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Biomedical subjects

T O'Malley

Publications and source records attributed to T O'Malley.

11 recordsLinked to original sources
PubMed2001

Enzyme replacement therapy in feline mucopolysaccharidosis I.

Enzyme replacement therapy (ERT) has long been considered an approach to treating lysosomal storage disorders caused by deficiency of lysosomal enzymes. ERT is currently used to treat Gaucher disease and is being developed for several lysosomal storage disorders now that recombinant sources of the enzymes have become available. We have continued development of ERT for mucopolysaccharidosis I (MPS I) using the feline model. Recombinant alpha-L-iduronidase was administered intravenously at low dose (approximately 0.1 mg/kg or 25,000 units/kg) to four cats and high dose (0.5 mg/kg or 125,000 units/kg) to two cats on a weekly basis for 3- or 6-month terms. Clinical examinations showed distinct clearing of corneal clouding in one cat although clinical effects in the others were not evident. Biochemical studies of the cats showed that the enzyme was distributed to a variety of tissues although the liver and spleen contained the highest enzyme activities. Glycosaminoglycan storage was decreased in liver and spleen, and the histologic appearance improved in liver, spleen, and renal cortex. Enzyme was not consistently detected in cerebral cortex, brainstem, or cerebellum and the histologic appearance and ganglioside profiles did not improve. A variety of other tissues showed low variable uptake of enzyme and no distinct improvement. IgG antibodies to alpha-L-iduronidase were observed in five cats with higher titers noted when higher doses were administered. Mild complement activation occurred in three cats. Enzyme replacement therapy was effective in reversing storage in some tissues at the biochemical and histologic level in MPS I cats but an improved tissue distribution and prevention of a significant immune response could make the therapy more effective.

Animals↗
PubMed2001

Early increase in levels of soluble inter-cellular adhesion molecule-1 (sICAM-1); potential risk factor for the acute coronary syndromes.

BACKGROUND: Studies have shown disparate results in relation to the role of plasma concentrations of cell adhesion molecules in atherosclerosis. Moreover, the differentiation of primary vs secondary alterations of these markers, in response to myocardial injury, has not been clear. We measured specific soluble cell adhesion molecules and inflammatory markers in men admitted acutely with chest pain and compared them to healthy controls. METHODS AND RESULTS: We prospectively studied men (total n=241), admitted acutely with chest pain (7.4+/-9.4 h, 71% within 10 h), unstable angina (n=67), acute myocardial infarction (n=47) and chest pain without ischaemic heart disease (n=45) and compared them with a stratified sample of randomly selected healthy controls (n=82). Soluble intercellular adhesion molecule (sICAM-1), endothelial selectin, vascular cell adhesion molecule, interleukin-6 and C-reactive protein were measured by ELISA and P-selectin expression by flow cytometry. Multiple regression analysis was used to control for the impact of classical risk factors. At baseline ICAM-1, interleukin-6 and C-reactive protein were significantly elevated in patient groups whereas no difference in vascular cell adhesion molecule or endothelial selectin was found. At 3 month follow-up, ICAM-1 level was unchanged in ischaemic heart disease patients. In all groups C-reactive protein and interleukin-6 levels were lower at review. ICAM-1 levels at follow-up were higher in ischaemic heart disease groups (but not in chest pain without ischaemic heart disease) relative to controls and remained so only in the unstable angina group following regression. sICAM-1, interleukin-6 and C-reactive protein strongly correlated with smoking. In the acute phase, ICAM-1 was confounded by smoking following regression and C-reactive protein and interleukin-6 remained significant in both ischaemic heart disease groups after multiple regression. There was no relationship to events which occurred in 23% of ischaemic heart disease patients (further acute myocardial infarction 5.3%, sudden cardiac death 0.9% or recurrent angina 16.7%). CONCLUSION: We found an inflammatory response with higher sICAM-1, interleukin-6 and C-reactive protein in patients presenting soon after developing an acute coronary syndrome. As sICAM-1 was not affected by the acute event this plasma marker may be an important risk factor for the development of the acute coronary syndrome, particularly unstable angina.

Biomarkers↗
PubMed2000

Effects of bone marrow transplantation on the cardiovascular abnormalities in canine mucopolysaccharidosis VII.

The genetic mucopolysaccharidoses (MPS) are a family of lysosomal storage diseases resulting from defective catabolism of glycosaminoglycans (GAGs). Echocardiographic abnormalities in dogs with MPS type VII (Sly syndrome, beta-glucuronidase deficiency) included mitral valve thickening and insufficiency, large aortic dimensions in both the long and short axes, and thickened aortic valves. Grossly, at post mortem examination, there was nodular thickening of the mitral valve, a prominent ductus diverticulum, and a dilated aorta with thickened walls. Histologically, cytoplasmic vacuolation was seen in cells of the mitral valves, coronary arteries, and aorta. By electron microscopy, the cells of the mitral valve were packed with electron-lucent cytoplasmic vacuoles. The mean residual activity of beta-glucuronidase in the aorta and myocardium was <1% of normal, the mean hexosaminidase A activity >2. 5 times normal, and the mean GAG concentrations more than twice normal. In three MPS VII dogs that received heterologous BMT at 6 weeks of age, the echocardiographic abnormalities were improved, and the histopathologic and ultrastructural pathology was reduced. In the aorta and myocardium, the mean beta-glucuronidase activity of the BMT group was 4.5% and 11% of normal, respectively, and the hexosaminidase A activity and GAG concentrations were normalized. Bone Marrow Transplantation (2000) 25, 1289-1297.

Animals↗
PubMed1996

Measurement of platelet volume using a variety of different anticoagulant and antiplatelet mixtures.

Mean platelet volume (MPV), a measure of platelet size, has previously been noted to change in a time dependent manner in ethylene-diaminetetraacetic acid (EDTA) and citrate anticoagulants. We measured MPV in healthy volunteers using several different anticoagulants and at different temperatures. In ten volunteers MPV was measured (Sysmex NE 8000 autoanalyser) serially over a 29 h period in 15 different anticoagulant/antiplatelet combinations kept at room temperature and on ice-water mixture. We evaluated the following mixtures: K3EDTA, K3EDTA/prostaglandin E1 (PGE1), K3EDTA/PGE1/theophylline, Na2EDTA, Na2EDTA/PGE1, citrate 1:9, citrate 1:4, citrate 1:9/PGE1/theophylline, citrate 1:4/PGE1/theophylline, citrate 1:9/PGE1, citrate 1:9/dextrose, citrate 1:4/dextrose, acid-citrate-dextrose (ACD) 15%, ACD 11.9%, ACD 11.9%/Na2EDTA. In a second experiment we evaluated MPV, at room temperature only, in a further 20 volunteers in K3EDTA, citrate 1:9, ACD 11.9%/Na2EDTA, ACD 11.9% (total = 30) and citrate-phosphate-dextrose-adenine (CPDA; total = 20). Over the 29 h period there was a significant positive trend of increasing MPV in K3EDTA, CPDA and ACD 11.9%/Na2EDTA and a negative trend in citrate 1:9. ACD 11.9% showed no significant change in MPV with time at room temperature. This methodology should enable the wider application of MPV measurement for routine clinical and research studies.

Adult↗
PubMed1995

Platelet size in stroke patients.

BACKGROUND AND PURPOSE: Large platelets are more reactive, produce more prothrombotic factors, and aggregate more easily. Platelet size can be readily estimated using automated analyzers, although accurate estimation depends on precise methodology. The disparate results from previous studies of mean platelet volume in cerebral ischemia may be explained by varying methodology. We have studied these variables using a precise methodology in an unselected group of stroke patients and compared them with data from age- and sex-matched control subjects. METHODS: We studied 58 stroke patients consecutively admitted to a geriatric medical unit. Platelet variables were measured in the acute (< 48 hours after stroke) and chronic (> 6 months) phases of cerebral ischemia and compared with control variables. Control patients, admitted to the same unit, were of similar age and sex and without evidence of acute vascular events. RESULTS: Mean platelet volume was higher in acute stroke (11.3 compared with 10.1 fL in control subjects; P < .001, Student's t test). In addition, platelet count was reduced in stroke patients (255 x 10(9)/L) compared with control subjects (299 x 10(9)/L; P < .01). Repeated measurements of mean platelet volume and platelet count in available survivors showed no significant change from the acute phase. Platelet changes did not relate to outcome measured at 6 months. CONCLUSIONS: With the use of more precise methodology, these findings show that an increase in mean platelet volume and a reduction in platelet count are features of both the acute and nonacute phases of cerebral ischemia. It is possible that these changes precede the vascular event, and further studies are warranted.

Aged↗
PubMed1975

Residency training in primary care internal medicine. Report of an operational program.

The Primary Care Program at the Massachusetts General Hospital is designed to develop competence in the full range of problems encountered by general internists delivering primary care. House staff spend 3 years in the program, which starts with internship, includes a senior residency, and fulfills the requirements for board eligibility in internal medicine. Half of the training is provided in outpatient care settings. House staff assume responsibility for organization and operation of an ambulatory medical unit. In addition, there is supervised instruction in office gynecology, orthopedics, ear, nose and throat, dermatology, and psychiatry. Close integration with the traditional inpatient-oriented training program is maintained to ensure commensurate growth and competence in management of acute, life-threatening disease.

Boston↗
PubMed1975

The antiarrhythmic and hemodynamic actions of alpha, alpha-dimethyl-4-(alpha, alpha, beta, beta-tetrafluorophenethyl) benzylamine (MK-251).

Alpha,alpha-Dimethyl-4-(alpha,alpha,beta,beta-tetrafluorophenethyl)benzylamine (MK-251) has been found to prevent certain types of experimentally induced ventricular arrhythmias and at maximally effective doses possesses substantial hemodynamic safety in contrast to standard antiarrhythmic agents. MK-251 prevented or modified ventricular arrhythmias produced by injection of tetrafluorohexachlorobutane into the coronary artery of dogs and baboons. In dogs, the dose estimated to prevent 80% of the arrhythmic impulses (ED80) was 0.5 mg/kg i.v. and 5.0 mg/kg p.o. The duration of action after oral administration of 5.0 mg/kg to the dog or baboon exceeded 5 to 6 hours. MK-251 delayed the onset of arrhythmias resulting from coronary artery ligation, reduced their severity and permitted a conversion back to normal sinus rhythm earlier than in control dogs. In cats, the doses of digoxin required to induce ventricular ectopic activity, ventricular tachycardia and ventricular fibrillation were elevated by MK-251. In anesthetized dogs, 4 times the i.v. ED80 produced no change in blood pressure, cardiac contractility or output, or in ventricular conduction. The only effect after 8 times the ED80 was a slight decrease in contractility. In contrast. lidocaine at its ED80 (0.21 mg/kg/min), decreased blood pressure and contractility; there was no change in ventricular conduction. Quinidine at the ED80 (8.8 mg/kg i.v.) and above produced hypotension, decreased contractility and prolonged conduction in a dose-related manner.

Amines↗