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Biomedical subjects

C Morrison

Publications and source records attributed to C Morrison.

At least 19 recordsLinked to original sources
PubMed1999

Mre11 is essential for the maintenance of chromosomal DNA in vertebrate cells.

Yeast Mre11 functions with Rad50 and Xrs2 in a complex that has pivotal roles in homologous recombination (HR) and non-homologous end-joining (NHEJ) DNA double-strand break (DSB) repair pathways. Vertebrate Mre11 is essential. Conditionally, MRE11 null chicken DT40 cells accumulate chromosome breaks and die upon Mre11 repression, showing frequent centrosome amplification. Mre11 deficiency also causes increased radiosensitivity and strongly reduced targeted integration frequencies. Mre11 is, therefore, crucial for HR and essential in mitosis through its role in chromosome maintenance by recombinational repair. Surprisingly perhaps, given the role of Mre11 in yeast NHEJ, disruption of NHEJ by deletion of KU70 greatly exacerbates the effects of MRE11 deficiency, revealing a significant Mre11-independent component of metazoan NHEJ.

Animals↗
PubMed1999

Disruption of ATM in p53-null cells causes multiple functional abnormalities in cellular response to ionizing radiation.

ATM is a member of the large phosphatidylinositol-3 kinase family and plays an important role in cellular response to DNA damage. To further define the physiological roles of ATM at the cellular level, we created an isogenic set of stable cell lines differing only in their ATM status from the chicken B cell line DT40 by targeted integration. These stable DT40 cell lines, as most of transformed chicken cell lines, do not express p53. However, ATM-/- DT40 cells displayed retarded cellular proliferation, defective G2/M checkpoint control and radio-resistant DNA synthesis. Furthermore, ATM-/- DT40 cells were sensitive to ionizing radiation and showed highly elevated frequencies of both spontaneous and radiation-induced chromosomal aberrations. In addition, a slight but significant reduction in targeted integration frequency was observed in ATM-/- DT40 cells. These results suggest that ATM has multiple p53-independent functions in cell cycle checkpoint control and in maintenance of chromosomal DNA. These ATM deficient DT40 clones therefore provide a useful model system for analysing p53-independent ATM functions.

Animals↗
PubMed1999

Increasing the impact of cardiological treatments. How best to reduce deaths.

AIMS: To determine the extent to which increases in the uptake of effective treatments could further reduce coronary heart disease mortality in Scotland. METHODS AND RESULTS: A cohort-based mortality model combining effectiveness data from published meta-analyses with available information on uptake of all coronary heart disease treatments in all patient categories in Scotland (population 5.1 million). In 1994, medical and surgical coronary disease treatments prevented or postponed an estimated 2722 deaths (minimum estimate 1373, maximum estimate 5986). Increasing treatment uptake to 100% of all eligible patients was considered unrealistic. Increasing uptake to 80% would have prevented or postponed a further 4078 deaths (39% from increases in secondary prevention therapies, 29%, 13%, 10% and 9% from the treatments of heart failure, acute myocardial infarction, hypertension and angina respectively). CONCLUSIONS: Many eligible patients are currently not receiving treatment that is effective in reducing coronary heart disease mortality. Increasing treatment uptake could prevent or postpone a further 4080 deaths each year in Scotland, approximately, more than doubling the present benefit from treatment. By implication, about 30 000 additional deaths could be prevented, annually, in the U.K. Comparable symptom and morbidity benefits might also be expected. Future clinical audit activities should focus particularly on secondary prevention and heart failure treatments.

Cohort Studies↗
PubMed1999

The essential functions of human Rad51 are independent of ATP hydrolysis.

Genetic recombination and the repair of double-strand DNA breaks in Saccharomyces cerevisiae require Rad51, a homologue of the Escherichia coli RecA protein. In vitro, Rad51 binds DNA to form an extended nucleoprotein filament and catalyzes the ATP-dependent exchange of DNA between molecules with homologous sequences. Vertebrate Rad51 is essential for cell proliferation. Using site-directed mutagenesis of highly conserved residues of human Rad51 (hRad51) and gene targeting of the RAD51 locus in chicken DT40 cells, we examined the importance of Rad51's highly conserved ATP-binding domain. Mutant hRad51 incapable of ATP hydrolysis (hRad51K-133R) binds DNA less efficiently than the wild type but catalyzes strand exchange between homologous DNAs. hRad51 does not need to hydrolyze ATP to allow vertebrate cell proliferation, form nuclear foci, or repair radiation-induced DNA damage. However, cells expressing hRad51K-133R show greatly reduced targeted integration frequencies. These findings show that ATP hydrolysis is involved in DNA binding by hRad51 and suggest that the extent of DNA complexed with hRad51 in nucleoprotein influences the efficiency of recombination.

Adenosine Triphosphate↗
PubMed1999

Sister chromatid exchanges are mediated by homologous recombination in vertebrate cells.

Sister chromatid exchange (SCE) frequency is a commonly used index of chromosomal stability in response to environmental or genetic mutagens. However, the mechanism generating cytologically detectable SCEs and, therefore, their prognostic value for chromosomal stability in mitotic cells remain unclear. We examined the role of the highly conserved homologous recombination (HR) pathway in SCE by measuring SCE levels in HR-defective vertebrate cells. Spontaneous and mitomycin C-induced SCE levels were significantly reduced for chicken DT40 B cells lacking the key HR genes RAD51 and RAD54 but not for nonhomologous DNA end-joining (NHEJ)-defective KU70(-/-) cells. As measured by targeted integration efficiency, reconstitution of HR activity by expression of a human RAD51 transgene restored SCE levels to normal, confirming that HR is the mechanism responsible for SCE. Our findings show that HR uses the nascent sister chromatid to repair potentially lethal DNA lesions accompanying replication, which might explain the lethality or tumorigenic potential associated with defects in HR or HR-associated proteins.

Animals↗
PubMed1999

Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2.

Significant correlation of body sodium and potassium with blood pressure (BP) may suggest a role for aldosterone in essential hypertension. In patients with this disease, the ratio of plasma renin to plasma aldosterone may be lower than in control subjects and plasma aldosterone levels may be more sensitive to angiotensin II (Ang II) infusion. Because essential hypertension is partly genetic, it is possible that altered control of aldosterone synthase gene expression or translation may be responsible. We compared the frequency of 2 linked polymorphisms, one in the steroidogenic factor-1 (SF-1) binding site and the other an intronic conversion (IC), in groups of hypertensive and normotensive subjects. In a larger population, the relationship of aldosterone excretion rate to these polymorphisms was also evaluated. In 138 hypertensive subjects, there was a highly significant excess of TT homozygosity (SF-1) over CC homozygosity compared with a group of individually matched normotensive control subjects. The T allele was significantly more frequent than the C allele in the hypertensive group compared with the control group. Similarly, there was a highly significant relative excess of the conversion allele over the "wild-type" allele and of conversion homozygosity over wild-type homozygosity in the hypertensive group compared with the control group. In 486 subjects sampled from the North Glasgow Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) population, SF-1 and IC genotypes were compared with tetrahydroaldosterone excretion rate. Subjects with the SF-1 genotypes TT or TC had significantly higher excretion rates than those with the CC genotype. The T allele was associated with higher excretion rates than the C allele. However, no significant differences were found in excretion rate between subjects of different IC genotype. Urinary aldosterone excretion rate may be a useful intermediate phenotype linking these genotypes to raised BP. However, no causal relationship has yet been established, and it is possible that the polymorphisms may be in linkage with other causative mutations.

Adult↗
PubMed1999

The Lys198Asn polymorphism in the endothelin-1 gene is associated with blood pressure in overweight people.

There is accumulating evidence that endothelin-1 plays an important role in vascular pathophysiology. Our objective was to examine whether molecular variations at the endothelin-1 locus were involved in susceptibility to myocardial infarction and variation in blood pressure. The entire coding sequence and 1.4 kb of the 5' flanking region were screened. Five polymorphisms were detected, which were genotyped in the ECTIM (Etude Cas-Témoin de l'Infarctus du Myocarde) Study, a multicenter study comparing 648 male patients who had survived a myocardial infarction and 760 population-based controls. The polymorphisms were not associated with myocardial infarction, nor did they contribute to blood pressure levels in the population at large. However, a G/T polymorphism predicting an Lys/Asn change (ET1/C198) strongly interacted (P<0.001) with body mass index in the determination of blood pressure levels. There was a steeper increase of blood pressure with body mass index in carriers of the T allele than in GG homozygotes. As a consequence, the T allele was associated with an increase of blood pressure in overweight subjects (body mass index >/=26 kg/m2), while no significant effect was observed in lean subjects (body mass index <26 kg/m2). To determine whether this finding could be replicated, the ET1/C198 was genotyped in the Glasgow Heart Scan Study, a population-based study including 619 men and 663 women. Subjects homozygous for the T allele had higher resting blood pressure levels than others (P<0.05). A similar interaction between the T allele and body mass index was observed on the maximum blood pressure achieved during a treadmill exercise test (P<0.001). In conclusion, results from 2 independent studies suggest that the ET1/C198 polymorphism is associated with blood pressure levels in overweight people.

Adult↗
PubMed1999

Cortisol effects on body mass, blood pressure, and cholesterol in the general population.

The effects of excess cortisol secretion on blood pressure and fat deposition are well documented, but the importance of this glucocorticoid in controlling these processes in normal individuals is less clear. We studied the relationship between cortisol excretion rate (tetrahydrocortisol [THF]+allo-THF+tetrahydrocortisone [THE]) and a range of important cardiovascular risk factors in 439 normal subjects (238 male) sampled from the North of Glasgow (Scotland) population. There were marked gender differences: female subjects were lighter and had lower blood pressures and cortisol levels, whereas HDL cholesterol was higher. The pattern of cortisol metabolism was also different; the index of 11beta-hydroxysteroid dehydrogenase activity (THF+allo-THF/THE) was lower and that of 5alpha-reductase (allo-THF/THF) was higher. There was a strong correlation of blood pressure (positive), cholesterol (positive), and HDL cholesterol (negative in women, positive in men) with age. Cortisol excretion rate did not correlate with blood pressure but correlated strongly with parameters of body habitus (body mass index and waist and hip measurements [positive]) and HDL cholesterol (negative). With multiple regression analysis, there remained a significant association of cortisol excretion rate with HDL cholesterol in men and women and with body mass index in men. These results suggest that glucocorticoids regulate key components of cardiovascular risk.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

Tubing failure during prolonged roller pump use: a laboratory study.

Little is known about the mechanical forces acting on extracorporeal circuit tubing with prolonged roller pump use during extracorporeal membrane oxygenation (ECMO). We examined the time to tubing rupture of three different materials during actual roller pump use, mean and standard deviation (SD) (SD shown in parentheses): Tygon (control) 243.7 h (175.4); LVA 121 h (14.3); and SRT 6.6 h (2.1). Failure times for both LVA and SRT were significantly different from the control (paired t-test, p = 0.02 and p < 0.001, respectively). The minimum failure times for Tygon and LVA were 99 and 101 h, respectively. We then examined Tygon under conditions of pure compression, demonstrating that even after 3.67 million compression cycles at full occlusion crack formation did not occur. If the tubing was over-occluded, cracks appeared within 24 h. Scanning electron microscopy of Tygon, which has been used during clinical ECMO, and the failure pattern during destruction testing demonstrate that shear stress and compression coexist during clinical ECMO. Use of under-occlusive pump settings could improve tubing life.

Equipment Failure Analysis↗
PubMed1998

Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells.

Eukaryotic cells repair DNA double-strand breaks (DSBs) by at least two pathways, homologous recombination (HR) and non-homologous end-joining (NHEJ). Rad54 participates in the first recombinational repair pathway while Ku proteins are involved in NHEJ. To investigate the distinctive as well as redundant roles of these two repair pathways, we analyzed the mutants RAD54(-/-), KU70(-/-) and RAD54(-/-)/KU70(-/-), generated from the chicken B-cell line DT40. We found that the NHEJ pathway plays a dominant role in repairing gamma-radiation-induced DSBs during G1-early S phase while recombinational repair is preferentially used in late S-G2 phase. RAD54(-/-)/KU70(-/-) cells were profoundly more sensitive to gamma-rays than either single mutant, indicating that the two repair pathways are complementary. Spontaneous chromosomal aberrations and cell death were observed in both RAD54(-/-) and RAD54(-/-)/KU70(-/-) cells, with RAD54(-/-)/KU70(-/-) cells exhibiting significantly higher levels of chromosomal aberrations than RAD54(-/-) cells. These observations provide the first genetic evidence that both repair pathways play a role in maintaining chromosomal DNA during the cell cycle.

Amino Acid Sequence↗
PubMed1998

Prediction of outcome in congenital diaphragmatic hernia.

The case records of 59 patients with congenital diaphragmatic hernia (CDH) who presented between 1984 and 1997 were studied retrospectively. Included in the study were infants born with CDH who required respiratory support within the first 6 h of life. Twenty-three were excluded from the study for various reasons; 36 were enrolled in the study; the male-to-female ratio was 18:18. Twenty-nine hernias were left-sided and 7 were right-sided. All patients were ventilated using conventional techniques. Arterial blood gases were measured on average 1.76 h following admission and the initial period of resuscitation (range 1-4 h). Three formulae were applied in an attempt to predict outcome: ventilation index against PCO2, alveolar-arterial oxygen gradient, and a newly derived formula from this institution (Red Cross formula) that comprises respiratory rate x PCO2 x FiO2 x mean airway pressure/PaO2 x 6000. Seventeen patients (47.2%) survived and 19 died (52.8%); 21 became stable enough to undergo surgery. The average time from presentation until surgery was 1.98 days (range 6 h to 4 days). The Red Cross formula, with a 100% predictive value for mortality, 85% predictive value for survival, and an overall predictive value of 91.6%, appeared to be superior to the other formulae studied. The availability of a highly accurate predictive formula may facilitate management of this frequently lethal disease.

Blood Gas Analysis↗
PubMed1998

The biomechanical properties of fascia lata grafts: a preliminary study.

The mechanical properties of fascia lata in the form of a sheet and as a tubulised structure have been determined. The stiffness of the sheet was 3.3 +/- 0.58 N/mm and the stiffness of the tube was 6.2 +/- 1.06 N/mm. The ultimate tensile strength of the tube was 35.7 +/- 14.1 N.

Biomechanical Phenomena↗
PubMed1998

Salicylate toxicity masquerading as malignant hyperthermia.

We report a case of hyperpyrexia presumed due to topical salicylate toxicity occurring immediately following general anaesthesia for appendicectomy in an eleven year old boy. Some of the features strongly suggested the diagnosis of malignant hyperpyrexia.

Administration, Topical↗
PubMed1998

Should we screen for asymptomatic left ventricular dysfunction to prevent heart failure?

A programme to detect and treat asymptomatic left ventricular dysfunction would seem to fulfil all five principles of screening. Indeed, such a programme would appear to be at least as firmly based as those already in existence for, for example, cervical and breast cancer. Further evaluation of the screening of high risk groups to detect asymptomatic left ventricular systolic dysfunction with the aim of giving treatment to prevent the development of heart failure is merited.

Clinical Trials as Topic↗
PubMed1998

Homologous recombination, but not DNA repair, is reduced in vertebrate cells deficient in RAD52.

Rad52 plays a pivotal role in double-strand break (DSB) repair and genetic recombination in Saccharomyces cerevisiae, where mutation of this gene leads to extreme X-ray sensitivity and defective recombination. Yeast Rad51 and Rad52 interact, as do their human homologues, which stimulates Rad51-mediated DNA strand exchange in vitro, suggesting that Rad51 and Rad52 act cooperatively. To define the role of Rad52 in vertebrates, we generated RAD52(-/-) mutants of the chicken B-cell line DT40. Surprisingly, RAD52(-/-) cells were not hypersensitive to DNA damages induced by gamma-irradiation, methyl methanesulfonate, or cis-platinum(II)diammine dichloride (cisplatin). Intrachromosomal recombination, measured by immunoglobulin gene conversion, and radiation-induced Rad51 nuclear focus formation, which is a putative intermediate step during recombinational repair, occurred as frequently in RAD52(-/-) cells as in wild-type cells. Targeted integration frequencies, however, were consistently reduced in RAD52(-/-) cells, showing a clear role for Rad52 in genetic recombination. These findings reveal striking differences between S. cerevisiae and vertebrates in the functions of RAD51 and RAD52.

Animals↗
PubMed1998

The obesity gene in swine: sequence and expression of porcine leptin.

Leptin is a 16-kDa protein secreted by adipocytes that has been proposed to regulate feed intake in mice, rats, and humans. The present study was designed to characterize porcine leptin structure and expression. Successful RT-PCR resulted in development of a cDNA clone to the full length coding region of porcine leptin. Sequence data demonstrate 85% base homology to rodent, 88% to human, and a 92% homology to the bovine sequence. For assessment of porcine leptin gene expression, total RNA was extracted from the subcutaneous adipose tissue of genetically selected high backfat pigs and from contemporary crossbred swine. Total RNA derived from genetically selected high fat pigs contained 113% higher (P < .05) concentrations of porcine leptin mRNA than total RNA derived from contemporary crossbred pigs. Western blotting was used to evaluate serum levels of porcine leptin in genetically selected high backfat and contemporary, crossbred pigs. Relative levels of porcine leptin in sera from obese swine were approximately 306% higher (P < .05) than levels present in sera from contemporary, crossbred swine. These data indicate that leptin is expressed in pigs, the expressed protein is secreted into the bloodstream, and obese swine express higher levels of leptin mRNA and protein than nonobese swine at similar body weight.

Adipose Tissue↗
PubMed1998

Fibromyalgia and its primary care implications.

Fibromyalgia is a complex condition affecting up to six million patients. In this literature review, the prevalence, proposed etiology, differential diagnosis, and signs and symptoms of the disorder are presented. Diagnostic criteria, treatment options, and the importance of patient education are explored.

Diagnosis, Differential↗