Biomedical subjects
C Morrison
Publications and source records attributed to C Morrison.
Highly differentiated keratinizing squamous cell cancer of the cervix: a rare, locally aggressive tumor not associated with human papillomavirus or squamous intraepithelial lesions.
The purpose of this study is to report an unusual variant of cervical squamous cell carcinoma, not associated with either human papillomavirus infection or antecedent squamous intraepithelial lesions. Five women had a diagnosis of invasive cervical cancer discovered at hysterectomy performed for prolapse (two cases), leiomyoma (one case), or a vaginal fistula (two cases). The women ranged in age from 47 to 78 years (mean 59 years). Four of the five had a history of normal Papanicolaou (Pap) smears; the other had a Pap smear diagnosis of atypical squamous cells of undetermined significance (ASCUS). All had large cervical tumors (two with parametrial involvement and one with vaginal involvement) that showed extensive keratin formation, an inverted pattern of growth, and, except for one case, minimal cytologic atypia. There was extensive hyperkeratosis and parakeratosis adjacent to each tumor; none had evidence of squamous intraepithelial lesion. Human papillomavirus testing by polymerase chain reaction in situ hybridization and reverse-transcribed polymerase chain reaction in situ was negative in each case, compared with a detection rate of 107 of 108 (99%) for squamous intraepithelial lesion-associated cervical squamous cell and adenocarcinomas. Two of the women died of extensive local recurrence; two other women were recently diagnosed. We conclude that highly differentiated keratinizing squamous cell carcinoma of the cervix is a rare entity not associated with human papillomavirus infection or squamous intraepithelial lesion and thus difficult to detect on routine cervical cancer screening.
In situ determination of B-cell heavy chain and kappa/lambda light chain expression patterns: methodology and clinical utility.
The authors describe a reverse transcriptase in situ polymerase chain reaction (RT in situ PCR) method that allows the determination of B-cell clonality as defined by expression of kappa and lambda mRNA as well as the different VH families that comprise the entire heavy chain (IgH) sequence using paraffin-embedded, formalin-fixed tissue. Polyclonal expression of B-cell light and heavy chains was documented in two reactive lymph nodes and a spleen in the same histologic distribution as the B-cell marker CD20. Monoclonal expression of kappa versus lambda mRNA was documented in 11 cases of B-cell lymphoma and was corroborated in 5 cases by flow cytometry; each case showed monoclonal expression of IgH. The authors analyzed seven additional tissues where a definitive diagnosis of B-cell lymphoma could not be rendered based on histologic, immunohistologic. and clinical analysis. RT in situ PCR for IgH and kappa versus lambda expression differentiated the B-cell lymphomas (n = 2) from reactive B-cell processes (n = 3) and from two cases of B-cell-rich T-cell lymphoma. The described RT in situ PCR methodology allows routine determination of the monoclonal versus multiclonal expression patterns of B cells, which will facilitate the diagnosis of B-cell lymphomas and aid in understanding the pathogenesis of B-cell malignancies using archival, paraffin-embedded tissues.
Nurse led shared care for patients on the waiting list for coronary artery bypass surgery: a randomised controlled trial.
OBJECTIVE: To evaluate the effectiveness of a nurse led shared care programme to improve coronary heart disease risk factor levels and general health status and to reduce anxiety and depression in patients awaiting coronary artery bypass grafting (CABG). DESIGN: Randomised controlled trial. SETTING: Community, January 1997 to March 1998. STUDY GROUPS: 98 (75 male) consecutive patients were recruited to the study within one month of joining the waiting list for elective CABG at Glasgow Royal Infirmary University NHS Trust. Patients were randomly assigned to usual care (control; n = 49) or a nurse led intervention programme (n = 49). INTERVENTION: A shared care programme consisting of health education and motivational interviews, according to individual need, was carried out monthly. Care was provided in the patients' own homes by the community based cardiac liaison nurse alternating with the general practice nurse at the practice clinic. OUTCOME MEASURES: Smoking status, obesity, physical activity, anxiety and depression, general health status, and proportion of patients exceeding target values for blood pressure, plasma cholesterol, and alcohol intake. RESULTS: Compared with patients who received usual care, those participating in the nurse led programme were more likely to stop smoking (25% v 2%, p = 0.001) and to reduce obesity (body mass index > 30 kg/m(2)) (16.3% v 8.1%, p = 0.01). Target systolic blood pressure improved by 19.8% compared with a 10.7% decrease in the control group (p = 0.001) and target diastolic blood pressure improved by 21.5% compared with 10.2% in the control group (p = 0.000). However, there was no significant difference between groups in the proportion of patients with cholesterol concentrations exceeding target values. There was a significant improvement in general health status scores across all eight domains of the 36 item short form health survey with changes in difference in mean scores between the groups ranging from 8.1 (p = 0.005) to 36.1 (p < 0.000). Levels of anxiety and depression improved (p < 0.000) and there was improvement in time spent being physically active (p < 0.000). CONCLUSIONS: This nurse led shared care intervention was shown to be effective for improving care for patients on the waiting list for CABG.
Characterization of polymorphic structure of cathepsin G gene: role in cardiovascular and cerebrovascular diseases.
Cathepsin G (CTSG), a serine protease released from activated neutrophils, may cause platelet activation, leading to intravascular thrombosis, thus contributing to cardiovascular and cerebrovascular disease. Applying the candidate gene approach, we screened the 5'-flanking region and the entire coding region of the CTSG gene for genetic variation by using polymerase chain reaction/single-strand conformation polymorphism analysis from 96 patients at high risk for myocardial infarction (MI). We identified 4 polymorphisms in the 5'-flanking region (G-618C, G-315A, C-179T, and C-160T) and 1 polymorphism in the coding region (Asn125Ser) of the gene and genotyped the participants in the Etude Cas-Temoins sur l'Infarctus du Myocarde (ECTIM Study), a case-control study for MI, and in the Etude du Profil Génétique de l'Infarctus Cérébral (GENIC Study), a case-control study for brain infarction (BI), for all identified genetic variants. The potential in vitro functionality of the 4 variants in the 5'-flanking region was investigated with transient transfection analyses in U937 cells with different allelic promoter constructs by using a luciferase assay. Our in vitro analyses did not reveal any differences for the investigated allelic constructs with respect to promoter activity, and none of the polymorphisms in the 5'-flanking region was associated with the available phenotypes in either study. Allele and genotype distributions of all identified polymorphisms did not globally differ between cases and controls in the ECTIM Study. However, in patients from the ECTIM Study, the Ser125 allele was significantly associated with elevated plasma fibrinogen levels (P=0.006), but this effect was not seen in controls (case-control heterogeneity, P=0.04). There was a significant interaction between CTSG Asn125Ser and the beta-fibrinogen gene polymorphism G-455A on plasma fibrinogen levels (P=0.04). In the GENIC Study, the odds ratio for BI associated with CTSG Ser125 carrying was 1.82 (95% CI 1.16 to 2.84, P=0.008) in patients without a history of cardiovascular or cerebrovascular diseases. Our results indicate that the CTSG Ser125 allele is associated with plasma fibrinogen levels in MI patients from the ECTIM Study and with BI in the GENIC Study. Further studies should be carried out to define the underlying mechanisms.
In situ determination of T-cell receptor beta expression patterns.
A definitive diagnosis of T-cell lymphoma may be contingent on the rearrangement profile of the T-cell receptor. This is most accurately done by molecular analysis of the beta-chain of the T-cell receptor (TCR beta) by Southern blotting hybridization that requires unfixed tissue. We describe a reverse transcriptase in situ PCR (RT in situ PCR) method that permits the target-specific direct incorporation of the reporter nucleotide into the different transcripts that comprise the TCR beta, using paraffin-embedded, formalin-fixed tissue. Each of the 25 possible V beta segment rearrangements was documented in three lymph nodes with nonspecific lymphadenitis, with clonal expansion evident in a case of metastatic melanoma. Monoclonal expression was documented in seven tissues diagnostic of a T-cell lymphoma. We analyzed five additional tissues for which a definitive diagnosis of T-cell vs B-cell lymphoma could not be rendered on the basis of histological, immunohistological, and flow cytometric analysis. RT in situ PCR for TCR beta expression with CD3 co-labeling demonstrated which of these lesions was a B-cell-rich T-cell lymphoma. We conclude that the RT in situ PCR methodology will allow the routine determination of monoclonal vs multiclonal expression patterns of the TCR beta using archival paraffin-embedded tissues.(J Histochem Cytochem 49:139-145, 2001)
Women report being more likely than men to model their relationships after what they have seen on TV.
Students (21 men and 50 women) anonymously answered questions about imitating relationships seen on TV. The women were more likely than men to report trying to model family life after what they saw on TV situational comedies and to expect their significant other to act as those seen on TV. They also more frequently reported experiencing a significant other acting as those on TV. There was no difference by sex in current age, parents' marital status during the students' formative years, or age of separation, divorce, or widowing if any occurred. For neither women nor men did a broken home during the formative years correlate with looking to TV for information on relationships.
Platelet-activating factor antagonism and streptokinase-induced hypotension in clinical acute myocardial infarction.
Continuing efforts are being made to improve thrombolytic therapy for acute myocardial infarction (AMI). The rate of streptokinase (SK) infusion is commonly limited by the hypotension that is induced. If this could be avoided, an accelerated regimen of SK could be given, analagous to that used for other thrombolytic agents such as alteplase. The mechanism of the SK-induced hypotension is unknown, but there is some evidence that platelet-activating factor (PAF) plays a role. The potent PAF receptor antagonist lexipafant (10 mg) (n=35), or matching placebo (n=36), was administered intravenously over 5 min, in a randomized double-blinded protocol, to consecutive patients about to receive SK for AMI; all but three had inferior MI, because of the preference for strategies other than SK therapy in patients with anterior MI. The rate of infusion of SK was set to give 1.5x10(6) units over 30 min, anticipating significant hypotension. Blood pressure fell sharply over the first 10 min of SK administration. The maximum fall in systolic blood pressure occurred between 8 and 12 min, and averaged 43+/-28 mmHg (mean+/-S.D.) and 40+/-26 mmHg in patients given placebo and lexipafant respectively. Systolic pressure having fallen to <90 mmHg, according to protocol the SK administration rate was reduced in 21 of 36 (58%) of patients given placebo and in 19 of 35 (54%) of patients given lexipafant. The total SK dose was given to all subjects over 40.3+/-17.5 and 40.2+/-13.4 min for the placebo and lexipafant groups respectively. Peak and time integrals of creatine kinase were not different in the two groups. There were no adverse effects attributable to lexipafant. It is concluded that the PAF receptor antagonist lexipafant has no significant effect on SK-induced hypotension and does not facilitate an accelerated regimen of administration.
Redesigning processes in ambulatory chemotherapy: creating a patient appointment scheduling system: Part 1..
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Redesigning processes in ambulatory chemotherapy: creating a patient appointment scheduling system: Part II.
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Domain interactions in the gelatinase A.TIMP-2.MT1-MMP activation complex. The ectodomain of the 44-kDa form of membrane type-1 matrix metalloproteinase does not modulate gelatinase A activation.
On the cell surface, the 59-kDa membrane type 1-matrix metalloproteinase (MT1-MMP) activates the 72-kDa progelatinase A (MMP-2) after binding the tissue inhibitor of metalloproteinases (TIMP)-2. A 44-kDa remnant of MT1-MMP, with an N terminus at Gly(285), is also present on the cell after autolytic shedding of the catalytic domain from the hemopexin carboxyl (C) domain, but its role in gelatinase A activation is unknown. We investigated intermolecular interactions in the gelatinase A activation complex using recombinant proteins, domains, and peptides, yeast two-hybrid analysis, solid- and solution-phase assays, cell culture, and immunocytochemistry. A strong interaction between the TIMP-2 C domain (Glu(153)-Pro(221)) and the gelatinase A hemopexin C domain (Gly(446)-Cys(660)) was demonstrated by the yeast two-hybrid system. Epitope masking studies showed that the anionic TIMP-2 C tail lost immunoreactivity after binding, indicating that the tail was buried in the complex. Using recombinant MT1-MMP hemopexin C domain (Gly(285)-Cys(508)), no direct role for the 44-kDa form of MT1-MMP in cell surface activation of progelatinase A was found. Exogenous hemopexin C domain of gelatinase A, but not that of MT1-MMP, blocked the cleavage of the 68-kDa gelatinase A activation intermediate to the fully active 66-kDa enzyme by concanavalin A-stimulated cells. The MT1-MMP hemopexin C domain did not form homodimers nor did it bind the gelatinase A hemopexin C domain, the C tail of TIMP-2, or full-length TIMP-2. Hence, the ectodomain of the remnant 44-kDa form of MT1-MMP appears to play little if any role in the activation of gelatinase A favoring the hypothesis that it accumulates on the cell surface as an inactive, stable degradation product.
Helping patients to maintain a healthy fluid balance.
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Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies.
To evaluate the response rate and potential toxicities, a phase II trial was conducted of fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated low-grade and select intermediate-grade lymphoid malignancies. Symptomatic patients with preserved end organ function received cyclophosphamide 600 mg/m(2) intravenous (iv) day 1 and fludarabine 20 mg/m(2) iv days1 through 5, followed by filgrastim 5 microg/kg subcutaneous starting approximately day 8. Treatment was repeated every 28 days until maximum response or a maximum of 6 cycles. Sixty patients, median age 53.5 years, were enrolled. Thirty-seven patients with non-Hodgkin lymphoma (NHL) were stage IV and 6 were stage III. Eleven of 17 patients with chronic lymphocytic leukemia (CLL) were Rai intermediate risk and 6 were high risk. The overall complete response (CR) rate was 51% and the partial response (PR) rate was 41%. Of patients with CLL, 47% achieved a CR and the remaining 53% achieved a PR. Of patients with follicular lymphoma, 60% achieved CR and 32% achieved a PR. Although the toxicity of this regimen was mainly hematologic, significant nonhematologic toxicities, including infections, were seen. Twenty-four patients subsequently received an autologous or allogeneic stem cell transplant. Engraftment was rapid, and there were no noticeable procedure toxicities in the immediate posttransplant period attributable to the fludarabine and cyclophosphamide regimen. Fludarabine, cyclophosphamide, and filgrastim make up a highly active and well-tolerated regimen in CLL and NHL.
The controlling role of ATM in homologous recombinational repair of DNA damage.
The human genetic disorder ataxia telangiectasia (A-T), caused by mutation in the ATM gene, is characterized by chromosomal instability, radiosensitivity and defective cell cycle checkpoint activation. DNA double-strand breaks (dsbs) persist in A-T cells after irradiation, but the underlying defect is unclear. To investigate ATM's interactions with dsb repair pathways, we disrupted ATM along with other genes involved in the principal, complementary dsb repair pathways of homologous recombination (HR) or non-homologous end-joining (NHEJ) in chicken DT40 cells. ATM(-/-) cells show altered kinetics of radiation-induced Rad51 and Rad54 focus formation. Ku70-deficient (NHEJ(-)) ATM(-/-) chicken DT40 cells show radiosensitivity and high radiation-induced chromosomal aberration frequencies, while Rad54-defective (HR(-)) ATM(-/-) cells show only slightly elevated aberration levels after irradiation, placing ATM and HR on the same pathway. These results reveal that ATM defects impair HR-mediated dsb repair and may link cell cycle checkpoints to HR activation.
The connective tissue framework in the normal prostate, BPH and prostate cancer: analysis by scanning electron microscopy after cellular digestion.
The objective of this study was twofold: (1) to determine if a cellular digestion process can facilitate examination of the morphology of the connective tissue framework of the prostate, and (2) to examine the connective tissue framework in normal prostate tissue, benign prostatic hyperplasia (BPH) and prostate cancer. Ten prostate glands were examined. Using the Ohtani method of digestion, the cellular elements were removed. This enabled scanning electron microscopy analysis of the connective tissue framework within the prostatic tissue. Light microscopy of tissue blocks determined the histology of specimens. The prostate is supported by a highly structured network of collagen fibres. This network of fibres varies in normal and diseased states. In benign prostatic hyperplasia, the collagen network is dense, with an increased number of fibres. In prostatic adenocarcinoma, there is non-uniform swelling with a loss and disintegration of collagen fibres. In conclusion, sodium hydroxide cellular digestion provides an excellent method for demonstrating the connective tissue framework of prostatic tissue. The morphological changes in collagen fibres in normal prostate, benign prostatic hyperplasia and prostatic adenocarcinoma have implications for prostate growth in normal and diseased states.
An investigation into factors associated with Helicobacter pylori infection.
This study aims to estimate the prevalence of Helicobacter pylori in Glasgow, and to provide a systematic analysis of factors associated with this prevalence. The data used are from a random population sample of 793 men and 838 women aged 25-64 years conducted in 1995. The prevalence is estimated to be 66% (95% confidence interval: 63-68%); a level that is more typical of developing countries. Prevalence increases with age and social deprivation (P<0.0001) and is slightly higher in men than women (P = 0.07). After adjustment for age, social class, and sex group, H. pylori prevalence increases with increased cotinine (tobacco consumption) (P = 0.0005), increased number of siblings (P<0.0001), and decreased height (P = 0.03). Prevalence of coronary heart disease, hypertension, diabetes and intermittent claudication, alcohol consumption, fibrinogen, total serum cholesterol, HDL cholesterol, triglycerides, marital status, systolic and diastolic blood pressure had no independent association. The infection seems to be spread more readily in deprived, relatively crowded living conditions in childhood. The independent relationship with smoking suggests a possible second source of spread of infection in later years. The high degree of social deprivation in Glasgow is suggested as a major explanation of the high H. pylori prevalence found there.
Genetic analysis of homologous DNA recombination in vertebrate somatic cells.
The maintenance of genomic stability and the ability to repair induced DNA damage in vertebrate cells require homologues of the yeast RAD52 epistasis group genes. The homologous recombination carried out by the products of these genes is essential and appears to be closely linked to DNA replication. Defects in recombination and associated activities are implicated in human cancer. This review summarises recent biochemical and genetic findings on the roles played by the vertebrate RAD52 group gene products in recombination. We describe the phenotypic analysis of genetically engineered mammalian and chicken mutants of homologous recombination genes.
Angiotensin II type-I receptor and ACE polymorphisms and risk of myocardial infarction in men and women.
BACKGROUND: Findings relating an association between an insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene and myocardial infarction (MI) have been mixed. While other loci, such as the angiotensin II type-I receptor (AT1R), may modulate risk, few studies have adequately documented the risk in women. We aimed to study whether the findings in respect of ACE and AT1R in UK men were borne out in women. METHODS: Cases of MI (305 women, 391 men) in Belfast and Glasgow have been compared to controls (291 women, 356 men). These new samples augment the original men (200 cases, 181 controls) included from Belfast in the ECTIM study. RESULTS: Among men, the odds ratio for MI for ACE (DD vs. ID + II) was 1.03 (0.79, 1.34) and among women, 0.69 (0.47, 1.01). This heterogeneity between the risks in men and women was significant in Glasgow (P = 0.02). Among men and women the odds ratio for MI for AT1R (CC vs. AC + AA) was 1.02 (0.71, 1.47). There was a small gradient in risk, such that the odds ratio for DD genotype was 0.86 (0.63, 1.17) among subjects homozygous for the common AT1R allele (AA): 0.94 (0.67, 1.30) among heterozygotes and 1.21 (0.53, 2.77) among CC subjects; but this interaction was not statistically significant. CONCLUSIONS: Some of the contradictory findings concerning the ACE polymorphism and the risk of MI may be due to heterogeneity in the risk between men and women. The AT1R1196 polymorphism is not an independent risk factor for MI in either sex.