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Biomedical subjects

A S Jaffe

Publications and source records attributed to A S Jaffe.

At least 91 records · Page 5Linked to original sources
PubMed1990

Insulin independence after islet transplantation into type I diabetic patient.

Effective clinical trials of islet transplantation have been limited by the inability to transplant enough viable human islets into patients with type I (insulin-dependent) diabetes mellitus to eliminate their exogenous insulin requirement. We report the first type I diabetic patient with an established kidney transplant on basal cyclosporin immunosuppression who was able to eliminate the insulin requirement after human islet transplantation into the portal vein. We successfully isolated approximately 800,000 islets that were 95% pure from 1.4 cadaver pancreases containing 121 U of insulin. Islets were proven viable by in vitro insulin response to glucose challenge. After 7 days of 24 degrees C culture, the islets were transplanted into the portal vein under local anesthesia. Seven days of Minnesota antilymphoblast globulin (20 mg/kg) administration followed the islet transplantation, with maintenance of the cyclosporin. Blood glucose was kept under strict control via intravenous insulin for 10 days posttransplantation, when all insulin therapy was stopped. Off insulin, the average 24-h blood glucose level remained less than 150 mg/dl, with the fasting glucose level at 115 +/- 6 mg/dl and the 2-h postprandial level at 141 +/- 8 mg/dl for 22 days posttransplantation (the time of this study). The C-peptide values post-Sustacal testing, although initially rising slower, exceeded the normal range, with peak values of 1.0-1.8 pmol/ml. This preliminary result represents the first essential step required to determine the feasibility of islet transplantation by future clinical trials.

Adult↗
PubMed1989

Enzymatic estimation of the extent of irreversible myocardial injury early after reperfusion.

To determine whether the extent of infarction can be estimated enzymatically soon after reperfusion, the rate of increase of creatine kinase (CK) activity in plasma early after coronary recanalization was compared with infarct size in 18 dogs and 10 patients. In dogs, reperfusion was initiated 2 to 4 hours after coronary occlusion. CK activity was measured in serial plasma samples and infarct size was assessed histochemically at 24 hours. A substantial and consistent fraction of the total CK appearing in plasma over 24 hours (cumulative CK) appeared in plasma soon after reperfusion, i.e., 21 +/- 2% (SE) within 30 minutes and 38 +/- 3% within 1 hour. The rate of increase of plasma CK activity correlated closely with infarct size when CK release was measured during the first 30 minutes (r = 0.92) or 60 minutes (r = 0.92) after reperfusion (n = 18). Similarly, in patients the rate of increase of CK activity measured within 2.5 hours of the time of reperfusion was closely related to infarct size delineated by positron emission tomography 1 to 2 weeks later (r = 0.93). Thus the rate of appearance of CK in plasma early after reperfusion reflects the extent of irreversible injury ultimately sustained and provides a criterion likely to be useful for prospective identification of patients at high risk after coronary recanalization.

Adult↗
PubMed1989

Normal left ventricular performance documented by Doppler echocardiography in patients with long-standing hypocalcemia.

INTRODUCTION: Several reports suggest significantly reduced left ventricular performance in subjects with chronic hypocalcemia. We prospectively investigated eight patients, aged 13 to 31 years, with long-standing hypocalcemia due to idiopathic hypoparathyroidism or pseudohypoparathyroidism by echocardiography. PATIENTS AND METHODS: Six subjects had symptomatic hypocalcemia manifested as recurrent tetany (four), seizures (four), mental retardation (three), behavior disorder (one), and skeletal abnormalities (four); three subjects were untreated when studied. None had cardiovascular symptoms. Each patient underwent clinical, biochemical, and cardiac studies, including Doppler, two-dimensional, and M-mode echocardiography, on the same day. RESULTS: In serum, both total and ionized calcium concentrations were reduced and averaged 7.2 mg/dl (range: 5.3 to 8.5 mg/dl; normal: 9.0 to 10.3 mg/dl) and 3.6 mg/dl (range: 3.0 to 3.9 mg/dl; normal: 4.5 to 5.3 mg/dl), respectively. Electrocardiograms revealed prolonged QTc intervals in six patients. Also noted were prominent U waves (five), T-wave abnormalities (four), and right-axis deviation (one). Resting echocardiography, however, demonstrated normal left ventricular function in all subjects. All M-mode measurements were normal. Two-dimensional-derived left ventricular end-diastolic and end-systolic volumes were 87.1 +/- 20.1 ml and 30.2 +/- 9.7 ml (mean +/- SD), respectively. Left ventricular ejection fraction was 65 percent (61.2 to 74.7 percent). Doppler-derived cardiac output and cardiac index averaged 5.1 liters/minute (2.9 to 6.7 liters/minute) and 3.0 liters/minute/m2 (1.7 to 4.3 liters/minute/m2), respectively. CONCLUSION: Our prospective study of eight subjects with functional hypoparathyroidism demonstrated that, despite electrocardiographic abnormalities, long-standing hypocalcemia was not associated with left ventricular dysfunction.

Adolescent↗
PubMed1989

Concordance of creatine kinase-MB activity and mass.

The recent availability of monoclonal antibodies that are highly specific for creatine kinase (CK; EC 2.7.3.2) MB isoenzyme should allow for the development of rapid, sensitive, and specific assays of CK-MB mass and activity. However, the relationship between the mass concentration of CK-MB and its activity in plasma has previously been thought by some to be variable. To determine the extent to which discrepancies of potential clinical significance might arise between measurements of activity and mass in plasma, we compared CK-MB activity and concentration in 1298 samples obtained from 226 patients admitted to the cardiac-care unit. CK-MB activity concentration was determined with an immunoadsorption assay, and mass concentration was measured by an automated "sandwich" assay (Magic Lite; Ciba Corning Diagnostics). Both of these assays are based on specific monoclonal antibodies for CK-MB. Values obtained with these assays correlated well (r = 0.94). Normal and abnormal values with the two assays were concordant in 96% of the samples. In all but three instances, differences occurred late after myocardial infarction and were characterized by minimal increases as determined by one method vs values at the upper limit of normal as determined with the other. Thus, measurements of CK-MB mass and activity concentrations in plasma with assays based on these specific monoclonal antibodies are comparable for the detection or exclusion of acute myocardial infarction.

Creatine Kinase↗
PubMed1988

Differential effects of activation of prothrombin by streptokinase compared with urokinase and tissue-type plasminogen activator (t-PA).

We have previously reported paradoxical prothrombotic effects manifest by elevations of fibrinopeptide A (FPA) after administration of streptokinase to patients with acute myocardial infarction. To characterize mechanisms responsible and their dependence on streptokinase (SK) as opposed to other activators of the fibrinolytic system, the present study was performed to compare effects of streptokinase, tissue-type plasminogen activator (t-PA), and urokinase on plasma and on purified prothrombin in concentrations similar to those achieved pharmacologically. The effects of plasmin were assessed to determine the extent to which the elevations of FPA seen could be attributed to activation of plasminogen. Elevations of FPA were observed after incubation of each of the activators with citrated plasma at 37 degrees C for 60 minutes. However, they were most marked with streptokinase (64.5 +/- 4.6 pmol FPA/ml (mean +/- SE) with 100 IU SK/ml, and 77.6 +/- 5.0 pmol/ml with 500 IU SK/ml). Elevations of FPA induced by streptokinase were attenuated by 100 IU/ml heparin [15.2 +/- 1.9 pmol/ml after 100 IU of SK (p less than 0.001 compared with results with streptokinase without heparin)]. Human plasmin, 2.5 CTA/ml, caused changes similar to those induced by streptokinase. The minimal elevations of FPA induced by t-PA or urokinase (less than 10 pmol/ml without heparin) were not significantly attenuated by heparin. Incubation of barium citrate adsorbed plasma (vitamin K factor depleted) with streptokinase markedly attenuated elevation of FPA. Addition of prothrombin (1.5 microM) and streptokinase (100 IU/ml) to the barium citrate adsorbed plasma elicited elevations of FPA similar to those induced by streptokinase in citrated plasma. Amidolytic activity with the "thrombin" substrate H-D-phenylalanyl-L-pipecolyl-L-arginine-p-nitroanilide dihydrochloride (S-2238) was evident when streptokinase, plasminogen (0.24 microM), and prothrombin (1.5 microM) were incubated in buffer. Thus, concentrations of streptokinase that are low in terms of therapeutic blood levels activate prothrombin in plasma, likely due to activation of plasminogen. Neither tissue-type plasminogen activator nor urokinase in pharmacologically comparable concentrations increase thrombin activity appreciably perhaps because of less intense activation of plasminogen. Consideration of the prothrombotic effects observed may be relevant to selection of specific agents for therapeutic thrombolysis, to appropriate titration of dose, and to the need for the use of heparin conjointly with particular activators of the fibrinolytic system such as streptokinase.

Fibrin Fibrinogen Degradation Products↗
PubMed1988

Significance of Doppler-detected mitral regurgitation in acute myocardial infarction.

To define the incidence of mitral regurgitation (MR) and elucidate its potential contribution to the development of severe congestive heart failure after acute myocardial infarction (AMI), Doppler echocardiograms were obtained within 48 hours of onset of AMI in 59 patients. The presence of MR was determined from the apical 4-chamber and parasternal long-axis views with pulsed Doppler. MR was detected in 23 of the 59 patients (39%) and was similarly frequent in patients with anterior (11 of 24 or 46%) and inferior AMI (12 of 34 or 35%). Patients with MR were older (71 +/- 3 vs 62 +/- 2 years, p less than 0.005), had a higher incidence of prior AMI (8 of 23 vs 4 of 36, p less than 0.05) and larger end-diastolic volume indexes by radionuclide ventriculography (112 +/- 9 vs 72 +/- 4, p less than 0.005). A systolic murmur was heard in only 10 of 23 patients with MR detected by Doppler. Mortality determined 8 to 14 months after the index AMI was 48% (11 of 23) in patients with MR but only 11% (4 of 30) in those without it (p less than 0.01). Thus, this study determined that clinically silent MR frequently complicates AMI and its presence is associated with and is a potential determinant of severe congestive heart failure and mortality.

Aged↗
PubMed1988

Prompt detection of myocardial injury by assay of creatine kinase isoforms in initial plasma samples.

To determine the sensitivity and specificity of assays of isoforms of the MM isoenzyme of creatine kinase (CK) and MB-CK for the diagnosis or exclusion of acute myocardial infarction in plasma samples obtained at the time of presentation to the emergency room of patients with suspected myocardial infarction, 50 patients in whom the diagnosis was ultimately established and 31 in whom infarction was ultimately excluded were evaluated. Of the 50 patients in whom infarction was ultimately established, 47 had an increased ratio of the MM3 to the MM1 isoform or elevated MB-CK in the plasma sample initially available. The specificity of the approach was 77%, sensitivity 94%. The availability of rapid assays for MM-CK isoforms and for MB-CK should facilitate determination of the presence or absence of acute myocardial injury sufficiently promptly so that decisions regarding treatment can be made optimally.

Adult↗
PubMed1988

Relationship of QRS scoring system to enzymatic and pathologic infarct size: the role of infarct location.

A method for estimating infarct size from 12-lead ECGs has been developed but not extensively validated. To assess its accuracy, ECG scores from 62 patients admitted to the coronary care unit at Barnes Hospital were compared to infarct size calculated from plasma MB creatine kinase (MB-CK) activity. A second cohort of 29 patients enrolled in the Multicenter Investigation of the Limitation of Infarct Size (MILIS) was evaluated as a test set and to provide pathologic correlates. Patients with conduction system disease, ventricular hypertrophy, or multiple infarctions were excluded, as were those in the Barnes group who had undergone thrombolytic therapy. ECGs obtained early (days 3 to 7 in the Barnes group and day 3 in the MILIS group) or late (days 8 to 14 in the Barnes group) were scored manually and by computer. QRS scores from early ECGs of patients with anterior infarctions correlated closely with MB-CK estimates of infarct size (r = 0.71 [Barnes] and 0.85 [MILIS] and with anatomic data (r = 0.78). Enzymatic and pathologic infarct size also correlated well (r = 0.85). Correcting for body surface area by means of total CK-derived infarct size or use of QRS scores from late ECGs did not alter the correlation coefficients. Among patients with inferior infarctions QRS scores corresponded poorly with MB-CK infarct size (r = 0.28 [Barnes] and r = -0.42 [MILIS]) and pathologic infarct size (r = -0.20), despite a significant relationship between pathologic and MB-CK estimates (r = 0.62).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Rate of disappearance of creatine kinase-MB after acute myocardial infarction: clinical determinants of variability.

The apparent rate of disappearance (Kd) of creatine kinase (CK)-MB is used in the calculation of the size of acute myocardial infarction (AMI), but little is known about the determinants of variability of this parameter. We therefore evaluated the relationship between clinical characteristics and apparent Kd in 328 patients with AMI without evidence of recurrent infarction. Patients with a history of cigarette smoking within 6 months had higher rates of disappearance of CK-MB, but no relationship was found between renal function and apparent Kd. Slower rates of disappearance of CK-MB were correlated with longer times from the onset of symptoms to peak CK-MB value (p less than 0.001), while higher peak CK-MB levels were not correlated with apparent rates of enzyme clearance. Decreased rates of disappearance of CK-MB were found in patients who had congestive heart failure during or after the hospitalization (both p less than 0.05), and who died during the hospitalization or during study follow-up (both p less than 0.05). Slower rates of disappearance were also significantly correlated with lower ejection fractions on radionuclide ventriculography at 10 days (p less than 0.001) and at 3 months (p less than 0.05) after AMI. These data suggest that patients with slower rates of disappearance of CK-MB may have poorer prognoses, perhaps reflecting continuing necrosis and enzyme release from jeopardized myocardium.

Creatine Kinase↗
PubMed1988

Prognostic significance of location and type of myocardial infarction: independent adverse outcome associated with anterior location.

To determine the relative prognostic significance of location (anterior or inferior) and type (Q wave or non-Q wave) of infarction, the hospital course and follow-up outcome (mean duration 30.8 months) of 471 patients with a first infarction were analyzed. Analyses were performed grouping the patients according to infarct location (anterior, n = 253; inferior, n = 218), infarct type (Q wave, n = 323; non-Q wave, n = 148), and both location and type (inferior non-Q wave, n = 85; inferior Q wave, n = 133; anterior non-Q wave, n = 63; and anterior Q wave, n = 190). Patients with anterior infarction had a substantially worse in-hospital and follow-up clinical course compared with those with inferior infarction, evidenced by a larger infarct size (21.2 versus 14.9 g Eq/m2 creatine kinase, MB fraction [MB CK], p less than 0.001), lower admission left ventricular ejection fraction (38.1 versus 55.3%, p less than 0.001) and higher incidence of heart failure (40.7 versus 14.7%, p less than 0.001), serious ventricular ectopic activity (70.2 versus 58.9%, p less than 0.05), in-hospital death (11.9 versus 2.8%, p less than 0.001) and total cumulative cardiac mortality (27 versus 11%, p less than 0.001). Patients with Q wave infarction similarly experienced a worse in-hospital course compared with patients with non-Q wave infarction, evidenced by a larger infarct size (20.7 versus 12.7 MB CK g Eq/m2, p less than 0.001), lower admission left ventricular ejection fraction (43.7 versus 50.6%, p less than 0.001), and a higher incidence of heart failure (31.9 versus 21.6%, p less than 0.05) and in-hospital death (9.3 versus 4.1% p less than 0.05). However, there was no increased rate of reinfarction or mortality in hospital survivors with non-Q wave infarction compared with those with Q wave infarction, and total cardiac mortality was similar (16 versus 21%, p = NS). To evaluate the role of infarct location and type independent of infarct size, patients were grouped according to quartile of infarct size, and outcome was reanalyzed within each group. Patients with anterior infarction demonstrated a lower left ventricular ejection fraction on admission and after 10 days than did patients with inferior infarction, even after adjustment for infarct size, as well as a higher incidence of congestive heart failure and cumulative cardiac mortality.(ABSTRACT TRUNCATED AT 400 WORDS)

Actuarial Analysis↗
PubMed1988

Effect of hyaluronidase on mortality and morbidity in patients with early peaking of plasma creatine kinase MB and non-transmural ischaemia. Multicentre investigation for the limitation of infarct size (MILIS).

A multicentred, randomised, blind study was started in 1978 to compare propranolol or hyaluronidase with placebo in patients with acute myocardial infarction admitted within 18 hours of onset of symptoms. Patients were randomised to group A and received hyaluronidase, propranolol, or placebo, or, if propranolol was contraindicated, to group B and received hyaluronidase or placebo. Hyaluronidase (500 U/kg given every six hours for 48 hours) had no effect on mortality or infarct size in the overall population. Because spontaneous reperfusion was more common in patients with early peaking of plasma creatine kinase MB or non-transmural electrocardiographic changes or both, the results were reanalysed for two subgroups: those in whom plasma creatine kinase peaked less than 15 hours after the onset of symptoms (early peak, n = 184) and those with a peak greater than 15 h after the onset of symptoms (late peak, n = 546). The distribution of time to peak activity of creatine kinase MB was similar in the hyaluronidase and placebo groups. In the early peak patients who were given hyaluronidase (groups A and B) total mortality and cardiac-specific four year mortality were significantly lower. This was most pronounced in group B in which the total mortality was 45% and cardiovascular mortality was 47% less than in the placebo group. Similarly, mortality from cardiovascular disease in patients (groups A and B) with nontransmural ischaemia (ST-T changes) given hyaluronidase was significantly lower, with group B showing a 50% reduction. In the subsets of patients with late peaking of creatine kinase MB or those presenting with transmural electrocardiographic changes there was no difference in total mortality or deaths from cardiac disease between those given hyaluronidase and those given placebo. Hyaluronidase was associated with improved survival in patients with early peaking of plasma creatine kinase MB, suggesting the possibility of salvage of myocardium in patients who have early spontaneous reperfusion and possibly after therapeutic reperfusion.

Clinical Trials as Topic↗
PubMed1988

Characterization in vivo of the fibrin specificity of activators of the fibrinolytic system.

Development of appropriate clinical dose regimens of individual plasminogen activators such as tissue-type plasminogen activator (t-PA) has generally relied primarily on nonpharmacological endpoints such as angiographically documented clot lysis. The recent availability of monoclonal antibodies that differentiate products of plasmin lysis of fibrin from those of lysis of fibrinogen should permit delineation of the relative fibrin specificity of different plasminogen activators or of different doses of the same activator in vivo. Thus, their use should accelerate and facilitate development of implementation of optimal dose regimens for diverse activators and combinations of activators. The present study was designed to determine whether assay of such markers effectively differentiates effects of two doses of t-PA, each of which are comparably effective in opening infarct-related arteries, in patients studied at the Washington University Clinical Unit of the National Institutes of Health-sponsored Thrombolysis in Myocardial Infarction Trial. The extent of lysis of fibrin and of lysis of fibrinogen by plasmin resulting from administration of t-PA was evaluated in 19 patients given 150 mg t-PA over 6 hours and 17 given 100 mg over the same interval by assay of serially obtained plasma samples for crosslinked fibrin degradation products (XL-FDP) and B beta 1-42, a peptide released when fibrinogen is degraded to fragment X by plasmin. XL-FDP were markedly elevated after 6-hour infusions of both doses of t-PA. However, elevations were not more with the higher dose [peak value, 4,321 +/- 986 ng/ml (+/- SEM)] compared with the lower dose (3,397 +/- 1,096 ng/ml) (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1988

Myocardial infarct extension: occurrence, outcome, and risk factors in the Multicenter Investigation of Limitation of Infarct Size.

The occurrence, outcome, and predictors of myocardial infarct extension were determined in 848 patients with acute myocardial infarction. An increase in the level of plasma MB creatine kinase activity was used to detect extension, which occurred in 71 of 848 patients (8.4%). For these patients, hospital mortality was more than four times higher than for those without extension (30% versus 7%, P less than 0.01). However, for patients surviving the initial hospitalization, there was no significant difference in mortality during the following year (12% compared with 9%). Multivariable analyses indicated that extension was more likely to occur in patients with recurrent ischemic pain during the second hospital day, a history of previous myocardial infarction, and ST segment depression on the admission electrocardiogram. The occurrence of extension in patients with two of these risk factors was more than twice that of patients without any of the risk factors (15.1% compared with 5.8%). Patients with these risk factors should be considered for early coronary angiography and possible intervention to prevent infarct extension and its sequellae.

Analysis of Variance↗
PubMed1988

Quantitative analysis for isoforms of creatine kinase MM in plasma by chromatofocusing, with on-line monitoring of enzyme activity.

Changes in the proportions of individual isoforms of the MM isoenzyme of creatine kinase (CK; EC 2.7.3.2) in plasma promptly reflect both myocardial infarction and coronary recanalization. However, quantitative methods developed thus far are too slow or cumbersome for routine use in making clinical decisions. We report a convenient, quantitative chromatofocusing assay with on-line fluorometric detection of isoform activity in the column eluent that provides results within 40 min from the time of sample application. Sample eluted from a microbore chromatofocusing column (1.8-mL bed volume) is split between a reaction stream, into which CK reagents are added, and a reference stream. After incubation at 37 degrees C, NADPH formed by reaction of isoforms with CK reagent is detected at 340 nm. The system can detect activity of individual isoforms in plasma samples having total CK activity greater than or equal to 21 U/L (30 degrees C). Results correlated closely with those obtained by previously validated, but slow, chromatofocusing (r = 0.98, n = 30) and protein immunoblotting (r = 0.90, n = 20) procedures.

Animals↗
PubMed1987

Major depressive disorder in coronary artery disease.

Depression has been reported to be common in patients with coronary artery disease (CAD), using a variety of criteria for the diagnosis of depression. However, many studies have relied solely on the presence of symptoms such as a dysphoric mood and fatigue in making a diagnosis of depression. Both fatigue and dysphoric mood are also associated with medical illnesses, and psychiatric diagnoses based on such nonspecific symptoms may lack the specificity necessary to predict the need for psychiatric treatment. To assess the incidence of depression likely to require and respond to psychiatric treatment, 50 patients documented to have CAD by coronary angiography underwent psychiatric diagnostic interviews. Current research-based criteria (DSM-III) were used to make diagnoses of major depressive disorder. In addition, the applicability of a brief screening inventory the (Beck depression inventory) for detecting the presence of depression in these patients was tested. Nine patients (18%) met criteria (DSM-III) for major depressive episode. Depression was not related to the extent of CAD, age or use of beta blockers. There was a relation between depression and smoking. Only 2 of the 9 depressed patients had been diagnosed previously and were being treated for depression. When a score of greater than or equal to 10 on the Beck depression inventory was used to distinguish patients with depression, it had moderate sensitivity (78%) and specificity (90%) for the identification of depression.

Aged↗