Biomedical subjects
Publications and source records attributed to E Andrews.
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Methylmalonic acidemia resulting from genetic deficiency of methylmalonyl CoA mutase (MCM) is an often fatal metabolic disease. Somatic gene therapy for this disorder may require gene replacement in the liver. We describe overexpression of MCM in the liver of mice after in vivo gene delivery using asialoglycoprotein/polylysine/DNA (ASO/PL/DNA) targeted delivery to the liver of plasmids expressing recombinant MCM. After intravenous administration of the ASO/PL/DNA complex, the vector sequences are cleared from the blood with t1/2 = 2.5 min and > 95% of the vector is taken up by the liver. Vector sequences are cleared from the liver with t1/2 = 1.0-1.3 hr. MCM enzyme activity in the liver increases to levels 30-40% over baseline 6-24 hr after injection. No acute or chronic toxicity was observed. This net level of expression is likely to be therapeutic for MCM if the complex could be administered repetitively to treat acute episodes of life-threatening acidosis or establish a steady-state level of MCM activity. Repetitive administration of the ASO/PL/DNA complexes in mice was associated with formation of antibodies against asialo-orosomucoid and the asialo-orosomucoid complex but not against DNA.
Methylmalonyl-CoA mutase is an adenosylcobalamin-dependent enzyme which catalyzes isomerization of methylmalonyl-CoA to succinyl-CoA. Previous reports have described cloning and sequencing of a cDNA for human methylmalonyl-CoA mutase. This clone does not express an active apoenzyme after gene transfer into primary MCM-deficient fibroblasts and contains several sequences which differ from the consensus sequence of other cDNA clones. We describe reconstruction of a functional MCM cDNA and expression of recombinant enzyme activity in primary fibroblasts and Saccharomyces cerevisiae. This consensus human MCM cDNA is capable of complementing the inherited defect in mut MMA and overexpressing an enzyme in yeast with kinetic properties indistinguishable from the enzyme in murine or human tissues.
The objective of this effort was to assess the utility of the large automated database in Saskatchewan as a resource for pharmacoepidemiologic studies. To this end a study was undertaken to test the hypothesis that rheumatoid arthritis (RA) increases the risk of cancer, especially lymphoma. This was done by performing a retrospective cohort study based on record linkage data from Saskatchewan Health. From hospital discharge diagnoses in the hospital file an exposed group (RA) and two comparison groups matched to the RA group by age and sex were identified: (1) the RA group consisted of people with a discharge diagnosis of rheumatoid arthritis; (2) the osteoarthritis (OA) group consisted of people with OA discharge diagnoses; and (3) a comparison (CN) group consisted of hospitalized people with no discharge diagnoses of arthritis. Drug exposures were determined by linkage with the Prescription Drug File, cancer outcomes were determined by linkage with the Cancer Foundation file, and length of eligibility in the health plan and demographics information were determined by linkage with the registration file. The data were checked for quality of linkages across files and consistency with study definitions. Of 13,333 identified subjects, 2.8% were excluded because of apparent incorrect assignment to study group or age group or because of ineligibility in health plan during the study period. In order to decrease the possibility of misclassification of exposure (rheumatoid arthritis), hospital discharge diagnoses were used to exclude subjects with any inflammatory rheumatic diseases (IRD) from the CN (7.8%) and OA (8.3%) groups and subjects with IRD other than rheumatoid arthritis (4.6%) from the RA group. To decrease selection bias, those who had cancer within 1 year of enrollment (to exclude those in hospital because of symptoms of undiagnosed cancer) were excluded. Because RA subjects hospitalized by a rheumatologist were most likely to have valid rheumatoid arthritis diagnoses, each analysis was run twice: once with the entire RA group (N = 1210) and once with those in the RA group who were rheumatologist-hospitalized (N = 646). Logistic regression of incidence was used to control for age, sex, and use of individual disease-modifying anti-rheumatoid drugs (DMARDs). For the rheumatologist-hospitalized RA group compared to the CN group, a significant 4-fold greater risk for lymphoma/myeloma was detected when DMARD use was not controlled for, and a 3.4-fold increase in risk was detected even when use of individual DMARDs was controlled for.(ABSTRACT TRUNCATED AT 400 WORDS)
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Through a compassionate plea program (Treatment Investigational New Drug), 4805 patients with acquired immunodeficiency syndrome who previously had experienced Pneumocystis carinii pneumonia (PCP) received zidovudine (Retrovir, formerly azidothymidine). Overall survival at 44 weeks after initiation of therapy was 73% (+/- 2.1%). A positive association was found between survival and pretherapy clinical status as defined by hemoglobin level, functional ability, and stage of disease as measured by time since diagnosis of PCP. For patients with baseline hemoglobin levels of 120 g/L or greater, Karnofsky scores of 90 or greater, and PCP diagnosis within 90 days prior to initiation of therapy, 44-week survival was 88%. Adverse clinical experiences associated with zidovudine therapy were consistent with those from a double-blind, placebo-controlled trial. Survival experience of this large and diverse cohort is consistent with, and extends data from, this clinical trial. Comparison with available natural history data suggests that zidovudine therapy is associated with increased 44-week survival of post-PCP patients with acquired immunodeficiency syndrome.
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Pimozide has been successfully used in the treatment of delusions of infestation; however, it is not widely available in the United States. Similarities in both chemical structure and degree of potency suggest that haloperidol may be an alternative treatment for this syndrome. Three cases of delusions of infestation successfully treated with haloperidol are described. In all three the symptoms were relieved acutely; in two the improvement was maintained.
Despite extensive clinical use of thallium-201 (201TI) for myocardial imaging, the effect of ischemia on myocardial accumulation and release of 201TI independent of flow has not been fully defined. Therefore, myocardial accumulation of 201TI in response to ischemic-like myocardial injury was assessed in vitro using the cultured fetal mouse heart preparation. Cultured fetal mouse hearts (n = 311) were subjected to injury simulating ischemia by deprivation of oxygen and oxidizable substrates for periods ranging from 15 minutes to 10 hours. The extent of irreversible injury was determined by the percentage of lactic dehydrogenase (LDH) lost from the hearts to the culture medium during recovery from injury. Injury was essentially reversible at 1 hour of insult. The fraction of 201TI content in injured compared with control hearts was not significantly lower after 1 hour of insult. By 3 hours of insult, irreversible injury as assessed by loss of LDH was detectable and the extent of injury increased progressively through 10 hours. During the 3-10-hour period of irreversible injury, 201TI accumulation within injured hearts compared with controls was related in a monotonically decreasing fashion to the loss of LDH as described by a mathematical kinetic model that fit the observations closely (R2 greater than 0.99). These results indicate that in this organ culture preparation, in which there is effectively an unlimited reservoir of 201TI and no confounding effects of perfusion, the time-dependent 201TI accumulation is determined by the extent of irreversible injury.
We describe a patient who, in the absence of anterograde amnesia, experienced sudden onset of profound retrograde amnesia for the last forty years of his life. The amnesia encompassed all knowledge, including motor skills, acquired during these forty years. There has been no recovery in over eighteen months. His symptoms seem most consistent with a vascular etiology. Current understanding of memory disorders fails to explain these symptoms. It may be that his case represents a previously undescribed disorder.
Fetal mouse hearts in organ culture provide a model of ischemic-like injury in which the myocardial protective effect of pharmacological agents can be studied independent of blood flow. To investigate the potential protective effect of a diffusable purine under ischemic-like conditions, we used 4 mM inosine in fetal mouse heart organ cultures deprived of oxygen and oxidizable substrates for 1-10 hours. We studied hearts (n = 258) immediately after simulated ischemia (early) and after a 20-hour recovery period (late), by utilizing three indices of myocardial viability. Thallium-201 accumulation is an early marker of myocardial viability during injury, whereas the percentage of lactic dehydrogenase release from hearts to culture medium and the percentage of irreversibly injured myocytes assessed by planimetry of midventricular histological sections are late markers, used after recovery from injury. At 10 hours of injury, thallium-201 accumulation was 38% greater in inosine-supplied hearts, 3.50 +/- 0.16 vs. 2.54 +/- 0.08 (counts/min per mg wet weight)/(counts/min per microliter medium) (mean +/- SEM) (P less than 0.001). After recovery from 10 hours of injury, lactic dehydrogenase release was 29% less in inosine-supplied hearts, 35 +/- 3% vs. 49 +/- 3% (P less than 0.001). After recovery from 8 hours of injury, the percentage of histologically irreversibly injured tissue was 23% less in inosine-supplied hearts, 60 +/- 7% vs. 78 +/- 3% (P less than 0.05). These data indicate that inosine has a protective effect on fetal mouse myocardium during simulated ischemia and suggest that inosine deserves further evaluation.
The inadvertent intra-arterial injection of a dose of Tc-99m-MDP is reported. Limited quantitative studies were done on the distribution pattern. More extensive investigations of cases of this type may yield useful data on the behavior of radiopharmaceuticals.
Lactation occurs when the fully developed breast is released from the inhibitory influence which oestrogen and progesterone exert upon the action of prolactin. The use of oestrogens to suppress lactation depends on a continuation of the peripheral, that is, mammary, inhibition of prolactin. Androgens are also believed to act by inhibition of the action of prolactin on the mammary gland epithelium. Bromocriptine, when compared in a double-blind trial with orally administered methyl testosterone and placebo, gave almost complete relief of breast discomfort and congestion, though a small amount of milk production was seen. Methyl testosterone, in the dosage used in this study, was quite ineffective in suppressing lactation or breast symptoms.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.