Prognostic determinants in hypertrophic cardiomyopathy. Prospective evaluation of a therapeutic strategy based on clinical, Holter, hemodynamic, and electrophysiological findings. Patients with hypertrophic cardiomyopathy (HCM) frequently have arrhythmias and hemodynamic abnormalities and are prone to sudden death and syncope. An important need exists for improved risk stratification and definition of appropriate investigation and therapy. The relation of 31 clinical, Holter, cardiac catheterization, and electrophysiological (EP) variables to subsequent cardiac events in 230 HCM patients was examined by multivariate analysis. Studies were for cardiac arrest (n = 32), syncope (n = 80), presyncope (n = 52), ventricular tachycardia (VT) on Holter (n = 36), a strong family history of sudden death (n = 9), and palpitations (n = 21). Nonsustained VT on Holter was present in 115 patients (50%). Sustained ventricular arrhythmia was induced in 82 patients (36%). Seventeen cardiac events (eight sudden deaths, one cardiac arrest, and eight syncope with defibrillator discharges) occurred during a follow-up of 28 +/- 19 months. The 1-year and 5-year event-free rates were 99% and 79%, respectively. Two variables were significant independent predictors of subsequent events: sustained ventricular arrhythmia induced at EP study (beta, 3.5; p = 0.002) and a history of cardiac arrest or syncope (beta, 2.9; p less than 0.05). Only two of 66 patients without symptoms of impaired consciousness had a cardiac event (3-year event-free rate, 97%). In contrast, nonsustained VT on Holter was associated with a worse prognosis only in patients with symptoms of impaired consciousness: 11 of 79 symptomatic patients with VT on Holter (14%) had events versus only four of 85 symptomatic patients without VT on Holter (5%) (p = 0.057). Notably, none of 51 patients without symptoms of impaired consciousness in whom VT was not induced at EP study had a cardiac event. In HCM, VT on Holter is of benign prognostic significance in the absence of symptoms of impaired consciousness and inducible VT, and sustained VT induced at EP study, especially when associated with cardiac arrest or syncope, identifies a subgroup at high risk for subsequent cardiac events.


Echocardiographic study of the morphology and growth of the aortic arch in the human fetus. Observations related to the prenatal diagnosis of coarctation. In a study of normal and abnormal growth of the aorta before birth, high-resolution echocardiographic imaging of the aortic arch in 92 normal fetuses aged 16-38 weeks was used to establish normal values for aortic arch dimensions at varying gestational ages. From long-axis views of the aortic arch, the internal diameter of the aortic root, ascending aorta, transverse aortic arch, aortic isthmus, proximal descending thoracic aorta, and left common carotid artery were measured. Correlation coefficients for the diameter of each aortic arch segment when related to gestational age varied from r = 0.87 to r = 0.94 (p less than 0.001 for each), and growth curves were derived from the third and 97th percentiles around each linear regression analysis. In most of the fetuses, there was progressive tapering of the aortic arch, with the smallest diameter being at the isthmus. The ratio of the transverse aorta, isthmus, descending aorta, and aortic root to the ascending aorta remained relatively constant with gestational age, with mean values of 0.94, 0.81, 0.96, and 1.13, respectively. In five fetuses in whom a prenatal diagnosis of aortic coarctation was confirmed postnatally, transverse aortic and isthmic measurements fell on or below the third percentile for gestational age from the above data. In each case, the ratio of left common carotid artery to transverse aorta was greater than or equal to 0.73 compared with less than or equal to 0.62 for the 92 normal fetuses (mean ratios, 0.77 +/- 0.05 [SD] for coarctation versus 0.48 +/- 0.08 for normal fetuses; p less than or equal to 0.001). Use of normal growth curves for the developing aortic arch should facilitate the prenatal diagnosis of left heart and aortic arch abnormalities, particularly aortic coarctation, which until recently has been a difficult prenatal diagnosis to make with certainty.


Cross-sectional early mitral flow-velocity profiles from color Doppler in patients with mitral valve disease. Cross-sectional flow-velocity profiles from early mitral flow in 20 patients (10 with mitral regurgitation and 10 with mitral stenosis) were constructed from the velocity data from each point in sequentially delayed two-dimensional digital Doppler ultrasound maps. The data suggested that the early mitral flow studied in an apical four-chamber view was variably skewed in both patient groups. The maximum flow velocity overestimated the cross-sectional mean velocity at the same time by a factor of 1.12-1.86. The maximum time-velocity integral was 1.13-1.77-fold greater than the cross-sectional mean time-velocity integral. In patients with mitral regurgitation, the cross-sectional flow-velocity profile appeared to be most skewed at the level of the mitral leaflet tips. The level of the mitral annulus appeared to give the most homogenous flow-velocity distribution in both patient groups. When calculations of volume flow are based on pulsed Doppler ultrasound recordings with a single sample volume, the possibility of a skewed flow-velocity profile must be taken into account.


Detection of coronary atherosclerosis in young adult hearts using intravascular ultrasound. Coronary atherosclerosis has been demonstrated in young adults by postmortem pathology. Angiographic evaluation of coronary disease in young adults is limited by ethical issues and the insensitivity of angiography for detecting early pathology. Catheter-based intracoronary ultrasound has proven useful both in detecting and quantitating coronary disease, but the ultrasound appearance of young, angiographically normal, coronary arteries has not been well defined. Twenty-five subjects were examined with intracoronary ultrasound within 1 month of cardiac transplantation. Mean age of the donor hearts was 28 years (range, 14-43 years). Measurements of an index of intimal thickening were obtained at four left anterior descending coronary artery sites in each patient. All study patients had angiographically normal coronary arteries. Ultrasound in 14 subjects demonstrated a three-layered appearance of the coronary vessel wall with a mean intimal index of 0.16 +/- 0.07. The other 10 subjects, including all donors under the age of 25 years, had coronary vessel wall layers too thin to be imaged separately at the 30-MHz sound frequency. Five subjects had ultrasound evidence of focal intimal thickening greater than 500 microns. The donors of these hearts each had risk factors for coronary artery disease. Two subjects died within 5 weeks of their ultrasound study. Histological measurements of the vessel wall layers were similar to the corresponding ultrasound values. This study provides a reference for the intravascular ultrasound appearance of young adult coronary arteries and confirms pathology findings that young subjects with angiographically normal vessels have a range of coronary intimal thickening, which includes occasional evidence of focal, early atheromatous lesions.


Declining incidence of ventricular fibrillation in myocardial infarction. Implications for the prophylactic use of lidocaine. The purposes of the present investigation were 1) to track the incidence of primary ventricular fibrillation (VF) in the control and lidocaine-treated groups in the randomized control trials (RCTs) of lidocaine prophylaxis against primary VF in acute myocardial infarction, with particular emphasis on the time frame of the randomized trial, and 2) to estimate the number of patients who must receive lidocaine currently to prevent one episode of VF. The following variables from RCTs published between 1969 and 1988 were entered into logistic regression models to predict the percent of patients developing VF: year of publication of the RCT, method of data analysis used in the RCT, route and technique of lidocaine administration, duration of monitoring for VF, and exclusion criteria before randomization (congestive heart failure/cardiogenic shock, ventricular tachycardia/VF, or bradycardia/atrioventricular block). Year of publication was a significant predictor of VF in both the control and lidocaine groups (p less than or equal to 0.002) even after adjusting for other covariates. Based on a univariate logistic regression model with year as the predictor variable, it was estimated that the incidence of primary VF in the control group fell from 4.51% in 1970 to 0.35% in 1990 and from 4.32% down to 0.11% for the lidocaine group over the same time period. Thus, about 400 patients would currently need prophylaxis with lidocaine to prevent one episode of VF. Present estimates of the risk:benefit ratio of lidocaine prophylaxis should consider the low risk of VF in control patients and the large number who need lidocaine prophylaxis to prevent one episode of VF. When added to the previously reported trend toward excess mortality in lidocaine-treated patients, these data argue against the routine prophylactic use of lidocaine in patients with acute myocardial infarction.


Combined use of time and frequency domain variables in signal-averaged ECG as a predictor of inducible sustained monomorphic ventricular tachycardia in myocardial infarction. Time and frequency domain analyses of signal-averaged ECG (SAECG) have several individual limitations, and the results of the two methods sometimes vary considerably. The purpose of this study was to determine whether the combined use of time and frequency domain variables facilitates identification of patients who will have ventricular tachycardia (VT) induced during programmed ventricular stimulation (PVS). Nine myocardial infarction (MI) patients with clinically documented sustained monomorphic VT (SMVT), 40 MI patients without clinical VT, and 30 normal healthy control subjects were evaluated. PVS using three extrastimuli and SAECG recording were performed in the MI patients on day 36 +/- 4 after infarction. Of 40 MI patients, SMVT was inducible in 14, sustained polymorphic VT in three, nonsustained monomorphic VT in three, nonsustained polymorphic VT in two, and no inducible arrhythmia was obtained in 18. There were significant differences between MI patients with inducible SMVT and without inducible SMVT in the following SAECG variables: filtered QRS durations (high-pass filter setting, 25, 40, and 80 Hz); low-amplitude signal durations (LAS) under 10, 20, 30, and 40 microV (high-pass filter setting, 40 and 80 Hz); root-mean-square voltages (RMS) of the terminal 20, 30, 40, 50, and 60 msec (high-pass filter setting, 40 and 80 Hz); area ratio (area 20-50 Hz/area 0-20 Hz x 10(5)) of a 120-msec sampling interval starting 20 msec before QRS offset; factor of normality on lead X; and minimum value of the variables on lead X, Y, or Z. Stepwise logistic regression analysis selected only LAS under 30 microV (high-pass filter setting, 80 Hz) and area ratio as independent predictors of inducible SMVT. With these two variables, the predicted probability of inducible SMVT [p(VT)] was expressed as p(VT) = 1/[1+exp (6.2-0.11 LAS-0.01 area ratio)]. This function had 93% sensitivity, 81% specificity, 72% positive predictive value, 95% negative predictive value, and 85% predictive accuracy with greater than or equal to 0.3 as the criterion of a positive test. The combined use of time and frequency domain analysis of SAECG can enhance the accuracy of this technique as a screening test for results of PVS in MI patients without clinical VT.


Transient intermittent lymphocyte activation is responsible for the instability of angina. Blood clotting activation is an important component of the inflammatory response; the outbursts of unstable angina are usually associated with increased thrombin formation and coronary mural thrombosis. To investigate 1) whether monocyte activation is responsible for the enhanced thrombin formation during bursts of unstable angina and 2) what mechanism(s) might be responsible for monocyte activation, we studied patients with unstable angina (n = 31), stable effort angina (n = 23), left endoventricular thrombosis (n = 8), and control subjects (n = 44), measuring plasma fibrinopeptide A (FPA) levels and the capacity of monocytes to express procoagulant activity (PCA) and of lymphocytes to modulate this expression. Patients with unstable angina and patients with endoventricular thrombosis had significantly (p less than 0.0001) higher FPA plasma levels than patients with effort angina and control subjects. However, only monocytes from unstable angina patients expressed significantly increased PCA characterized as tissue factor-like activity (units/10(5) monocytes, median and range; 120, 1.1-463.2 versus 10.8, 0.8-39.1 in control subjects; p less than 0.0001 versus the other groups). When 14 patients with unstable angina were restudied 8-12 weeks later, they showed neither elevated plasma FPA levels nor monocyte PCA. In unstable angina patients, there was a correlation between FPA and PCA (r = 0.56, p less than 0.001). For expression of PCA by monocytes, both an incubation of at least 2 hours with lymphocytes and direct monocyte-lymphocyte contact were needed. In reconstitution and cross-mixing experiments, only lymphocytes from patients with active unstable angina induced the expression of PCA by monocytes from both control and patient groups. The results demonstrate that the increased thrombin formation in unstable angina patients is due to the expression of tissue factor-like activity by activated monocytes. The monocyte activation appears to be a part of a lymphocytic cell-instructed response intermittently triggered by unknown factors.


Different susceptibility to the development of nitroglycerin tolerance in the arterial and venous circulation in humans. Effects of N-acetylcysteine administration. Tolerance to the effects of organic nitrates develops rapidly during continuous exposure to these drugs; its main mechanism seems to be an intracellular sulfhydryl group depletion. However, the relative susceptibility to the development of nitroglycerin tolerance of the arterial or venous circulation in humans is still a matter of dispute. Twenty patients with coronary artery disease underwent a continuous 24-hour nitroglycerin infusion followed by a bolus administration of N-acetylcysteine. Forearm blood flow (ml/100 ml/min) and venous volume (ml/100 ml) were measured by strain gauge plethysmography under control conditions, at the end of nitroglycerin titration, after 24-hour infusion, and after N-acetylcysteine; vascular resistance was calculated as mean cuff blood pressure divided by flow. After 24 hours of nitroglycerin infusion, the initial increase in venous volume was reduced 48% (p less than 0.01), whereas the acute effects on vascular resistance were not attenuated in the whole group. N-Acetylcysteine completely restored nitroglycerin venodilator effects in all 10 patients in whom attenuation of the venous effects was observed during the infusion period. The data indicate that the susceptibility to the development of nitrate tolerance in humans is higher in the venous than in the arterial circulation, and that the sulfhydryl group donor N-acetylcysteine is extremely effective in reversing nitroglycerin tolerance in the venous circulation in humans.


High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Iron can induce lipid peroxidation in vitro and in vivo in humans and has promoted ischemic myocardial injury in experimental animals. We tested the hypothesis that high serum ferritin concentration and high dietary iron intake are associated with an excess risk of acute myocardial infarction. Randomly selected men (n = 1,931), aged 42, 48, 54, or 60 years, who had no symptomatic coronary heart disease at entry, were examined in the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) in Eastern Finland between 1984 and 1989. Fifty-one of these men experienced an acute myocardial infarction during an average follow-up of 3 years. On the basis of a Cox proportional hazards model adjusting for age, examination year, cigarette pack-years, ischemic ECG in exercise test, maximal oxygen uptake, systolic blood pressure, blood glucose, serum copper, blood leukocyte count, and serum high density lipoprotein cholesterol, apolipoprotein B, and triglyceride concentrations, men with serum ferritin greater than or equal to 200 micrograms/l had a 2.2-fold (95% CI, 1.2-4.0; p less than 0.01) risk factor-adjusted risk of acute myocardial infarction compared with men with a lower serum ferritin. An elevated serum ferritin was a strong risk factor for acute myocardial infarction in all multivariate models. This association was stronger in men with serum low density lipoprotein cholesterol concentration of 5.0 mmol/l (193 mg/dl) or more than in others. Also, dietary iron intake had a significant association with the disease risk in a Cox model with the same covariates. Our data suggest that a high stored iron level, as assessed by elevated serum ferritin concentration, is a risk factor for coronary heart disease.


Emergent use of balloon-expandable coronary artery stenting for failed percutaneous transluminal coronary angioplasty. The balloon-expandable intracoronary stent developed by Palmaz and Schatz is undergoing clinical evaluation for use in unfavorable anatomic situations and in the prevention of restenosis. Because the stent's mechanism of action would suggest effectiveness in salvaging certain percutaneous transluminal coronary angioplasty (PTCA) failures, we retrospectively examined the results of emergency unplanned coronary artery stenting for failed PTCA procedures, including acute occlusion. The study population consisted of all US patients receiving emergency unplanned stent implantation in a nonrandomized fashion at seven centers over a 2 1/2-year period (n = 56). All available medical records and angiograms were reviewed to determine retrospectively the reason for stenting: Group 1 consisted of 23 patients with a suboptimal angioplasty result; group 2 included patients with evidence of impending vessel closure after PTCA (n = 15); and group 3 were patients with frank acute occlusion after PTCA (n = 18). The immediate and final (30-day) results of stenting were examined with respect to major complications, which included death, need for coronary artery bypass graft surgery, and occurrence of myocardial infarction. Finally, restenosis rates (greater than or equal to 50% stenosis) based on follow-up angiography were calculated. Baseline characteristics of the study population included a mean +/- SD age of 58 +/- 11 years and a large prevalence of angiographic characteristics generally considered unfavorable for PTCA, which include lesion eccentricity (49%), intimal dissection (9%), or angiographically visible thrombus (6%). After conventional balloon angioplasty, there was an increased incidence of intimal dissection (74%) and thrombus formation (38%), and overall stenosis severity was unchanged (75 +/- 12% versus 70 +/- 27%, p = NS). Successful stent deployment was achieved in 55 (98%) of 56 patients with initial success (freedom from death, surgery, and infarction) in 52 (93%) of 56 patients. The success rate at 1 month fell to 71% primarily because of the occurrence of subacute stent thrombosis (16%) and its associated complications. Overall, major complications occurred in 16 (29%) of 56 patients within 30 days. The only predictor of subacute stent thrombosis in multiple stepwise logistic regression analysis was the presence of angiographically visible thrombus after stenting (p = 0.03). Angiographic restenosis was documented in eight (23%) of 35 eligible patients. Emergency stenting may be a useful and effective treatment for failed angioplasty. High initial success rates (greater than 90%) can be achieved, but subsequent complications, often related to subacute thrombosis, occur in a substantial portion of patients. Patients who receive stents on an emergency basis, particularly those with previous acute occlusion, should be considered to be at greater than usual risk for complications and receive more careful anticoagulation and follow-up.


Morphological predictors of acute complications after percutaneous excimer laser coronary angioplasty. Results of a comprehensive angiographic analysis: importance of the eccentricity index. Percutaneous excimer laser coronary angioplasty (ELCA) is a new technique for recanalization of arteries obstructed by coronary atherosclerosis. This study was conducted to assess the complication rate and determine the influence of clinical and angiographic characteristics on complications after ELCA. A detailed, quantitative, angiographic core laboratory analysis of patients undergoing ELCA was performed by two experienced angiographers who were not the primary laser angioplasty operators. Two hundred patients underwent 203 separate procedures on 220 lesions at three medical centers. Laser success was achieved in 180 lesions (81.8%) and procedural success in 199 (90.5%). Emergency coronary artery bypass graft (CABG) was required in five patients (2.5%). One patient suffered a Q wave myocardial infarction; there were no deaths. Also, acute closure and perforation occurred in 10 (4.5%) and three (1.4%) vessels, respectively. Coronary dissections after laser treatment were seen in 36 vessels (16.4%). Multivariate analysis found two independent preprocedural factors related to complications: eccentricity index, which is the percent deviation of the lesion lumen from the center of the artery (p = 0.0007), and proximal vessel diameter (p = 0.033). In addition, an abrupt proximal face of the lesion was associated with angiographic complications by univariate analysis (p = 0.051). Multivariate analysis showed the eccentricity index (p = 0.032) to be the only independent predictor for the occurrence of any one or more of the important complications (emergency CABG, perforation, acute closure, or Q wave myocardial infarction), whereas lesion angle greater than 45 degrees was a significant univariate predictor (p = 0.029). Other predictors of complications with balloon percutaneous transluminal coronary angioplasty, such as increased lesion length, rough edges, calcification, ulceration, and branch point, were not predictive of complications with the excimer laser. The degree of lesion eccentricity is the most powerful predictor of complications after ELCA. This and other morphological predictors may be of benefit in the selection of patients for ELCA as well as directing future development of this new technology.


Anatomical progression of coronary artery disease in humans as seen by prospective, repeated, quantitated coronary angiography. Relation to clinical events and risk factors. The INTACT Study Group. At present, there is extensive knowledge on the clinical course of coronary artery disease (CAD), whereas data on the underlying anatomical changes and their relation to clinical events are still limited. We investigated progression and regression of CAD prospectively over 3 years in 230 patients (average age, 53.2 years) with mild to moderate disease by applying quantitated, repeated coronary angiography. Minimal stenotic diameters, segment diameters, and percent stenosis were analyzed by the computer-assisted Coronary Angiography Analysis System (CAAS). Progression was defined either as an increase in percent stenosis of preexisting stenoses by greater than or equal to 20% including occlusions or as formation of new stenoses greater than or equal to 20% and new occlusions in previously angiographically "normal" segments. At first angiography, we found 838 stenoses greater than or equal to 20% (average degree, 39.3%) and 135 occlusions in the four major coronary branches (4.23 lesions per patient). At second angiography, 82 (9.8%) of the preexisting stenoses had progressed, 15 of them up to occlusion (1.8%; preocclusion degree averaging 46.6%; 29.7-65.6%). In addition, there were 144 newly formed stenoses (average degree, 39.2%) and 10 new occlusions. Hence, 25 (2.6%) of all stenoses had become occluded. Altogether, 129 patients (56.1%) showed progression: 68 (29.6%) with new lesions only, 27 (11.7%) with preexisting lesions, and 34 (14.8%) with both types. Regression (decrease in degree of stenoses greater than or equal to 20%) was present in 29 stenoses (3.6%) and 28 patients (12%). The incidence of new myocardial infarctions was low, with three originating from occluding preexisting stenoses and one from new stenoses; hence, only four (16%) of the 25 new occlusions led to myocardial infarctions. Risk factor analysis showed that cigarette smoking correlated significantly with the formation of new lesions (p = 0.001), whereas total cholesterol correlated with the further progression of preexisting stenoses (p = 0.017) but not with the incidence of new lesions. In patients with mild to moderate CAD, the angiographic progression is slow (in this study 18.7% of patients and 7% of stenoses per year) but exceeds regression (4.1% of patients and 1.2% of stenoses per year). Progression is predominantly seen in the formation of new coronary stenoses and less in growth of preexisting ones. Most of the stenoses were of a low degree (less than 50%), clinically not manifest including those going into occlusion and leading to myocardial infarction. Progression was influenced by risk factors, especially cigarette smoking (formation of new lesions) and high cholesterol levels (progression of preexisting stenoses).


Lipids and lipoproteins in symptomatic coronary heart disease. Distribution, intercorrelations, and significance for risk classification in 6,700 men and 1,500 women. The Bezafibrate Infarction Prevention (BIP) Study Group, Israel. Lipid and lipoprotein profiles of coronary heart disease (CHD) patients have usually not included data on high density lipoprotein cholesterol (HDL-C), except in small groups, and have not included information on women. Both aspects are meaningful in the evaluation of patients for risk classification and for the importance of HDL-C in dictating further evaluation. In the screening phase of a clinical trial, we obtained lipid and lipoprotein levels under Centers for Disease Control-standardized procedures in more than 6,700 men and 1,500 women aged 40-72 years. Mean total cholesterol (TC) was higher in women (by 15-24 mg/dl) but changed little with age. Mean HDL-C, however, progressively increased with increased age for both sexes (34.4 at age of less than 50 years to 37.5 mg/dl at age 65 or older in men and from 41.3 to 44.5 mg/dl for the respective age groups in women). Triglycerides (TG) were lower in elderly groups, particularly in men (151 mg/dl in 65-year-olds versus 189 in counterparts less than 50 years). The number of previous infarctions, severity of congestive heart failure, and severity of angina were negatively correlated with mean HDL-C in a dose-response manner, whereas the association with mean TG was inverted, creating a mirror image of that observed with HDL-C. More than half of patients (52%) with TC less than 200 mg/dl exhibited HDL-C levels consistent with the accepted "high-risk" range of less than 35 mg/dl, whereas an increasing percentage of desirable HDL-C level was found with increasing levels of TC (14% with HDL-C greater than or equal to 45 mg/dl at TC less than 200 mg/dl increasing gradually to 28% in patients with TC greater than 260 mg/dl). These results provide previously unavailable information on the lipid profile of female patients and appear to strongly establish the case for obtaining all three standard blood lipid determinations (TC, HDL-C, and TG) in coronary patients as well as in the framework of detecting and classifying individuals at high risk for CHD.


Influence of dietary fat, apolipoprotein E phenotype, and sex on plasma lipoprotein levels. The "Western" diet, sex, and apolipoprotein (Apo) E polymorphism have been implicated as codeterminants of lipid levels. In a retrospective analysis, we evaluated the combined impact of dietary fat, sex, and Apo E phenotype on lipoprotein levels in 67 subjects fed two contrasting, metabolically controlled diets: one a "Western" diet, with a low polyunsaturated to saturated (P:S) fatty acid ratio and the other a "therapeutic" diet, with a high P:S ratio. The high P:S diet compared with P:S diet exerted a far stronger predictive influence on lipoprotein concentrations than Apo E phenotype, sex, or the latter two factors combined. Apo E phenotype alone was associated with a stepwise increase in low density lipoprotein cholesterol (LDL-C), such that 3/2 less than 3/3 less than 4/3 on either the low or the high P:S diets. On the low P:S diet only, sex was shown to be a significant predictor of high density lipoprotein cholesterol (HDL-C) levels, with women greater than men, and the associated LDL/HDL ratio with men greater than women. On the high P:S diet, women displayed a dramatic fall in HDL-C, effectively raising the LDL/HDL ratio to equivalency with men and obliterating the sex influence seen with the low P:S diet. Controlled for dietary fat, Apo E and sex exerted independent, additive effects on lipoprotein levels on the low P:S diet only. Only the Apo E phenotype remained predictive on the high P:S diet. Women of the Apo E 3/2 phenotype stand to benefit the least from a high P:S diet because of reduction in the more "protective" HDL-C, whereas men of the 4/3 phenotype showed the greatest improvement in the LDL/HDL ratio.


Lipoprotein lipids in older people. Results from the Cardiovascular Health Study. The CHS Collaborative Research Group. Cardiovascular disease is the leading cause of death and disability in older people. There is little information about the distributions of risk factors in older populations. This article describes the distribution and correlates of lipoprotein lipids in people greater than or equal to 65 years old. Lipoprotein lipid concentrations were measured in 2,106 men (M) and 2,732 women (F) who were participants in the Cardiovascular Health Study, a population-based epidemiological study. Distributions of lipids by age and sex and bivariate and multivariate relations among lipids and other variables were determined in cross-sectional analyses. Mean concentrations of lipids were cholesterol: M, 5.20 +/- 0.93 mmol/l (201 +/- 36 mg/dl) and F, 5.81 +/- 0.98 mmol/l (225 +/- 38 mg/dl); triglyceride (TG): M, 1.58 +/- 0.85 mmol/l (140 +/- 75 mg/dl) and F, 1.57 +/- 0.78 mmol/l (139 +/- 69 mg/dl); high density lipoprotein cholesterol (HDL-C): M, 1.23 +/- 0.33 mmol/l (48 +/- 16 mg/dl), and F, 1.53 +/- 0.41 mmol/l (59 +/- 16 mg/dl); low density lipoprotein cholesterol (LDL-C): M, 3.27 +/- 0.85 mmol/l (127 +/- 33 mg/dl) and F, 3.57 +/- 0.93 mmol/l (138 +/- 36 mg/dl). The total cholesterol to HDL-C ratios were M, 4.49 +/- 1.29 and F, 4.05 +/- 1.22. TG, total cholesterol, and LDL-C concentrations were lower with increasing age, the last more evident in men than in women. TG concentration was positively associated with obesity (in women), central fat patterning, glucose intolerance, use of beta-blockers (in men), and use of estrogens (in women) and negatively associated with age, renal function, alcohol use, and socioeconomic status. In general, HDL-C had opposite relations with these variables, except that estrogen use was associated with higher HDL-C concentrations. LDL-C concentration was associated with far fewer variables than the other lipids but was negatively associated with age in men and women and positively correlated with obesity and central fat patterning and negatively correlated with renal function and estrogen use in women. There were no differences in total cholesterol and LDL-C concentrations among participants with and without prevalent coronary heart disease and stroke, but TG concentration was higher and HDL-C lower in men with both coronary heart disease and stroke and in women with coronary heart disease. Cholesterol and cholesterol/HDL-C ratio were lower and HDL-C higher than previously reported values in older people, suggesting that lipid risk profiles may be improving in older Americans. TG and HDL-C concentrations, and to a lesser extent LDL-C, were associated with potentially important modifiable factors such as obesity, glucose intolerance, renal function, and medication use.


Rate-dependent effects of diltiazem on human atrioventricular nodal properties. Tachycardia enhances the channel-blocking effects of antiarrhythmic drugs. In contrast to the extensive data regarding the rate-dependent effects of sodium channel blockers in humans, little is known about the frequency-dependent effects of calcium channel blockers on human atrioventricular (AV) nodal properties. Accordingly, the purpose of this study was to evaluate the importance of heart rate in modulating the electrophysiological effects of diltiazem in humans. Electrophysiological studies were performed in 25 patients. Sinus node, atrial, and AV nodal function were evaluated at multiple atrial rates under control conditions and after administration of one of three intravenous doses of diltiazem designed to produce low, intermediate, and high stable plasma concentrations (designated doses 1, 2, and 3, respectively). Results were analyzed in terms of the longest and shortest cycle lengths obtainable in each patient under control and drug conditions. Plasma concentrations of diltiazem were stable and averaged 43 +/- 4, 73 +/- 6, and 136 +/- 11 ng/ml for doses 1, 2, and 3, respectively. Sinus node recovery time, intra-atrial conduction time, atrial effective refractory period, and HV interval were unaffected by diltiazem infusion. Effects of diltiazem were limited to changes in AV nodal parameters. Stable, dose-dependent increases in Wenckebach cycle length were observed after all three doses of diltiazem (increases of 54 +/- 13, 84 +/- 18, and 174 +/- 33 msec for doses 1, 2, and 3, respectively). Small nonsignificant increases in AH interval and atrioventricular effective refractory period (AVERP) were observed after dose 1 of diltiazem. At long cycle lengths, diltiazem caused modest increases in AH interval (3 +/- 4 and 25 +/- 8 msec for doses 2 and 3, respectively) and AVERP (36 +/- 12 and 70 +/- 25 msec). Drug effects were far greater at short cycle lengths (45 +/- 17 msec, 58 +/- 12 msec for AH interval and 80 +/- 24 msec, 163 +/- 41 msec for AVERP; p less than 0.05 versus values at long cycle lengths). At rapid rates, effects of diltiazem on AVERP substantially exceeded those on AV conduction, a result that could account for the beneficial effects of diltiazem during paroxysmal AV reentrant tachycardia by decreasing the excitable gap. Depressant effects of diltiazem on human AV nodal function are highly dependent on atrial rate; the rate-dependent actions on AV nodal refractoriness probably contribute to beneficial effects of diltiazem in patients with supraventricular arrhythmias.


Effects of oxygen inhalation on skin microcirculation in patients with peripheral arterial occlusive disease. Oxygen administration is currently used in clinical medicine to improve peripheral oxygen delivery to tissues threatened by ischemia. However, conflicting results have been reported on the effects of oxygen in ischemic areas. This study was aimed at investigating the effects of 40% oxygen inhalation on the skin microcirculation in the feet of patients with peripheral arterial occlusive disease (PAOD). Transcutaneous oxygen tension (tc PO2) was measured on the dorsal skin of the foot, and the nailfold microcirculation was investigated by a combination of laser Doppler flowmetry (LDF) and dynamic capillaroscopy (CBV) in the great toes of 17 legs of 11 patients, with 13 legs of eight normal subjects as a control group. Inhalation of oxygen induced a significant decrease of both the total (delta LDF, -307%, p less than 0.02) and nutritional (delta CBV, -17%, p less 0.002) skin microcirculation in normal legs compared with baseline values. A similar response was observed in 10 legs of patients who showed a significant increase of the tc PO2 (greater than or equal to 10 mm Hg) (delta LDF, -14%, NS; delta CBV, -13%, p less than 0.005). By contrast, both the total (+21%, p less than 0.03) and nutritional (+52%, p less than 0.05) circulation significantly increased in the seven legs without significant tc PO2 increase. In addition, the flow motion, which was impaired in the patients, was significantly (p less than 0.05) improved by oxygen inhalation. Inhalation of 40% oxygen induces a vasoconstriction in the skin microcirculation of toes of the normal subjects and patients with moderate PAOD but induces an increase of the skin microcirculation in patients with severe PAOD.


Effect of intravenous adenosine infusion on myocardial perfusion and function. Hemodynamic/angiographic and scintigraphic study. Myocardial perfusion imaging during adenosine-induced hyperemia with dipyridamole or adenosine is an accepted method to diagnose coronary artery disease (CAD) and risk assessment. The mechanism of perfusion abnormality may be caused by disparate flow responses or coronary steal. This study examined the relation between 201Tl perfusion pattern and hemodynamic/angiographic changes during intravenous adenosine infusion. Patients with suspected CAD underwent sequential hemodynamic, coronary arteriographic, and left ventriculographic studies simultaneously with 201Tl imaging during adenosine infusion (140 micrograms.kg-1.min-1 for 6 minutes). There were 33 patients with CAD and 12 patients without CAD. The 201Tl images (using single-photon emission computed tomography) were abnormal in 31 patients with CAD (sensitivity, 94%) and normal in the patients without CAD (specificity, 100%). In patients with and without CAD, there were significant increases in heart rate and cardiac output (p less than 0.0001) and decreases in systemic vascular resistance and blood pressure (p less than 0.0001). There was a 77 +/- 38% increase in pulmonary capillary wedge pressure in normal subjects and a 125 +/- 83% increase in patients with CAD (p = 0.02). ST segment depression was observed in 11 patients with CAD (33%). In CAD patients, there was no change in percent diameter or area stenosis measured quantitatively during adenosine infusion. In 15 patients, contrast left ventriculography was repeated during adenosine infusion. In these patients, 201Tl perfusion defects were seen in 31 of 75 segments (41%) whereas only six of 75 segments (8%) developed regional wall motion abnormality (p less than 0.001); the remaining segments showed either no change or improved function. The left ventricular ejection fraction did not change significantly (73% versus 75%). There is a disparity between the effects of adenosine on left ventricular perfusion and function; most patients with CAD have perfusion defects whereas the global and regional systolic function remains unchanged or improves. Diastolic left ventricular dysfunction is a probable mechanism of the increase in pulmonary capillary wedge pressure.


Adenosine infusion for the reversal of pulmonary vasoconstriction in biventricular failure. A good test but a poor therapy. Elevation of pulmonary vascular resistance is an important determinant of right ventricular function in patients with end-stage biventricular heart failure. Vasodilator drug therapy directed at the pulmonary vasculature is used in the hemodynamic assessment of patients for orthotopic heart transplantation, and therapy aimed at decreasing pulmonary vascular resistance and transpulmonary pressure gradient has been advocated in patients awaiting heart transplantation. Adenosine infusion has been shown to cause selective pulmonary vasodilatation in normal subjects and in patients with primary pulmonary hypertension but has not been assessed in patients with biventricular heart failure. Using two infusion doses, we studied the pulmonary and renal hemodynamic effects of adenosine on patients referred for heart transplantation (n = 21) and compared it with sodium nitroprusside (n = 18). Patients received 30% oxygen via face mask throughout the study. Adenosine at 100 micrograms/kg min achieved the same percentage fall in pulmonary vascular resistance as nitroprusside (41 +/- 6% versus 42 +/- 4%) and a greater and more consistent fall in transpulmonary pressure gradient (35 +/- 6% versus 9 +/- 30%, p less than 0.02). The mean arterial blood pressure fell by 16 mm Hg with nitroprusside but was unchanged by adenosine, indicating that in contrast to nitroprusside, adenosine acted as a selective pulmonary vasodilator. Despite this, cardiac index showed only a modest increase with adenosine (1.73 +/- 0.09 to 1.89 +/- 0.16 l.m-2, p less than 0.05), and there was a rise in pulmonary capillary wedge pressure from baseline at the higher dose (29.7 +/- 2.5 to 33.4 +/- 3.4 mm Hg, p less than 0.05). Renal blood flow was unchanged during adenosine infusion. Adenosine is a potent selective pulmonary vasodilator in patients with biventricular heart failure and is preferable to sodium nitroprusside as a test for the reversibility of pulmonary vasoconstriction. However, its deleterious effects on left atrial pressure make it unsuitable as a therapeutic agent in patients awaiting heart transplantation.


Neurophysiological assessment of skeletal muscle fatigue in patients with congestive heart failure. Recent research has demonstrated that patients with congestive heart failure (CHF) exhibit significant functional impairment of skeletal muscle and that these changes may be important determinants of exercise capacity. Although muscle strength may be mildly reduced, the most significant abnormality is markedly enhanced muscle fatigue. The goal of the present study is to determine whether accelerated fatigue is caused by impaired muscle activation, as a result of inadequate central motor drive or neuromuscular transmission, or by a change in the muscle itself. The study population consisted of nine patients with New York Heart Association class I-III CHF and eight sedentary, age- and sex-matched control subjects. Maximal voluntary contraction force of the foot dorsiflexors (primarily the tibialis anterior) was quantified as a measure of muscle strength, isometric endurance was quantified by the time required for force to decline to 60% of maximal during a sustained maximal contraction, and dynamic endurance was defined as the number of maximal contractions required for force to decline to 60% of maximal under a protocol of six repetitions per minute with an incremental duty cycle. The degree of central motor drive failure was quantified by the degree of force augmentation produced by a superimposed tetanic stimulus delivered to the peroneal nerve during the initial maximal voluntary contraction and at the time when force during the sustained isometric contraction declined to 60% of maximal. Neuromuscular junction transmission was examined by quantifying the amplitude of the compound muscle action potential (M wave) in response to a single nerve stimulus during fatiguing exercise. Muscle strength was relatively preserved in the CHF patients versus the control subjects (93 +/- 41 versus 105 +/- 34 lb; p = NS), but isometric endurance (time to decline to 60%, 34 +/- 15 versus 54 +/- 19 seconds; p less than 0.02) and dynamic endurance (number of repetitions before decline to 60%, 30 +/- 6 versus 43 +/- 7 contractions; p less than 0.001) were both impaired. Tetanic nerve stimulation increased force by similar degrees in the two groups, and the amplitude of the M wave did not decline in either group during exercise. These findings indicate that enhanced muscle fatigue in patients with CHF is not caused by impaired central motor drive or an abnormality of neuromuscular junction transmission but rather by an abnormality in the muscle itself.


Respiratory muscle function and dyspnea in patients with chronic congestive heart failure. Patients with heart failure (HF) frequently experience exertional dyspnea. Using near-infrared spectroscopy, we have previously demonstrated accessory respiratory muscle deoxygenation during exercise in these patients by monitoring changes in light absorption at 760-800 nm. To investigate whether low-frequency respiratory muscle fatigue occurs, we performed supramaximal bilateral transcutaneous phrenic nerve stimulation before and after maximal bicycle exercise in 10 patients with HF (age, 62 +/- 10 years; ejection fraction, 18 +/- 7%) and six normal subjects (age, 50 +/- 8 years). Maximal rates of contraction and relaxation, peak twitch tension, and maximal transdiaphragmatic pressure (Pdi) were derived before and after exercise from analysis of six to 12 twitches obtained at functional residual capacity. Pdi, time in inspiration (Ti), time per breath (TTOT), respiratory gases, ratings of perceived dyspnea and fatigue, and 760-800 nm near-infrared spectroscopy absorbency changes of the serratus anterior muscle were measured throughout exercise. The tension time index (TTdi) of the diaphragm was derived. In both normal and HF subjects, all parameters of diaphragmatic function (i.e., maximal rates of contraction and relaxation, peak twitch tension, and maximal Pdi) were unchanged before and after exercise. Mean Pdi was comparable at rest (normal, 3.7 +/- 1; HF, 5.8 +/- 2.9 cm H2O; p = NS) but significantly greater in patients with HF at peak exercise (normal, 12.1 +/- 3; HF, 18.3 +/- 6.6 cm H2O; p less than 0.05). Ti/TTOT of both groups was similar at rest and throughout exercise. TTdi was significantly greater at rest (normal, 0.01 +/- 0.01; HF, 0.03 +/- 0.02; p less than 0.05) and at peak exercise (normal, 0.03 +/- 0.02; HF, 0.10 +/- 0.03; p less than 0.04) in patients with HF. Significant accessory respiration muscle deoxygenation was noted only in patients with HF (peak exercise; normal, -1 +/- 13; HF, 28 +/- 15 arbitrary units; p less than 0.01). Linear correlation analysis was performed between ratings of perceived dyspnea and parameters of pulmonary and diaphragmatic function. Significant correlations were observed between ratings of perceived dyspnea and maximal inspiratory and expiratory pressure, the TTdi of the diaphragm, near-infrared absorption changes, and forced expiratory volume in 1 second (FEV1) (all r greater than 0.5; p less than 0.05). Thus, respiratory muscle strength, work, and oxygenation were significantly correlated with the degree of dyspnea. We conclude that low-frequency diaphragmatic muscle fatigue does not occur despite accessory respiratory muscle deoxygenation during exercise in patients with HF. However, diaphragmatic work as assessed by the TTdi is dramatically increased in patients with HF and approaches levels previously shown to generate fatigue. The sensation of dyspnea appears closely related to respiratory muscle function.


Localization of the fast and slow pathways in atrioventricular nodal reentrant tachycardia by intraoperative ice mapping. Atrioventricular (AV) nodal reentrant tachycardia is classically described as a reentrant rhythm entirely contained within the compact AV node. Although the concepts of longitudinal dissociation of two intranodal pathways and a distal common pathway are accepted, the proximal portion of the circuit remains undefined. Current reports suggest that the two pathways may be separable by atrial tissue and not contained entirely within the compact node. We used an ice mapping method to demonstrate the slow and fast pathways of the reentrant circuit and their relation to the atrial septum around the AV node. Six patients with the usual form (slow-fast) of AV nodal reentrant tachycardia were mapped during surgery. In most patients, antegrade slow pathway localization was posterior and inferior to the compact AV node along the tricuspid annulus; in two patients, it was superior along the tendon of Todaro. Retrograde fast pathway localization was anterior or superior to the compact AV node in all patients. In all patients, anatomic distinction was made between the two pathways and the compact node. We conclude that no upper common pathway exists within the compact AV node in the usual type of nodal reentrant tachycardia and that the perinodal atrial tissue is a requisite part of the tachycardia circuit.


Abnormal left ventricular intracavitary flow acceleration in patients undergoing aortic valve replacement for aortic stenosis. A marker for high postoperative morbidity and mortality. We examined the clinical and echocardiographic characteristics of patients undergoing aortic valve replacement for aortic stenosis whose continuous wave Doppler studies showed abnormal intracavitary flow acceleration. The clinical and Doppler echocardiographic records of 53 consecutive patients undergoing aortic valve replacement for aortic stenosis were reviewed. Doppler echocardiography was performed at a mean of 6.6 days (range, 0-22 days) after surgery. Thirteen patients (group 1) had a dagger-shaped high-velocity systolic flow signal indicative of abnormal intracavitary flow acceleration on their postoperative Doppler study; group 2 comprised 40 aortic stenosis patients who underwent aortic valve replacement but had no postoperative evidence of abnormal intracavitary flow acceleration. Group 1 postoperative abnormal intracavitary flow velocities ranged from 1.8 to 6.8 m/sec (mean, 4.9 +/- 0.9 m/sec): Resulting dynamic gradients ranged from 10 to 184 mm Hg (mean, 104.6 +/- 32 mm Hg). Compared with group 2, group 1 patients had a distinctive ventricular geometry with more-pronounced hypertrophy, smaller cavities, and higher ejection fraction. Systolic anterior motion of the mitral valve did not accompany abnormal intracavitary flow acceleration in any patient. Six of 13 group 1 patients suffered postoperative hemodynamic compromise characterized by severe hypotension despite adequate pulmonary capillary wedge pressures; group 1 postoperative mortality was significantly greater than that seen in group 2 patients (38% versus 12%, p less than 0.05). Abnormal intracavitary flow acceleration after aortic valve replacement for severe aortic stenosis is associated with a distinctive ventricular geometry and supernormal systolic function but not systolic anterior motion of the mitral valve. Such flow acceleration appears to be a marker for increased postoperative morbidity and mortality. Preoperative and postoperative Doppler echocardiography may be useful in risk stratification and guiding therapy.


Long-term effects of percutaneous laser balloon ablation from the canine coronary sinus. Radiofrequency catheter ablation of left-sided accessory pathways is becoming the first line of therapy for patients with symptomatic Wolff-Parkinson-White syndrome. Nevertheless, alternative ablation techniques merit development, at least as supplementary modalities for cases in which conventional ablation approaches may prove unsuccessful. We recently reported the short-term results with transcatheter laser balloon ablation from the coronary sinus in a canine model, proving that the procedure is feasible for the potential ablation of left-sided accessory pathways. We now report the effects of percutaneous transcatheter laser balloon ablation in a chronic canine model. Twenty adult mongrel dogs were studied. After baseline coronary arteriography, left ventriculography, and coronary sinus angiography were obtained, 15 dogs received two or three consecutive laser doses from the coronary sinus of 30-40 W for 15-30 seconds, for a total cumulative energy of 1,200-2,400 J. The five remaining animals underwent a procedure consisting of balloon sham inflation without laser exposure and served as controls. After a mean follow-up of 6 weeks, the angiographic procedures were repeated, and the animals were killed. The mean extent of the fibrotic lesion was 15 mm long, 6 mm wide, and 4.5 mm deep and involved the coronary sinus wall, atrium, and, frequently, the summit of the posterior left ventricular wall. Six animals (four in the study group and two in the control group) showed asymptomatic narrowing of the coronary sinus lumen but always with total angiographic reconstitution due to extensive collateral circulation. The circumflex artery and mitral valve were intact angiographically and histologically in all animals. Percutaneous transcatheter laser balloon ablation via the coronary sinus produces a lesion that may be anatomically well suited for left-sided accessory pathway ablation. Although coronary sinus narrowing may occur, adverse physiological effects are unlikely due to the development of extensive collateral circulation. Systematic clinical studies of this new approach to catheter ablation appear warranted.


Cellular mechanisms of differential action potential duration restitution in canine ventricular muscle cells during single versus double premature stimuli. We tested the hypothesis that action potential duration (APD) restitution of normal ventricular muscle cells is different during double premature stimuli (S3) compared with a single premature stimulus (S2). We propose a possible ionic mechanism for such a difference. Action potentials and isometric tension were recorded simultaneously from isolated canine right ventricular trabeculae (2 x 2 x 10 mm) (n = 35). APD and tension restitution curves (APD) and peak tension versus diastolic interval [DI] of S2 and S3 were constructed by the extrastimulus method during pacing at 1,500 msec. The following results were obtained. 1) The APD restitution curve of S2 was different from that of S3. During the restitution of S2, an early biphasic upward hump was present at short DIs. In contrast, a smooth exponential rise was consistently seen during S3 restitution. 2) Peak tension remained significantly (p less than 0.001) lower during the restitution of S2 than during S3 restitution at all DIs tested. 3) The variation of APD during the initial 100 msec of DI was significantly longer during S3 than S2 (22 +/- 5 msec versus 41 +/- 5 msec, p less than 0.001). 4) Caffeine (2 mM, n = 5) and ryanodine (10 microM, n = 5) blocked cyclic variations of tension, presumably by blocking cyclic variations of intracellular calcium ion concentrations ([Ca2+]i), and eliminated the differences in APD restitution between S2 and S3. 5) Nisoldipine at high (5 microM) but not at lower (2 microM, n = 5) concentration eliminated the differences in restitution of both APD and tension between S2 and S3. 6) BAY K 8644 (100 nM, n = 5) had no effect on this difference. Greater variations of APD occur during the restitution of S3 than during S2 at short DIs. These differences appear to be caused by cyclic variations in tension and thus in [Ca2+]i. Calcium-sensitive outward currents could explain these differences in APD restitution.


Dipyridamole potentiates the myocardial infarct size-limiting effect of ischemic preconditioning. Recent studies implicated a key role for adenosine (ADO) receptor activation in the enhancement of ischemic tolerance by ischemic preconditioning. In this study, we aimed to test the hypothesis that dipyridamole, an ADO transport inhibitor, enhances the preconditioning effect. Six groups of rabbits underwent 30-minute coronary occlusion and 72-hour reperfusion. Infarct size (IS) and the area-at-risk (AR) were determined by histology and by use of fluorescent particles, respectively. IS expressed as the percentage of AR (%IS/AR) was 46.5 +/- 3.4% (n = 13) in control rabbits. Preconditioning with 2-minute ischemia tended to limit %IS/AR (%IS/AR, 35.5 +/- 3.5%, n = 9), and that possible protection was abolished by pretreatment with 10 mg/kg 8-phenyltheophylline (8-PT), an ADO receptor antagonist (%IS/AR, 43.9 +/- 5.8%, n = 9). Administration of dipyridamole (0.25 mg/kg) before the 2-minute preconditioning markedly limited %IS/AR to 13.8 +/- 2.6% (n = 12), indicating the potentiation of the preconditioning effect by this agent. Furthermore, this enhancement of preconditioning effect by dipyridamole treatment was significantly attenuated by 8-PT (%IS/AR, 27.6 +/- 2.1%, n = 11). Dipyridamole given before the 30-minute ischemia, without preconditioning, did not reduce %IS/AR (55.3 +/- 5.2%, n = 7), and a previous study from this laboratory had demonstrated that the present dose of 8-PT alone did not modify IS in the rabbit. Dipyridamole significantly potentiated the IS-limiting effect of preconditioning. This finding strongly supports the hypothesis that stimulation of ADO receptors by endogenous ADO, which builds up during preconditioning ischemia, mediates the increased ischemic tolerance afforded by preconditioning.


Myocardial protective effects of adenosine. Infarct size reduction with pretreatment and continued receptor stimulation during ischemia. We hypothesized that 1) endogenous adenosine released during ischemia conferred an inherent cardioprotection, and 2) a pretreatment dose of adenosine before ischemia would provide additional protection independent of hemodynamic effects. Thirty-six anesthetized New Zealand White rabbits underwent 30 minutes of regional ischemia produced by coronary occlusion followed by 2 hours of reperfusion. The adenosine group (ADO, n = 9) received a 5-minute pretreatment infusion of 140 micrograms/kg/min of adenosine before ischemia. A control group (SAL, n = 9) received saline before ischemia. To separate the effects of adenosine used as a pretreatment versus the effects during ischemia, a third group (ADO+SPT, n = 9) received adenosine as pretreatment followed by 10 mg/kg 8-p-sulfophenyl theophylline (8-SPT), an A1/A2-receptor antagonist given before ischemia, thus allowing pretreatment with adenosine but antagonizing its effects during ischemia. To preclude any protection from endogenous adenosine released during ischemia, the fourth group (SAL+SPT, n = 9) received saline as pretreatment and 8-SPT before ischemia. Area of necrosis within the area at risk (infarct size) was determined with tetrazolium and Evans blue stains, and transmural blood flow was measured using radioactive microspheres. Collateral blood flow in the area at risk was similar in all groups, as was the size of the area at risk. Infarct size was reduced by adenosine pretreatment (ADO, 8.4 +/- 7.2%) in contrast to saline vehicle (SAL, 27.8 +/- 6.3%; p less than 0.05 versus ADO). alpha 1/alpha 2-Receptor blockade after adenosine pretreatment abolished the ischemic protection provided by pretreatment adenosine (ADO+SPT, 42.7 +/- 8.3%; p less than 0.05 versus ADO). Finally, receptor blockade of endogenously released adenosine without adenosine pretreatment increased infarct size by 24% over the nonpretreated saline group (SAL+SPT, 51.5 +/- 9.0%; p less than 0.05 versus SAL). We conclude that 1) endogenous adenosine building up during ischemia is cardioprotective, and 2) pretreatment with adenosine confers cardioprotection independent of hemodynamic effects. Whether pretreatment effects of adenosine subsequently modulate the effects of endogenous adenosine (through alterations in receptor population or sensitivity) or endogenous and exogenous adenosine represent additive compartments is unclear.


A practical approach to coma diagnosis in the unresponsive patient. Diagnosis of coma in the unresponsive patient can be done in a relatively short time by making key observations that will confirm disease of either the brain stem or the hemispheres, the two locations in which coma originates. Determining the location of the lesion is the primary goal in early assessment of the unresponsive patient. Examination of the patient's eyes is the single most important step in understanding coma.


Calcium-channel blocking agents as therapy for amphotericin B nephrotoxicity. Amphotericin B is a broad-spectrum antifungal agent shown to be effective in the treatment of systemic fungal infections. Unfortunately, therapeutic doses are often associated with a variety of adverse effects, including nephrotoxicity. Studies of the deleterious effects of amphotericin B on the renal microvasculature are yielding clues to sparing kidney function. In selected patients, concomitant use of a calcium-channel blocker may prevent the nephrotoxic effects of amphotericin B and allow full therapeutic doses to be used.


Pharmacotherapy of multiple sclerosis: current status. Pharmacotherapy plays an important part in the overall management of patients with multiple sclerosis. Most therapies directed at altering the natural history of the underlying disease process are only partially effective or are controversial or experimental. However, many effective symptomatic therapies are available to the clinician. The action and uses of corticosteroids in multiple sclerosis are discussed, and approaches to the treatment of spasticity, paroxysmal disorders, bladder dysfunction, cerebellar ataxia, neurobehavioral manifestations, fatigue, and acute and chronic pain in patients with multiple sclerosis are examined.


Wolman disease: morphological, clinical and genetic studies on the first Scandinavian cases. On the Aland Islands, a 1-month-old girl was diagnosed as having Wolman disease. The diagnosis was confirmed neurochemically; a decreased activity of acid lipase was noted in the proband and her parents had typical carrier values. This is the first Scandinavian case reported. The skin biopsy revealed cytoplasmic accumulations identical to those noted in two sibs who highly probably had Wolman disease during the 1950s. Both these sibs died at the age of about 3 months and presented a heavy accumulation of lipid material in lymph nodes, spleen, adrenal glands, liver, gut, and also some pathological alterations in other organs. Electron microscopic findings from deparaffinized samples showed cytoplasmic accumulation of lipid material similar to that noted in Wolman disease. Genealogical analyses revealed that the index families had ancestors from the same restricted area and also common ancestors during the 17th century. The parents of the two affected sibs were born on a small island and were related in many different ways. On the basis of genealogical studies and other genetic investigations performed, the importance of founder and drift effect for manifestations of rare hereditary disorder in isolates is stressed.


Primary angiitis of the central nervous system: diagnostic criteria and clinical approach. Primary angiitis of the central nervous system has until recently been considered rare, usually progressive, and untreatable. In 1987, preliminary diagnostic criteria for the disorder were proposed in the hope of gaining a more accurate description of the disease. We used these criteria in reviewing all cases reported in the English language (99 cases) and those seen at The Cleveland Clinic Foundation (9 cases). We believe that the disorder is heterogeneous, and has a better prognosis than previously thought. Furthermore, a relatively benign subset of this disorder, termed "benign angiopathy of the central nervous system," can be defined on clinical grounds. We propose a revised set of diagnostic criteria and a practical approach to treatment.


Congenital heart defects, hamartomas of the tongue and polysyndactyly in a sister and brother. We report a sister and brother with congenital heart defects, hamartomas of the tongue and polydactyly. Both had coarctation of the aorta, which was repaired in early infancy. In addition, the girl had atrioventricular canal. She died postoperatively at age 4 years. The boy had subaortic stenosis and died of pneumonia at age 2 years. Both children had normal psychomotor development. The parents were healthy and unrelated. The familial occurrence could be due to a previously unrecognized autosomal recessive syndrome or parental gonadal mosaicism for a dominant syndrome.


Doppler echocardiographic assessment of constrictive pericarditis, cardiac amyloidosis, and cardiac tamponade. Doppler echocardiography is useful in assessing diastolic dysfunction. Pulsed-wave Doppler echocardiographic interrogation of the atrioventricular valves and the central veins has been used in conjunction with respiratory monitoring to characterize abnormal diastolic function of the heart in diseases such as constrictive pericarditis, restrictive cardiomyopathy, and cardiac tamponade. Constrictive pericarditis has distinct Doppler flows with marked respiratory variation because the pericardial shell separates the intracardiac pressures from intrathoracic pressure. This is not the case with restrictive cardiomyopathy, as in cardiac amyloidosis. Cardiac amyloidosis shows a spectrum of the Doppler flows which evolve as the disease progresses from abnormal relaxation in the early phase to pseudo-normal in the intermediate phase and to restrictive in the advanced phase. Doppler echocardiography can be used to assess the hemodynamic significance of pericardial effusion and to detect cardiac tamponade.


Lung and heart-lung transplantation: the state of the art. Lung and heart-lung transplantation is one of the most rapidly evolving transplantation fields. Survival has been improving with better patient selection, better graft preservation, and better immunosuppression. This paper outlines criteria for patient selection, reviews the surgical options involving lung transplantation, and discusses factors influencing morbidity and survival in these patients. The Cleveland Clinic Foundation experience with these procedures is presented. Lung and heart-lung transplantation has emerged from the experimental realm to the therapeutic, and can now be offered as an effective treatment option to many patients with previously fatal heart and lung disorders.


Time of pubertal onset, testosterone levels and intelligence in 47,XXY males. This study examined the relations between verbal and performance IQs, time of pubertal onset and testosterone levels from 13 to 16 years of age in a sample of 30 males with a supernumerary X chromosome. The findings indicated that verbal IQs measured prior to puberty, during puberty and at mid-adolescence were strongly related to relatively early pubertal onset and testosterone levels. Performance IQs had little or no relationship with the same variables. The results are discussed in terms of several different psychobiological models.


Viral hepatitis in the 1990s, Part I: Current principles of management. Recent years have brought major advances in the diagnosis and treatment of viral hepatitis. Treatment of acute uncomplicated hepatitis is supportive rather than curative. Treatment of fulminant hepatic necrosis is directed towards preventing and treating complications while preparing suitable patients for liver transplantation. Corticosteroids do not improve survival rates in patients with fulminant hepatic necrosis and should be avoided in nearly all patients with hepatitis A. Although liver histology in acute viral hepatitis is highly characteristic, biopsy is usually superfluous, except in transplant patients with acute hepatic dysfunction. Hepatitis A virus infection is frequently asymptomatic, and data on its incidence are poor. The virus is frequently transmitted before the patient becomes ill; therefore, curtailing hepatitis A spread depends in large measure on hygienic practices. Passive immunization is possible with immune globulin. Inactivated and attenuated vaccines may be licensed within the next 2 years.


Circadian rhythms and migraine.

Circadian rhythms and migraine. To determine whether migraine exhibits a circadian rhythm or occurs randomly throughout the day, we analyzed the time of migraine onset in 15 migraine suffers (migraineurs) over 20 weeks. The patients suffered 211 migraine attacks over 20 weeks (range 3 to 30, median 13). Twelve of the 15 migraineurs had 50% or more of headache onsets during a 4-hour block of time. As a group, the migraineurs showed a circadian variation in migraine onset, with a marked increase in attacks between 6 AM and 8 AM, peak frequency of migraine onset between 8 AM and 10 AM, and a dramatic decrease in frequency between 8 PM and 4 AM. The circadian rhythm of migraine onset parallels that of myocardial infarction, platelet aggregability, plasma cortisol, and plasma catecholamines. These associations suggest that alteration of vasomotor tone may be involved in the initiation of migraine attacks.


Elevated serum levels of creatine kinase BB in autosomal dominant osteopetrosis type II--a family study. A markedly elevated BB isoenzyme fraction of serum creatine kinase was noted in four male siblings and correlated with typical radiographic findings of autosomal dominant osteopetrosis Type II (ADO Type II). Patients with other sclerosing bone diseases had no elevation of CK-BB. The precision of the electrophoretic mobility patterns and correlation by I-125 tagged radioimmunoassay method confirms that this is CK-BB. We postulate that the dysfunctional and/or immature osteoclasts in ADO are more dependent on CK-BB than on the usual tricarboxylic acid cycle for the production of energy. The correlation of marked elevation of serum CK-BB with radiographic evidence of ADO Type II may prove to be of value as a biologic marker in the early diagnosis of the illness and lead to better understanding of the metabolism of bone.


DNA screening of hyperlipidemic Afrikaners for familial hypercholesterolemia. Three different point mutations of the low-density lipoprotein receptor (LDLR) gene are responsible for familial hypercholesterolemia (FH) in about 90% of Afrikaner patients. Screening of hyperlipidemic Afrikaner individuals for these founder-related mutations was performed to determine the distribution of the mutations in individuals with different lipid profiles, and to provide guidelines for screening of the mutations in hyperlipidemics. Rapid DNA methods, based on restriction enzyme analysis or allele-specific hybridisation of enzymatically-amplified genomic DNA, have been used to analyse the LDLR gene mutations in four groups of Afrikaner individuals. Group 1 included 84 individuals in whom FH was diagnosed on clinical data. Groups 2-4 included 89 hyperlipidemic individuals who did not fulfil the criteria for inclusion in the FH study group. The founder-related LDLR gene mutations were present in 36% of the hyperlipidemics whose clinical diagnosis excluded them from the FH study group. This indicates that conventional methods for the diagnosis of FH, based mainly on lipid determinations and a family history of coronary heart disease, do not always allow an accurate diagnosis of the disease. Screening of hyperlipidemic Afrikaner individuals for specific founder-related LDLR gene mutations can provide a definite diagnosis of FH, which may lead to better counselling and optimal treatment.


Confirmation of true mosaic trisomy 20 in a phenotypically normal liveborn male. A new case of prenatally detected mosaic trisomy 20 (79% trisomy 20 cells in amniocyte cultures) that was confirmed in newborn tissue is presented. A healthy male infant was delivered at term, with no dysmorphology or apparent malformations; this baby is developing normally. Twenty-five percent of foreskin and 17% of fetal cord cells also showed trisomy 20, while no trisomic cells were detected in newborn blood. High frequency mosaicism for trisomy 20 in this case was thus due to true embryonic origin. Extensive counseling and prenatal follow-up in this case led to an unaffected liveborn, and guarded optimism may be warranted for future cases of mosaic trisomy 20 detected prenatally.


Pitted enamel hypoplasia in tuberous sclerosis. Thirty patients with tuberous sclerosis (from 29 different families) were examined for evidence of macroscopically visible pitted enamel hypoplasia. Of 23 patients with permanent teeth, 11 (48%) showed multiple enamel pits (mean 4.6 pits, range 3-9), but none were seen in six patients with deciduous teeth. Five of 563 controls (0.88%) had similar pitted enamel hypoplasia. Simple dental examination may be a useful adjunct in the assessment of patients with permanent teeth when a diagnosis of tuberous sclerosis is being considered, but is less likely to be helpful in the pre-school child.


Linkage analysis in properdin deficiency families: refined location in proximal Xp. Properdin is a component of the alternative activation pathway of the complement system. Deficiency or dysfunction of the protein is inherited in an X-linked recessive manner. Affected males have an increased risk of developing meningococcal disease. Six multi-generation families with different types of properdin deficiency were analyzed using microsatellite and other polymorphisms on the X chromosome. Based on multipoint data, it was found that the disease gene maps close to DXS255 (Zmax = 13.3 at theta max = 0.00) and DXS426 (Zmax = 12.9 at theta max = 0.00) on the Xp-arm near the centromere. There was no indication of genetic heterogeneity among the six families analyzed. Thus it is now possible to perform accurate DNA-based determination of the inheritance of the mutation in affected families.


Characterization of aerobic non-lipophilic coryneforms from human feet. Aerobic coryneform bacteria from human feet have been studied by analysis of the cell-wall sugars, lipids and diamino acids and by phenotypic tests. Although many isolates studied fall into the established genus Brevibacterium at least two previously unreported taxa of coryneform have been identified bringing the number of aerobic, non-lipophilic taxa known on skin to four. Simple tests can be used to distinguish between these taxa. Studies on the human skin flora continue to reveal the diversity of organisms present.


Junctional epidermolysis bullosa: a mild variant in two Indian sisters. Two sisters developed a bullous skin disease in early childhood. The disease had features of junctional epidermolysis bullosa but differed clinically from previously recorded variants.


Oral papillary plasmacytosis resembling candidosis without demonstrable fungus in lesional tissue. Two cases with exuberant papillary and nodular hyperplasia of the hard and soft palates are described. Both were elderly edentulous men with bilateral angular stomatitis. The papillary hyperplasia extended as far as the epiglottis and was associated with swelling and fissuring of the upper lip in patient 1. In patient 2, the palatal change extended to the maxillary gingiva and was associated with smooth plaques and fissuring of the dorsal tongue. Histology of both cases showed a dense polyclonal plasma-cell infiltrate with overlying epithelial hyperplasia, parakeratinization and neutrophil micro-abscesses suggesting Candida infection but fungal elements could not be demonstrated. Patient 1 also showed defective cellular immunity to Candida antigen which was reversed by treatment with ketoconazole and levamisole, antedating clinical improvement.


Unusual manifestations of primary cutaneous amyloidosis in association with Raynaud's phenomenon and livedo reticularis. A patient with unusual manifestations of primary cutaneous amyloidosis, including macules, papules, oedematous plaques and urticarial lesions is described. Raynaud's phenomenon and livedo reticularis were an associated finding. During the acute phase, single doses of systemic corticosteroids resulted in an impressive, long-lasting improvement in cutaneous manifestations.


Unusual cutaneous lesions associated with chronic myelomonocytic leukaemia. A 69-year-old man presented with unusual nodular cutaneous lesions of 3 years duration predominantly involving the chest, upper back and scalp. Histopathological changes in biopsy specimens from affected skin resembled those seen with granuloma annulare even though there was a lack of epithelioid cells. Based on the sluggish course of the condition, leukocytosis with monocytosis in peripheral blood and the findings on electron microscopic examination of peripheral blood cells, he was diagnosed as having chronic myelomonocytic leukaemia (CMMoL). At lower magnification under the electron microscope, the nodular skin lesions showed pleomorphic cell features with monocytes and histiocytic cells of abnormal appearance. The skin lesions were thus considered to be an unusual type of leukaemia cutis.


Long-term undiagnosed syphilis with clinical presentation of meningitis. A 43-year-old woman, with an 11-year history of progressive cutaneous lesions, was considered to have granuloma annulare and was treated as such for 4 years. She then developed chronic meningitis. Serological investigation revealed active syphilis. Appropriate antibiotic treatment led to a rapid resolution of the clinical symptoms. The recent reports of similar cases indicate the importance of an adequate knowledge of clinical manifestations and pathological patterns of syphilis.


Systemic sclerosis sine scleroderma presenting with vitiligo-like depigmentation and interstitial pulmonary fibrosis. We report a case of systemic sclerosis sine scleroderma in which vitiligo-like depigmentation and early interstitial pulmonary fibrosis predominated. The pigmentary changes occurring in systemic sclerosis are reviewed and the distinctive features of the case discussed.


Mycosis fungoides mimicking perioral dermatitis. A 71-year-old woman under PUVA-treatment for mycosis fungoides developed erythematous patches around the nasolabial folds and papules on the chin with clinical features of perioral dermatitis. Histology showed a specific infiltrate of mycosis fungoides with predominance of medium to large-sized pleomorphic lymphocytes and immunoblasts. Immunohistochemical analysis revealed the T-phenotype of the neoplastic cells. Small clusters of B-lymphocytes could also be observed within the infiltrate. Perioral dermatitis-like lesions can be added to the spectrum of rare and unusual clinical manifestations of mycosis fungoides.


Subacute cutaneous lupus erythematosus in a patient with Crohn's disease. A case of anti-Ro (SS-A) antibody-positive subacute cutaneous lupus erythematosus (LE) occurring in a 47-year-old male with Crohn's disease is described. This is a previously undescribed association.


Urticarial vasculitis, IgA deficiency and C1 esterase inhibitor deficiency in the presence of an IgG monoclonal gammopathy--a case report. A female patient, currently aged 40, has attended our Lupus Clinic for 8 years with a clinical picture of urticarial vasculitis, joint pains, severe myalgias and abdominal pain which has occurred in bouts at irregular intervals. She has been found to have consistently reduced C4 levels, C1-esterase inhibitor deficiency and a persistent monoclonal band in the gamma region on electrophoresis. Her serum IgA level has been continuously low. Her symptoms have failed to respond to antihistamines and a variety of other measures but have been partially alleviated by immunosuppressive therapy ('pulsed' cyclophosphamide). We believe that this is the first patient described showing this combination of clinical and laboratory features.


The immunogenetic background of scleroderma--an overview. Currently it may be stated that the MHC associations in scleroderma support the classification of disease subsets, but in no ethnic group is the overall association strong enough for clinical use. In different ethnic groups, the distribution of MHC alleles varies, as does the degree of linkage disequilibrium between alleles of the linked loci. This concept is even relevant to relatively close populations. Thus Whiteside noticed that, if those patients referred from more than 100 miles from the study centre were excluded, then the strength of the DR1 association increased. The environmental contribution to scleroderma is unknown, except in the case of toxin or solvent associated disease. Different causal environmental agents found in different global regions might result in separate MHC associations and hence explain the discrepancies noted above. There are indications that associations between specific subsets of SSc patients and genetic markers will assume greater importance both diagnostically and prognostically. The lung fibrosis group look prime candidates, for example. Genetic markers are also a useful means of relating chemically-induced SSc-like disorders to the classical disease. Vinyl chloride disease provides an example. There is much heterogeneity within the disease, in terms of extent of skin involvement, severity, and of organ involvement. It is clear that the different clinical subsets of scleroderma are characterized by different associated MHC alleles. There are also many cases of clinical overlap with related diseases, and certain of these diseases have a different HLA association, which could detract from the primary HLA type associated with SSc.(ABSTRACT TRUNCATED AT 250 WORDS)


Cutaneous manifestations in systemic trichosporonosis. Trichosporonosis due to Trichosporon beigelii is increasingly recognized in neutropenic immunocompromised patients. We report the clinical and histological presentation of three cases, as well as a study of the prevalence of T. beigelii colonization of normal-looking skin in patients receiving intensive chemotherapy for cancer.


Erythema elevatum diutinum: a clinicopathological study. Erythema elevatum diutinum is a syndrome of vasculitis in which lesions, typically over the extensor surfaces, showed a mixed inflammatory infiltrate on biopsy. We describe a series of 13 patients. The most common association in our series was with hypergammaglobulinemia; both mono and polyclonal. Chronic infection, not streptococcal, was a less frequent finding although two of three patients had a positive reaction to the intradermal injection of streptococcal antigen. Dapsone remains the initial treatment of choice.


Actinic reticuloid: action spectra and UVA protection factor sunscreens. This study compares the action spectra on two new patients with actinic reticuloid (AR), with one previously reported patient. All three patients had exquisite photosensitivity in the UVB range being up to 27 times more sensitive than controls. Sensitivity also increased into the UVA Range, all up to 335 nm and, one into the visible. Their photosensitivity made evaluation of the Sun Protection Factor (SPF) of selected, more recent, high-numbered sunscreens easier to compare, because of the shorter time of the minimal erythema dose when tested with a solar simulator. A sunscreen containing butyl methoxydibenzoylmethane (Parsol 1789) with an overall SPF of 16 was not as effective at protecting the actinic reticuloid patients as a higher SPF numbered sunscreen containing a benzophenone (SPF of 40). The Parsol 1789 gave a protection value of 5 in the UVA Range, compared to one of 3 given by the sunscreen containing benzophenone. The SPFs of seven of these commerically available high-numbered sunscreens were compared with controls.


The bare:ensheathed anagen root ratio as a function of the speed of epilation. Small tufts of chest hair were epilated at different rates and the roots classified as to growth phase, presence or absence of root sheaths and whether the shafts were fractured. With respect to anagen roots, a slow epilation gives bare roots whereas an increase in the rate of epilation increases the proportion of ensheathed roots. As the rate of epilation increases, the proportion of fractured hair shafts increases. These findings are relevant to epilation used as a diagnostic procedure because it is not possible to have both a high proportion of well-formed ensheathed anagen roots without some breakages.


Characterization of anti-interferon-alpha antibodies appearing during recombinant interferon-alpha 2a treatment. Patients with malignant midgut carcinoid tumours received recombinant interferon-alpha 2a (rIFN-alpha 2a) or rIFN-alpha 2a and chemotherapy (streptozocin and doxorubicin) for 6 months, and then rIFN-alpha 2a alone. Antibodies, mainly of IgG type, binding to rIFN-alpha 2a developed in nine of 22 patients (41%), as determined by immunoassay. In seven patients, antibodies also neutralized the biologic (anti-viral) activity of rIFN-alpha 2a. Anti-IFN-alpha 2a antibodies were equally frequent in both sexes and treatment groups, but were not observed in those patients (n = 8) that had previously received other types of IFN. Antibodies appeared after a median of 6 months of rIFN-alpha 2a treatment and had a median duration of 6 months. The anti-IFN-alpha 2a antibody titres declined with time with no obvious relation to change of therapy, also during continued IFN-alpha 2a treatment. High titres of neutralizing antibodies appeared to impair anti-tumoural effects in individual potential responders. Anti-IFN-alpha 2a antibodies further examined in six patients bound to native IFN-alpha subtypes present in both allogenic and autologous leucocyte IFN-alpha. Such autoantibodies neutralized the biologic activity of autologous IFN-alpha in two patients, and in a third were partially neutralizing.


A comparison of anti-lymphocyte immunotoxins containing different ribosome-inactivating proteins and antibodies. Immunotoxins were prepared with several single-chain ribosome-inactivating proteins (RIPs type 1) and with the A-chain of ricin linked to the F(ab')2 fragment of sheep anti-mouse IgG. The cytotoxic activity of these conjugates was tested on human lymphocytes pretreated with an anti-CD3 murine MoAb. The immunotoxins inhibited DNA synthesis in phytohaemagglutinin (PHA)-stimulated lymphocytes with IC50S (concentrations causing 50% inhibition) ranging from 8.9 x 10(-13) to 5.7 x 10(-11) M (immunotoxins containing dianthin 32, saporin, pokeweed antiviral protein from seeds (PAP-S), bryodin, momordin, momorcochin, and trichokirin), 1 x 10(-8) M (immunotoxin containing gelonin) and 5 x 10(-9) M (immunotoxin containing ricin A-chain). The immunotoxin containing saporin linked to the anti-mouse IgG F(ab')2 fragment was also highly toxic to human lymphocytes pretreated with anti-CD2, -CD3, -CD5 and -CD45 MoAbs, with IC50S less than or equal to 10(-11) M. Immunotoxins were prepared also with saporin linked to MoAbs against various CD antigens. The immunotoxin prepared with the anti-CD3 antibody had the highest specific cytotoxicity to human lymphocytes.


Predictors of infection in chronic lymphocytic leukaemia (CLL). A group of patients with chronic lymphocytic leukaemia (CLL) were studied to determine whether particular clinical and laboratory parameters might help to identify those patients at risk of recurrent infection who would benefit from immunoglobulin replacement therapy. The case notes of 59 patients were reviewed with regard to stage and duration of disease, chemotherapy and frequency of infection over the preceding 2 years. Serum IgG levels and specific antibodies to tetanus, diphtheria and pneumococcal capsular polysaccharide were measured at the end of the 2-year period. A group of 56 healthy age-matched volunteers were used as controls. Eighteen patients had severe or multiple infections during the study period, 11 patients had recurrent infections and the remaining 30 patients had only minimal infections. Overall, serum IgG levels were low in 32 patients but in none of the control group (P = 8.8 x 10(-11). However, less than half of those patients with hypogammaglobulinaemia suffered from severe or multiple infections. Specific antibodies to pneumococcal capsular polysaccharide were low in 23 patients compared with six of the control group (P = 4.9 x 10(-4)). The majority of patients with severe or multiple infections (13/18) had low levels of both total IgG and specific antibodies to pneumococcal capsular polysaccharide. However, in the groups of patients with less frequent infections, a higher proportion had low serum IgG than low pneumococcal antibody levels. Low levels of pneumococcal antibodies were particularly associated with severe or multiple infections (P = less than 0.00001).


The macrophage response to bacteria. Modulation of macrophage functional activity by peptidoglycan from Moraxella (Branhamella) catarrhalis. Moraxella (Branhamella) catarrhalis organisms have been shown to be particularly efficient in inducing in a pure population of bone marrow-derived mononuclear phagocytes secretory and cellular activities. In the present study, the ability of peptidoglycan from this Gram-negative organism to trigger a macrophage response was compared with that elicited by peptidoglycan from Staphylococcus aureus and Bacillus subtilis. The results show that the three peptidoglycans were similarly active in triggering the secretion of tumour necrosis factor and tumouricidal activity but differed considerably in their ability to induce the generation of nitrite in macrophages; in this respect, peptidoglycan from M. catarrhalis was particularly potent. The impressive capacity of M. catarrhalis peptidoglycan to induce in low concentration the secretion of tumour necrosis factor and nitrite and tumouricidal activity may, in addition to its lipopolysaccharide, contribute to the extraordinary potential of this organism to trigger the functional activities of macrophages.


The pattern of mycobacterial antigen recognition in sera from Mantoux-negative individuals is essentially unaffected by bacille Calmette-Guérin (BCG) vaccination in either south India or London. Paired sera were obtained before and 8 weeks after routine BCG vaccination from 20 PPD-S Mantoux-negative individuals who were living adjacent to the Chingleput BCG vaccine trial area in Tamil Nadu and from seven Mantoux-negative school-children in London, UK. Most subjects became Mantoux-positive after vaccination. In ELISA tests against soluble extracts of BCG or Mycobacterium tuberculosis H37Rv or against PPD-S, pre-vaccination antibody titres of South Indian subjects were about twice those of British subjects but there was no increase in titre of antibodies after vaccination of either population. Western blotting showed that even before vaccination, and even in British subjects, antibodies were present that recognized numerous antigenic components in extracts of BCG and M. tuberculosis. There was no consistent difference between band patterns with South Indian and British subjects and any effect of vaccination on the patterns was minimal.


Ivermectin-facilitated immunity in onchocerciasis. Reversal of lymphocytopenia, cellular anergy and deficient cytokine production after single treatment. A longitudinal investigation has been conducted into the cell-mediated immune responses of onchocerciasis patients after a single-dose treatment with ivermectin. Untreated patients tested for delayed cutaneous hypersensitivity (DCH) to seven recall antigens showed lower responses than infection-free control individuals (P less than 0.01), but 6 and 14 months after treatment DCH reactions increased to similar levels to those seen in the controls. The in vitro cellular reactivity to Onchocerca volvulus-derived antigen (OvAg) was reduced in untreated patients as compared with controls, and the lymphocyte blastogenic responses to OvAg and streptolysin-O clearly improved up to 14 months after treatment. Peripheral blood mononuclear cells (PBMC) from untreated patients produced IL-1 beta, tumour necrosis factor-alpha (TNF-alpha) and IL-6 in response to mitogenic stimulation with phytohaemagglutinin (PHA), only low levels of IL-1 beta, IL-2 and TNF-alpha in response to OvAg, but higher amounts of IL-4 and interferon-gamma (IFN-gamma) in response to OvAg than control individuals. After ivermectin treatment, the OvAg-induced production of IL-1 beta and TNF-alpha increased significantly 1 and 14 months after treatment. The PHA-induced production of IL-2 and IL-4 increased 1 month after treatment and remained significantly elevated until 14 months after treatment, whereas the OvAg-specific secretion of IL-2, IL-4 and IFN-gamma did not change after ivermectin treatment. Flow cytometric analysis of lymphocyte-subsets in the peripheral blood of untreated patients revealed a relative and absolute (P less than 0.01) diminution of CD4+ cells and a significantly smaller CD4+/CD8+ cell ratio as compared with controls. By 4 weeks after treatment and thereafter, CD4+ T cells increased relatively and absolutely (P less than 0.01); likewise there was an absolute increase in T-helper-inducer cells (CD4+CD45RO+) and a temporarily improved CD4+/CD8+ cell ratio (P = 0.001). The expression of the low-affinity receptor for IgE (CD23) on total lymphocytes decreased from 14% to 7% by 14 months after treatment. The CD8+ cells and CD3+TCR gamma delta + cells were higher in patients than in controls and both remained elevated until 14 months after treatment. These results suggest a distinctly improved cellular immunity in human onchocerciasis that was facilitated by ivermectin therapy.


Prevalence of anti-Fab antibodies in patients with autoimmune and infectious diseases. Sensitive ELISA were devised to examine the specificity of circulating IgM and IgA autoantibodies for whole human IgG, Fc and Fab fragments of human IgG. Sera from patients with autoimmune and infectious conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), tuberculosis (TB), infectious mononucleosis (IM) and cystic fibrosis (CF) were studied. Results of the ELISA assays using whole human IgG as antigen revealed that a proportion of patients in each of the groups studied had circulating IgM and IgA rheumatoid factors (RF). Fifteen normal individuals studied were negative. In the latex positive RA group, IgM RF and IgA RF had primarily anti-Fc reactivity (100% and 93% respectively), although 3/15 patients also showed IgM anti-Fab reactivity and one patient had high IgA anti-Fab activity. Patients with SLE and TB who had detectable RF levels also revealed predominantly anti-Fc specificity. In contrast, examination of 25 patients with IM showed positivity for IgM RF activity in 8% of patients using whole IgG as antigen, 24% positivity using purified Fc fragments as antigen and 45% positivity when plates were coated with Fab fragments. Similarly, a large number of CF patients (54%) also showed predominantly IgM anti-Fab activity. Of interest, 69% of the CF patients who were all studied at the time of bacterial infection had detectable IgA RF levels, with 46% of these patients showing both IgA anti-Fc and anti-Fab activity. These findings suggest that autoantibody specificities in autoimmune and infectious diseases are different.


Agalactosyl IgG in pristane-induced arthritis. Pregnancy affects the incidence and severity of arthritis and the glycosylation status of IgG. The effect of pregnancy on the incidence and severity of pristane-induced arthritis was examined along with the glycosylation status of IgG during the ante-natal and post-partum periods. It was found that pristane-induced arthritis is prevented by pregnancy. In addition, the levels of agalactosyl IgG fall during pregnancy but rise to greater than normal within a few days of parturition, before resetting towards the norm shortly afterwards. Interestingly, the level of agalactosyl IgG correlates with the severity of arthritis. As previously reported IL-6 may be an important factor, not necessarily the only one, in the production of agalactosyl IgG. Here it is clearly demonstrated that the kinetics of IL-6 activity post-pristane injection parallels the kinetics of agalactosyl IgG production. In addition, the overshoot in agalactosyl IgG levels immediately post-partum coincides with a burst in IL-6 activity. It is considered that these changes in IgG glycoform levels, or the factors which control them, may be related to the mechanisms underlying prevention/remission of arthritis during pregnancy.


Oestrogen-induced suppression of collagen arthritis; 17 beta-oestradiol is therapeutically active in normal and castrated F1 hybrid mice of both sexes. The F1 hybrid mouse strain, from B10Q and DBA/1 parentals (the QD strain), is highly susceptible to induction of type II collagen-induced arthritis, an experimental model for rheumatoid arthritis. Males are more susceptible than females. Oophorectomy enhances susceptibility to arthritis and treatment with physiological doses of 17 beta-oestradiol (E2) suppresses disease. E2 treatment lowers the incidence of arthritis also in non-castrated and castrated males, showing that the anti-arthritic effect by oestrogen is not dependent on either sex hormone imprinting effects or interference with male sex hormones. Testosterone treatment of normal females, but not of castrated females, exaggerated development of the disease. In the testosterone-treated normal females, the oestrogen effect on vaginal smear was abolished and ovarian weight decreased, suggesting that the testosterone-mediated enhancing effect is caused by inhibition of ovarian oestrogen production. The crucial importance of oestrogens for the development of arthritis is focused on the effectiveness of treatment with gestation-related doses of E2 of normal, non-castrated females.


T cell responses to synthetic TSH receptor peptides in Graves' disease. Twenty-eight peptides, representing the entire extracellular domain of the TSH receptor, were synthesised to investigate which parts of this autoantigen may be targets for the T cell response in Graves' disease (GD). T cells from 11 of 21 controls and 26 of 36 newly diagnosed GD patients proliferated in response to one or more peptides with a stimulation index (SI) of greater than 2.0 (chi 2 = 2.31, P greater than 0.1). The response of patients and controls to any of the individual peptides was also not statistically different. However, individual patients gave high SIs with certain peptides to which controls either gave an absent or very weak response. HLA-DR3 was not associated with any particular response to TSHR peptides. Three out of seven GD patients whose T cells were evaluated before and after treatment showed a response of this kind only early in the course of their disease. Intrathyroidal T cells from four GD patients did not give a consistent proliferative response to pools of five peptides, and depleting peripheral blood T cells of their CD8+ population did not affect the proliferative response. These results indicate that the T cell response to the TSH receptor in GD does not seem to be directed against any one particular epitope on the peptides we have tested which cover the extracellular domain.