correlated positively with their degree of differentiation and organisation; however, both cell lines had loss of heterozygosity of E-cadherin. Interestingly, E-cadherin production was downregulated in the poorly differentiated cell line 1, and this was associated with major chromosomal rearrangements of 16q. This cell line also had a mutation in the homophilic binding domain of exon 4, which was associated with disaggregation by low titres of a function blocking antibody, and an invasive phenotype. CONCLUSIONS: These multiple biological alterations further characterise the complex association that E-cadherin has with tumour heterogeneity and suggest that this series of cell lines may be a useful model of colitis associated or HNPCC associated tumorigenesis.

Agar↗
PubMed1999

Reduced cadherin/catenin complex expression in celiac disease can be reproduced in vitro by cytokine stimulation.

Celiac disease is characterized by a chronic immune response to dietary gluten, in which T cell responses result in elevated mucosal levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, interferon (IFN)-gamma, and transforming growth factor (TGF)-beta, which induce profound mucosal remodeling associated with increased enterocyte proliferation, apoptosis, and migration. Reduced intestinal expression of the morphoregulatory cell adhesion molecule E-cadherin, which forms complexes with beta-catenin, can increase enterocyte proliferation and migration. However, its mechanism of action in gastrointestinal inflammatory conditions and any involvement in celiac disease is unknown. In this study, we describe changes in E-cadherin and beta-catenin expression in celiac disease tissue and determine the effect of cytokines on their expression in an in vitro model. We assessed E-cadherin and beta-catenin expression in intestinal biopsies from 24 patients with celiac disease, 12 patients with treated celiac disease, and 10 healthy patients by immunohistochemistry, Western blotting, and confocal microscopy. Using Caco-2 cells, we examined the effect of TNF-alpha, IL-1, IFN-gamma, and TGF-beta on E-cadherin expression. E-cadherin transcription was assessed in both intestinal biopsies and Caco-2 cells by in situ hybridization and RT-PCR, respectively. A marked reduction in protein expression of E-cadherin and beta-catenin that returns to normal levels after treatment was observed in celiac disease; this reduction was associated with reduced levels of E-cadherin mRNA. E-cadherin expression in Caco-2 cells was significantly reduced after TNF-alpha, IL-1, and IFN-gamma stimulation. The effect of TNF-alpha on E-cadherin expression was maximal after stimulation for 48 hours and also induced modest reductions in beta-catenin expression. The action of TNF-alpha on E-cadherin was reversible and was shown to act at the transcriptional level. These results demonstrate the novel findings that E-cadherin and beta-catenin expression are reversibly down-regulated in celiac disease and that such changes in epithelial cadherin/catenin complexes may be mediated by cytokines acting on cadherin transcription.

Base Sequence↗
PubMed1998

The right to die: a case for reform.

The debate over patients' right to die is a complex one. Here one nurse looks at the statutory requirements and ethical considerations and makes a case for the development of living wills.

Ethics, Medical↗
PubMed1995

Exercise ECG's.

Explore the source record for details and available documents.

Aerospace Medicine↗
PubMed1994

[Pulmonary embolism despite inferior vena cava filter].

The Greenfield filter is an effective and safe means of preventing postoperative pulmonary embolism in high-risk patients. However, it does not give absolute protection. We report a 69-year-old man who presented with deep vein thrombosis. Medical work-up revealed pancreatic tumor (Trousseau's sign). The Greenfield filter was placed in the inferior vena cava before operation. 11 days after total pancreatectomy clinical signs of pulmonary embolism appeared and the diagnosis was confirmed by ventilation-perfusion scan; anticoagulant therapy was instituted. The incidence of pulmonary embolism following interruption of the inferior vena cava by introducing the Greenfield filter is low (2.2%). Nevertheless, the diagnosis of pulmonary embolism should be considered in any patient with appropriate clinical signs, regardless of whether a filter was inserted.

Aged↗
PubMed1994

Maternal factors and development of cardiovascular risk: evidence from a study of blood pressure in children.

It has been suggested that risks of hypertension and cardiovascular disease begin in utero and that maternal nutrition plays an important role. We have examined the relation between maternal factors and BP in a study of 1,311 children in which physical measurements at 9-11 years of age have been linked to a parental questionnaire; birth record data were also available in a subsample of 662 children. Maternal height was inversely related to childhood BP after adjustment for the child's current height. However, several social factors related to maternal nutrition in pregnancy in earlier studies (including social class, housing tenure, maternal educational attainment and maternal smoking in pregnancy) showed weak and inconsistent relations with BP at 9-11 years. Minimum maternal haemoglobin in pregnancy and change in mean corpuscular volume in pregnancy (identified as potentially important markers of maternal nutrition in earlier studies) showed no consistent relationships either with placental weight to birthweight ratio or with childhood BP, although both factors showed strong inverse associations with birthweight. The association between maternal height and childhood BP may reflect the influence of early life factors on cardiovascular risk. However, the absence of consistent relationships between social factors and BP in offspring provides little support for the possibility that maternal diet is an important influence on cardiovascular risk factors in childhood. Minimum maternal haemoglobin and change in maternal mean corpuscular volume are unlikely to be specific markers of maternal nutrition in pregnancy. More specific hypotheses relating maternal nutrition to the development of cardiovascular risk in offspring are required.

Adult↗
PubMed1993

A simplified method for culture of endothelial cells and analysis of adhesion of blood cells under conditions of flow.

We have developed a simplified technique for culturing human umbilical vein endothelial cells under shear flow conditions, using prefabricated glass microcapillary tubes ("microslides") with a well-defined rectangular cross section and good optical quality. These microslides have been incorporated into a controlled flow system for quantitative video-microscopic analysis of the adhesion of blood cells to endothelial cells. Microslides were pretreated with 3-aminopropyltriethoxy-silane, or gelatin, and then loaded with a suspension of endothelial cells. After the cells had settled and attached to the substrate, the microslides were inserted into a flow-based culture system. Medium was drawn through them at intervals or continuously until confluency was reached (approximately 24 hr). Cells were cultured at wall shear stresses over a range 0.06 to 2.2 Pa. For adhesion assays, the endothelialized microslides were attached to microscope slides, and suspensions of blood cells were drawn through at desired wall shear stresses (0.02-0.5 Pa). Adhesion of malarial-infected red blood cells and of neutrophilic granulocytes was quantitated by direct microscopic observation. The adhesive behavior of both cell types closely resembled that previously described by ourselves and others using flow chambers incorporating endothelial-coated glass coverslips. The use of microslides represents a significant simplification of methodology for endothelial cell growth and adhesion studies under flow conditions.

Blood Cells↗
PubMed1993

Effect of activation on adhesion of flowing neutrophils to cultured endothelium: time course and inhibition by a calcium channel blocker (nitrendipine).

1. Adhesion of neutrophils to vascular endothelium plays an important role in inflammation and thrombosis. Modulation of adhesion may be therapeutic in these conditions. 2. A flow model was used to quantify adhesion of neutrophils to human cultured umbilical vein endothelial cells. The time course of the neutrophil response to activation by N-formyl-methionyl-leucylphenylalanine (fMLP, 10(-7) M) was studied and the inhibitory effects of the calcium-channel blockers, nitrendipine and nifedipine, were investigated. 3. Neutrophils adhered firmly to the endothelial cells without rolling, but initial attachment was highly dependent on shear stress; doubling the stress from 0.05 to 0.1Pa decreased the number of neutrophils adhering by over 80%. 4. Adhesion rapidly increased after activation of neutrophils by fMLP, peaking at 1-3 min post-treatment, and then decreased over the next 10-12 min. A monoclonal antibody to the beta 2-integrin component CD18 inhibited adhesion by over 80% for activated or unactivated cells. 5. The Ca-channel blocker, nitrendipine, but not nifedipine, significantly inhibited the fMLP-induced increase of adhesion in a dose-dependent manner (10(-8) to 10(-6) M). Dihydropyridines may be useful agents for modifying neutrophil function.

Adult↗
PubMed1990

Hyperthyroidism, inappropriate plasma TSH and pituitary adenoma in three patients, two receiving long-term phenothiazine therapy.

Hypersecretion of TSH by a pituitary adenoma is thought to be a rare form of hyperthyroidism. We describe three such patients, each of whom presented with clinical hyperthyroidism and a diffuse goitre, without eye signs or dermatopathy. Two were receiving long-term phenothiazine, one of these was also acromegalic. Plasma thyroxine, free T4 and tri-iodothyronine were repeatedly raised in each; plasma TSH was grossly elevated in one and inappropriately normal in the other two. Plasma TSH did not rise in response to thyrotrophin-releasing hormone or metoclopramide and was not suppressed by L-dopa in any patient. Anti-thyrotrophin receptor antibodies were undetectable. Skull radiographs showed erosion and expansion of the pituitary fossa and CT scans confirmed a pituitary mass in each patient. A pituitary adenoma was removed by transphenoidal surgery in two patients and a TSH-secreting adenoma was confirmed by immunocytochemical staining and electron microscopy. Both patients were clinically euthyroid post-operatively but still had evidence of TSH excess. Pituitary surgery was technically unsuccessful in the third patient. Although two patients had hyperthyroidism of long duration, all three were diagnosed within one year of the introduction of a sensitive TSH assay to our laboratory. A TSH-secreting pituitary adenoma may be a more common cause of hyperthyroidism than has been believed.

Adenoma↗
PubMed1989

Fulminant severe retinopathy in a newly diagnosed diabetic without risk factors.

The authors describe a 26-year-old female developing severe proliferative retinopathy within 2 weeks of diagnosis of insulin-dependent diabetes mellitus. The patient presented with profound diabetic ketoacidosis, but had no other risk factors for retinopathy. She had marked bilateral myopia which did not protect her from retinopathy. Nine months after diagnosis of diabetes, she has profound visual impairment despite correction for myopia, and has also developed marked autonomic neuropathy and diabetic nephropathy.

Adult↗