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Biomedical subjects

J M Morgan

Publications and source records attributed to J M Morgan.

At least 73 records · Page 4Linked to original sources
PubMed1997

E-cadherin (E-cad) expression in duct carcinoma in situ (DCIS) of the breast.

E-cadherin (E-cad) is an epithelial cell-cell adhesion molecule whose loss or reduced expression is associated with a more invasive tumour phenotype. Ninety-six cases of screen detected pure ductal carcinoma in situ (DCIS) were analysed immunocytochemically for expression of E-cad using the HECD-1 mouse monoclonal antibody. The in situ component in each case was classified on the basis of cytonuclear grade, extent of necrosis, Van Nuys classification and a newly devised Cardiff classification. The amount of E-cad expression was assessed semi-quantitatively using an intensity distribution method. There is significantly more expression of E-cad in well-differentiated DCIS when compared with poorly differentiated DCIS and this finding is highly significant (P < 0.001) irrespective of the classification system used. These findings suggest that progressive loss of E-cad expression may occur at an early stage of breast cancer development.

Breast Neoplasms↗
PubMed1997

Loss of E-cadherin expression associated with lymph node metastases in small breast carcinomas.

The National Breast Screening Programme affords the opportunity to study breast carcinomas at an early stage in their development. E-cadherin is a calcium-dependent, intercellular adhesion molecule whose loss of expression may facilitate the processes of invasion and metastasis of some human tumours. From a group of screen-detected ductal carcinomas less than or equal to 10 mm in diameter, 16 with lymph node metastasis were identified and matched for grade, size and patient age with node negative tumours. The level of expression of E-cadherin (detected by immunocytochemistry) was compared in the matched pairs using a simple semi-quantitative intensity distribution scoring system. The results showed a significant (P = 0.05 Wilcoxon paired rank test) reduction of E-cadherin expression in tumours with lymph node metastases compared to those without. In the context of the small size of these tumours it is proposed that these results support the hypothesis that reduction in E-cadherin expression is an early event in the development of metastases.

Aged↗
PubMed1997

Immunoreactive p53 and metallothionein expression in duct carcinoma in situ of the breast. No correlation.

Immunocytochemically detectable MT and p53 have been found more commonly in comedo DCIS of the breast with high-grade cytology. The aim of this study is to confirm these findings and to investigate the relationship between MT and p53 in a single large series of cases of DCIS of the breast. To this end, 127 cases of DCIS were classified histologically according to architecture, cytonuclear differentiation (grade), presence and extent of intraduct necrosis, and using the Van Nuys system. Sections were immunostained for p53 and MT (E9) using established techniques, and the extent and intensity of staining were assessed semi-quantitively. The results confirmed that there was generally more MT and p53 positivity in poorly differentiated (grade 3) DCIS with extensive necrosis and that MT expression was greater in grade 2 lesions than p53 expression. However, overall there was no statistically significant correlation between p53 and MT staining. The results indicate that MT and p53 overexpression may arise from independent mechanisms in early breast neoplasia.

Breast Neoplasms↗
PubMed1997

Effect of renal impairment on the pharmacokinetics and pharmacodynamics of desirudin.

OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of desirudin in subjects with various degrees of renal impairment in comparison with subjects with normal renal function. METHODS: Eight subjects with normal renal function (creatinine clearance > 90 ml/min) received 0.5 mg/kg desirudin intravenously over 30 minutes. Four subjects with mild renal failure (creatinine clearance between 61 and 90 ml/min) received 0.5 mg/kg. Five subjects with moderate renal failure (creatinine clearance between 31 and 60 ml/min) received 0.25 mg/kg. Six subjects with severe renal failure (creatinine clearance < 31 ml/min) received 0.125 mg/kg. RESULTS: Specific maximum concentration values (maximum concentrations corrected to a dose of 1 mg/kg) increased slightly with decreasing creatinine clearance. Mean specific area under the plasma concentration-time curve increased by a factor of 1.15, 2.83, and 7.0 for subjects with mild, moderate, and severe renal failure, respectively, compared with healthy subjects. Total urinary excretion of desirudin was about 55% to 60% of the dose in all four groups; elimination was delayed for subjects with moderate and severe renal failure. Total and renal clearance of desirudin were proportional to creatinine clearance. Total plasma clearance of desirudin was proportional to renal clearance of the drug. Prolongation of activated partial thromboplastin time was increased among subjects with moderate and severe renal failure despite a dose reduction. Area under the dynamic activated partial thromboplastin time curve for subjects with moderate renal failure remained the same as that for healthy subjects despite a dose reduction by a factor of two. Area under the dynamic curve increased by a factor of about 1.5 for subjects with severe renal failure despite a dose reduction by a factor of four. CONCLUSION: A dose reduction by a factor of six is recommended for persons with severe renal failure.

Adult↗
PubMed1997

The effect of valsartan on the angiotensin II pressor response in healthy normotensive male subjects.

OBJECTIVE: Valsartan is an oral antagonist of angiotensin II that competes with angiotensin II for the AT1-receptor and is being developed as an antihypertensive agent. This study assessed the ability of 80 mg valsartan to inhibit the pressor effect of exogenous angiotensin II in healthy normotensive men, first after a single dose and then after multiple doses once daily for 7 days. METHODS: This was a single-center, double-blind, placebo-controlled, randomized crossover study. Six healthy men underwent angiotensin II challenges to determine a suitable dose required to increase their systolic blood pressure by approximately 30 mm Hg. Each subject then received an 80 mg dose of valsartan or matching placebo. The inhibition of the angiotensin II pressor effect was determined by the systolic blood pressure response to repeated angiotensin II challenges at multiple time points. RESULTS: Systolic blood pressure responses to angiotensin II challenges after single and multiple doses of valsartan were significantly lower than placebo, indicating that valsartan blocked the blood pressure response to angiotensin II. The maximum blocking effect was observed within 2 to 3 hours. Mean data suggested that differences in effect between valsartan and placebo were similar after both single and multiple doses and persisted up to 24 hours after administration. The angiotensin II blocking effect was maintained up to this time, despite low plasma valsartan levels and minimal accumulation after multiple doses. CONCLUSION: Valsartan, 80 mg, is a potent angiotensin II antagonist with a rapid onset of action and persistent angiotensin II inhibition up to 24 hours. There is no attenuation of this effect after multiple doses.

Adult↗
PubMed1997

Microdissection of stained archival tissue.

In many tissues the preinvasive stage of neoplastic progression can be identified histologically as dysplasia or in situ disease. There is much interest in defining the molecular events associated with the early stages of neoplasia. Retrieval of histologically recognisable preinvasive neoplastic tissue uncontaminated by inflammatory or stromal cells is important for genetic studies using polymerase chain reaction (PCR) assay. A novel method for microdissection is described in which 10 microns sections are dewaxed, stained with haematoxylin and eosin, dried, covered with Sellotape, and the tissue cut out using a scalpel blade under direct visual control. The method is quick, eliminates problems of operator tremor, preserves the architecture of the micro-dissected tissue (for photographic documentation) and requires no special equipment. The presence of Sellotape and adhesive in the reaction mixture has no detrimental effect on the ability to extract DNA or to perform PCR.

Breast Neoplasms↗
PubMed1997

Cutis marmorata telangiectatica congenita with hypoplasia of the right iliac and femoral veins.

We describe a 37-year-old woman with an extensive congenital reticulate vascular naevus affecting predominantly the right side of the body associated with a naevus anaemicus. Investigation of persistent ulceration and scarring of the lower legs revealed right-sided hypoplasia of the hemipelvis and underlying ipsilateral hypoplasia of the deep veins of the pelvis and leg. This association has not previously been reported and its implications for morbidity and management are discussed.

Adult↗
PubMed1996

Germline WT1 mutations in Wilms' tumor patients: preliminary results.

We conducted a comparative study of the prevalence of germline WT1 mutations in patients with Wilms' tumor. Patients in Group 1 have familial Wilms' tumor, bilateral disease, associated urogenital anomalies, and/or second cancers. Those in Group 2 are unilateral, sporadic Wilms' patients without other associated conditions. Patients with aniridia or Denys-Drash syndrome are known to have WT1 alterations, and are excluded from this study. Preliminary results on 96 subjects show that the overall germline WT1 mutation frequency is low (< 5%). The work to date establishes the feasibility of identifying patients with germline WT1 mutations and, in the future, offering genetic predisposition testing to at-risk relatives. However, genetic predisposition testing of children for WT1 mutations raises many ethical, legal, and psychosocial issues; research is needed to evaluate risks and benefits.

Base Sequence↗
PubMed1996

Identification of three isoforms of the InsP3 receptor in human myometrial smooth muscle.

The mechanisms responsible for the mobilisation of Ca2+ from intracellular stores sensitive to inositol trisphosphate (InsP3) were studied in saponin-permeabilised human myometrial cells in which the sarcoplasmic reticulum was pre-loaded with 45Ca2+. InsP3-induced 45Ca2+ release was measured over the InsP3 concentration range of 100 nM to 100 microM and showed a graded response. InsP3-induced 45Ca2+ release was inhibited by heparin (20-40 microg/ml) but not significantly affected by caffeine. The Ca2+ sensitivity of InsP3-induced Ca2+ release was measured under conditions which were designed to exclude interference with Ca2+ released by the ryanodine receptor/channel complex. The data showed a bell-shaped relationship with the InsP3 receptor (InsP3R) functional at 10 nM, becoming maximally activated at 300 nM but inhibited at 10 microM Ca2+. Messenger RNA encoding for three isoforms of InsP3R, type I, II and type III, was shown to be present. The relative expression levels of these messengers were obtained by ratio-PCR analysis and the levels of expression of the different isoforms were found to differ between individual patients.

Base Sequence↗
PubMed1996

Epidermal growth factor receptor status in hyperparathyroidism: immunocytochemical and In situ hybridization study.

The epidermal growth factor receptor (EGFr) family has been increasingly recognized as an important component in the control of normal cell proliferation and the pathogenesis of cancer. We have studied EGFr expression in 104 cases of hyperparathyroidism by immunocytochemistry (ICC) and by in situ hybridization (ISH). Using two different monoclonal antibodies, ICC for EGFr was performed on 66 cryostat sections and 38 wax-embedded parathyroid glands. ISH was performed on 49 of these glands using a cocktail of three anti-sense probes to EGFr mRNA and a nonspecific control probe to human HPV-18 virus. Breast and prostate tumors were employed as positive controls for both ICC and ISH. Controls demonstrated positive EGFr staining. None of the 104 parathyroid glands showed any ICC positivity. ISH displayed positive staining for EGFr mRNA in five of six carcinomas and eight of nine nonrenal hyperplastic glands. Only 3 of 15 adenomas and 3 of 19 renal hyperplastic glands showed positive staining. This difference was statistically significant between adenoma and carcinoma (p < 0.05) and between adenoma and nonrenal hyperplasia (p < 0.01) (Tukey's multiple comparison test). This study demonstrates that EGFr mRNA is present in parathyroid tumors. Expression in carcinoma and nonrenal hyperplasia is significantly different from adenoma and renal hyperplastic glands. In contrast, ICC failed to demonstrate EGFr protein expression. These findings suggest that either receptor numbers are too low to detect by ICC or there is a failure of mRNA translation. More studies are needed to establish whether the EGFr plays a role in the development of parathyroid cancer or hyperplasia.

Adenoma↗
PubMed1996

A critical appraisal of six modern classifications of ductal carcinoma in situ of the breast (DCIS): correlation with grade of associated invasive carcinoma.

The in-situ component of 180 cases of screen detected infiltrating duct carcinoma of the breast was classified according to six published classifications for ductal carcinoma in situ based on architecture, necrosis and cytology. All cases were assessed independently by two experienced observers to assess inter-observer variation. The differentiation of ductal carcinoma in situ as assessed by all the classification systems correlated with the grade of the associated invasive carcinoma (chi-squared between 50 and 107: P < 0.0001). Disagreements were commonest in the assessment of architecture and least common in the assessment of necrosis. For cytonuclear grade most disagreements (62.2%) involved the distinction between low and intermediate as against 33.9% disagreements for intermediate vs. high. Nuclear grade alone and necrosis alone were correlated with the grade of invasive carcinoma associated with the ductal carcinoma in situ and the Nottingham prognostic index of the patient. The Van Nuys classification of ductal carcinoma in situ is commended because it has a low inter-observer disagreement, is significantly correlated with the grade of the infiltrating carcinoma, uses simple well-defined criteria (with no requirement for percentage estimations), is applicable to small numbers of ducts and, most importantly, appears to correlate with disease-free survival.

Breast Neoplasms↗
PubMed1995

Isolation and partial cloning of ryanodine-sensitive Ca2+ release channel protein isoforms from human myometrial smooth muscle.

Partial cDNAs of the ryanodine receptor were cloned using PCR analysis from reverse transcribed total and mRNA, extracted from freshly isolated pregnant, non-pregnant, and cultured human myometrial smooth muscle. The identity of these clones was confirmed by nucleotide sequencing of the fragments and indicate the expression of both the skeletal and brain ryanodine receptor isoforms in these preparations. In freshly isolated non-pregnant myometrial tissue, membrane fractions displaying specific [3H]ryanodine binding activities were isolated using density gradient centrifugation. SDS-PAGE of the sucrose gradient fractions indicated the specific comigration of a polypeptide with a molecular mass of approximately 544 kDa with the ryanodine binding activity.

Amino Acid Sequence↗
PubMed1995

The modulation and characterisation of the Ca(2+)-induced Ca2+ release mechanism in cultured human myometrial smooth muscle cells.

The process of Ca(2+)-induced Ca2+ release (CICR) was studied in saponin permeabilised human myometrial smooth muscle cells in which the sarcoplasmic reticulum (SR) was pre-loaded with 45Ca2+. A rise in the free Ca2+ concentration of the bathing solution from 100 nM to 10 microM increased the rate of 45Ca2+ loss, while a reduction to 10 nM decreased the rate of 45Ca2+ loss. Ruthenium red (20 microM) lowered the basal rate of 45Ca2+ loss and reduced CICR. Caffeine did not activate 45Ca2+ release although ryanodine induced 45Ca2+ release and CICR was augmented in the presence of caffeine. These data suggest the operation of a Ca(2+)-activated 45Ca2+ release process which is similar in many of its properties to the CICR process described in many cells. The basic properties of the CICR mechanism in myometrium differs in many respects from the CICR process recently described in human vascular smooth muscle.

Adult↗
PubMed1995

Comparative pharmacokinetics and bioavailability of nitroglycerin and its metabolites from Transderm-Nitro, Nitrodisc, and Nitro-Dur II systems using a stable-isotope technique.

The pharmacokinetics and bioavailability of nitroglycerin (GTN) and its metabolites, 1,2-glyceryl dinitrate (1,2-GDN) and 1,3-glyceryl dinitrate (1,3-GDN), were compared after a single 14-hour application of Transderm-Nitro (Ciba-Geigy, Summit, NJ), Nitrodisc (GD Searle, Chicago, IL), and Nitro-Dur II (Key Pharmaceuticals, Kenilworth, NJ) systems to 18 healthy male subjects on 3 separate occasions. A 14-hour intravenous infusion of 15N-labeled GTN was given simultaneously to correct for changes in systemic clearance during the application of each system. Plasma concentrations of 15N-labeled GTN, unlabeled GTN, and their corresponding dinitrate metabolites were measured using a gas chromatography/mass spectrometry method. Results showed that the plasma concentration profiles of nitroglycerin and its metabolites for the three systems were similar during and after system removal. Mean (SD) total amounts (AUCp x CLiv) of GTN transdermally available after adjustment for 15N-labeled GTN clearance were 5.3 (2.1), 5.3 (2.0), and 5.4 (2.6) mg for Transderm-Nitro, Nitrodisc, and Nitro-Dur II, respectively. Mean (SD) AUC values for 1,2-GDN were 44.6 (15.8), 44.3 (16.1), and 42.8 (19.3) ng.h/mL for the 3 systems. Corresponding AUC values for 1,3-GDN were 9.3 (2.9), 9.7 (2.9), and 8.7 (3.0) ng.h/mL. Statistical analysis of the log-transformed data based on 90% conventional confidence interval showed that all 3 systems delivered equivalent amounts of nitroglycerin into the systemic circulation. The AUC ratios for 1,3-GDN to GTN, but not 1,2-GDN to GTN, were statistically different for the intravenous and transdermal routes during all 3 system applications, indicating that the formation and metabolism of 1,3-GDN was dependent on route of administration.

Administration, Cutaneous↗
PubMed1995

Environmental risk factors for Lyme disease identified with geographic information systems.

OBJECTIVES: A geographic information system was used to identify and locate residential environmental risk factors for Lyme disease. METHODS: Data were obtained for 53 environmental variables at the residences of Lyme disease case patients in Baltimore County from 1989 through 1990 and compared with data for randomly selected addresses. A risk model was generated combining the geographic information system with logistic regression analysis. The model was validated by comparing the distribution of cases in 1991 with another group of randomly selected addresses. RESULTS: In crude analyses, 11 environmental variables were associated with Lyme disease. In adjusted analyses, residence in forested areas (odds ratio [OR] = 3.7, 95% confidence interval [CI] = 1.2, 11.8), on specific soils (OR = 2.1, 95% CI = 1.0, 4.4), and in two regions of the county (OR = 3.5, 95% CI = 1.6, 7.4) (OR = 2.8, 95% CI = 1.0, 7.7) was associated with elevated risk of getting Lyme disease. Residence in highly developed regions was protective (OR = 0.3, 95% CI = 0.1, 1.0). The risk of Lyme disease in 1991 increased with risk categories defined from the 1989 through 1990 data. CONCLUSIONS: Combining a geographic information system with epidemiologic methods can be used to rapidly identify risk factors of zoonotic disease over large areas.

Environmental Exposure↗
PubMed1995

Calcitonin and calcitonin gene-related peptide mRNA detection in a population of hyperplastic parathyroid cells also expressing chromogranin B.

BACKGROUND: In contrast to chromogranin A, chromogranin B is found only in small amounts in parathyroid tissue. We have recently shown that hyperplastic parathyroid glands occasionally show a pronounced focal chromogranin B expression. The aim of the present study was to further investigate the properties of these chromogranin B-positive cells by means of immunohistochemistry and in situ hybridization. EXPERIMENTAL DESIGN: Routinely processed tissues from 22 normal, 86 hyperplastic, and 36 neoplastic parathyroid glands were immunohistochemically investigated with Ab against parathyroid hormone (PTH), chromogranin A and B, calcitonin, and calcitonin gene-related peptide (CGRP). Additionally, six hyperplastic glands with focal chromogranin immunoreactivity as well as chromogranin B-negative normal, hyperplastic, and neoplastic (two cases each) glands were used for in situ hybridization studies for the demonstration of calcitonin and CGRP mRNA. RESULTS: All normal, hyperplastic, and neoplastic parathyroids were immunohistochemically PTH- and chromogranin A-positive. Twelve of 86 hyperplastic glands showed a focal chromogranin B immunoreactivity; in 10 out of these 12 cases, calcitonin could be colocalized with chromogranin B, chromogranin A, and PTH. CGRP was found in a fraction of calcitonin-positive cells in four cases. In hyperplastic glands, calcitonin mRNA was detected in areas with immunohistochemical calcitonin and chromogranin B positivity. CGRP mRNA was demonstrated only in a few cells. CONCLUSIONS: The results from this study demonstrate that calcitonin and CGRP may be synthesized and stored in PTH-producing hyperplastic parathyroid cells. The calcitonin-positive cells also strongly express chromogranin B, which is immunohistochemically not detectable in normal parathyroid cells. The functional significance of these findings remains to be elucidated.

Base Sequence↗
PubMed1995

The clinician-information interface.

Technical advances now enable rapid data collection into sophisticated information systems, and the vision of the electronic patient record may soon be a reality. However, despite advances in the human-computer interface, little attention has been given to the structure of the clinical data to be collected in the electronic record. The 'clinician-information interface' embraces the cognitive, analytical, and decision processes that the clinician will need to undergo to capture clinical data in a structured, meaningful, and analyzable form. This paper discusses some of the issues which need to be addressed if the emerging opportunities for a detailed capture of clinical data are to be maximized.

Ambulatory Care↗