Treatment of acute lymphoblastic leukemia in childreq with "prophylactic" intrathecal methotrexate and intensive systemic chemotherapy.

Sventy-five children under the age of 15 years, with acute lymphoblastic leukemia, were treated with a multiple drug chemotherapy regimen (L-2) and intrathecal methodtrexate. Remission was achieved in all except 1. Three died from infection early in remission and 1 was lost to follow-up. Of the remaining 70, relapse occurred in 19; in 3 children this was confined to the central nervous system (CNS) and in 1 was in both the CNS and bone marrow. Fifty-one children continue in complete remission from 14 to 54 months. Fourteen of these children have completed 3 years of chemotherapy and are disease free 2 to 18 months posttreatment. The results indicate that periodic administration on intrathecal methotrexate with no CNA irradiation, plus intensive systemic chemotherapy, can effectively control CNA leukemia and prolong the duration of complete remissions.

Effects of adenine nucleotide translocase inhibitors on dinitrophenol-induced Ca2+ efflux from pig heart mitochondria.

Bongkrekic acid and atractyloside, inhibitors of adenine nucleotide translocase, do not inhibit Ca2+ uptake and H+ production by pig heart mitochondria. However, bongkrekic acid, but not atractyloside, inhibits dinitrophenol-induced Ca2+ efflux and H+ uptake. Conversely, ruthenium red blocks Ca2+ uptake and H+ production but does not prevent dinitrophenol-induced Ca2+ efflux and H+ uptake by mitochondria. These results suggest that mitochondrial Ca2+ uptake and release exist as two independent pathways. The efflux of Ca2+ from mitochondria is mediated by a bongkrekic acid sensitive component which is apparently not identical to the ruthenium red sensitive Ca2+ uptake carrier.

Electrophysiology of atropine.

The effect of atropine on the refractory periods of the human atrium, A-V node, and His-Purkinje system was studied. The A-V node in man appears more sensitive to atropine than the atria as evidenced by a reduction in the effective and functional refractory periods of the A-V node without alteration of atrial conduction. Although atropine does not directly alter the refractory periods of the His-Purkinje system, atropine-induced facilitation of A-V nodal conduction results in block of premature atrial impulses in the His-Purkinje system, demonstrating an indirect effect of atropine on His-Purkinje conduction. Rarely, atropine may precipitate re-entrant atrial tachycardia (one patient) through facilitation of A-V nodal conduction.

Electrophysiological significance of rapid atrial pacing as a test of atrioventricular conduction.

Although rapid atrial pacing is frequently used as a test of atrioventricular conduction, no studies have compared this method with other conduction parameters. The purpose of this study was to compare the results of rapid atrial pacing with refractory period measurements utilizing the extrastimulus technique. Determination of the refractory periods of the atrium, A-V node, and His-Purkinje system were accomplished in 41 patients undergoing diagnostic cardiac catheterization, and the results compared with rapid atrial pacing to the point at which A-V Wenckebach occurred (WP). The results showed significant correlation (P less than 0.01) between the WP and functional refractory period (FRP) of the A-V node (r=0.89, FRP=865-2.6 WP), and significant correlation between the WP and the effective refractory period (ERP) of the total A-V conducting system(r=0.81, ERP=729-2.6 WP). The relationship between WP and the refractory periods also allowed prediction of the occurrence of physiological His-Purkinje block during introduction of premature atrial contractions and the site of the effective refractory period of the total A-V conducting system. This study establishes a close relationship between these methods and confirms the usefulness of rapid atrial pacing as a reliable test of A-V conduction in man.

Divalent cation-activated ATP hydrolysis by mitochondrial ATP'ase--mechanism for energy depletion in ischemic reperfused myocardium.

Recovery of high-energy compounds by ischemic myocardium is believed to be important for its return to normal functioning. While it has been previously shown that oxidative phosphorylation is markedly reduced in mitochondria isolated from ischemic myocardium in the presence of all substrates, alterations in ATPase activity have not been confirmed. This study demonstrates that, although the rate of ATP hydrolysis produced by mitochondria isolated from 2-hr ischemic myocardium does not significantly differ from that produced by non-ischemic mitochondria, the rate produced by 2-hr ischemic, 2 hr reperfused mitochondria is significantly higher. Also, Ca++ content was observed to be higher in reperfused than in non-reperfused ischemic mitochondria. The addition of EDTA, EGTA, or oligomycin to the reperfused ischemic mitochondria resulted in the inhibition of ATPase activity. These results indicate that mitochondrial ATPase in ischemic myocardium is activated by Ca++ ions and that ischemic reperfused myocardium may contain mitochondria with uncontrolled ATPase activity such that high energy phosphate supplies are excessively depleted when the cells are reperfused.

The relationship of paroxysmal ventricular tachycardia complicating the acute phase and ventricular arrhythmia during the late hospital phase of myocardial infarction to long-term survival.

The long-term prognosis of paroxysmal ventricular tachycardia (PVT) complicating acute myocardial infarction remains unevaluated. Significant ventricular arrhythmia in the patient after infarction is said to carry a poor prognosis with regard to survival. To evaluate these two important aspects of myocardial infarction in man, 56 patients with documented myocardial infarction had Holter monitoring performed during the initial 24 hours and prior to hospital discharge. In 38 of the 45 survivors, Holter monitoring was repeated an average of 19 months after infarction. There were eight cardiac deaths during follow-up. Data analysis revealed that of 18 patients with PVT during the acute phase, one died during follow-up and 17 survived long-term. Even though the incidence of complex PVCs prior to hospital discharge and at long-term follow-up was higher in patients with PVT during the acute phase than in those without PVT, survival appeared unaffected. Thus, PVT during the acute phase of myocardial infarction and complex PVCs at the time of hospital discharge are not incompatible with long-term survival.

The relation of sinus rate to the frequency of paroxysmal ventricular tachycardia during acute myocardial infarction in man.

Continuous tape recordings of cardiac rhythm were made in 51 male patients with acute myocardial infarction within 24 hours of their infarction. These tracings were analyzed for the incidence of paroxysmal ventricular tachycardia (PVT) and the sinus rate immediately preceding each episode of PVT. In 26 patients, 112 episodes of PVT at a rate greater than 100 beats/min were documented. Although 67 per cent of the episodes of PVT were preceded by sinus rates between 60 and 100 beats/min, 15 per cent occurred at sinus rates below 60 beats/min and 18 per cent occurred at sinus rates above 100 beats/min. The data remained essentially unchanged regardless of whether ventricular tachycardia was defined at rates in excess of 100, 120 or 140 beats/min. The results of this study show that during the early phases of acute myocardial infarction in man, PVT was most common during sinus rates generally thought to be within the normal range (60 to 100 beats/min). A lower, but close to equal incidence of PVT was observed during sinus bradycardia and sinus tachycardia.

Outcomes after judicious antibiotic use for respiratory tract infections seen in a private pediatric practice.

BACKGROUND: Most respiratory tract infections (RTIs) in children have a viral cause, they resolve on their own, and antibiotics need not be prescribed. OBJECTIVE: We sought to provide evidence that judicious antibiotic use can be accomplished in private pediatric practice without observing an increase in return office visits or in the rate of bacterial infections that may follow. STUDY DESIGN: This was a prospective 12-month study from July 1, 1996 through June 30, 1997. On the same 1 day each week, a representative convenience sample of acute respiratory tract illness patients was enrolled, and laboratory studies performed as appropriate, including viral cultures on all. Children were then followed for 30 days to ascertain the outcomes of not prescribing antibiotics except when specific bacterial infections were present at the initial visit. RESULTS: Three hundred eighty-three children were enrolled; 293 (77%) did not receive antibiotics at the enrollment visit. Ninety children (23%) received antibiotics based on a diagnosis of acute otitis media (n = 53), acute streptococcal tonsillopharyngitis (n = 18), or other presumed or documented bacterial infections (n = 19). An unscheduled return visit related to the initial visit occurred for 86 (29%) of the 293 children not receiving antibiotics initially and in 40 (44%) of 90 children receiving antibiotics initially. Eighty-seven children (23%) had positive viral culture results. The most frequently isolated viruses were adenovirus, enterovirus, parainfluenzae virus, and influenza virus. CONCLUSION: Children with RTIs without a concomitant presumed or proven bacterial infection do not require antibiotics. In this busy office practice, >75% of the children presenting with an RTI did not have a presumed or proven bacterial infection. These children did not have a higher rate of return office visits or an increase in bacterial infections. This reinforces the judicious use of antibiotics in managing children with RTIs.outcomes, antibiotic, respiratory infections.

Localization of foot-and-mouth disease virus RNA by in situ hybridization within bovine tissues.

Foot-and-mouth disease is a highly contagious disease of cloven hooved animals. In cattle, both acute and long-term persistent infections occur. Foot-and-mouth disease virus (FMDV), a picornavirus, has been shown, using virus isolation procedures, to replicate in the pharynx and soft palate of cattle. In this study, in situ hybridization has been used to detect FMDV RNA within the cells of tissues removed from infected bovines. A digoxigenin-labelled anti-sense RNA probe was prepared corresponding to a region of the FMDV genome encoding part of the RNA-dependent RNA polymerase (3D). The efficacy and specificity of this probe for in situ hybridisation was determined using virus-infected cells in tissue culture. Strong cytoplasmic staining was only detected in FMDV-infected cells. Various tissue samples were collected from FMDV-infected cattle between 5 and 17 days post-infection. Viral RNA was detected by in situ hybridisation within cells of the soft palate, tonsil and pharynx up to 17 days post-infection. This technique is useful for the study of FMDV localization in cattle both during and after the acute clinical phase of disease and may assist in identifying specific sites of virus persistence.

Ventricular performance and biochemical alteration of regional ischemic myocardium after reperfusion in the pig.

Reperfusion of acutely ischemic myocardium may cause profound alterations in left ventricular wall performance and metabolism. This study evaluates regional left ventricular wall thickness, analyzes metabolic and biochemical alterations, and examines tissue hemorrhage during 15, 30, and 120 minutes of myocardial ischemia, each followed by 120 minutes of reperfusion. Reperfusion after 15 minutes of ischemia showed nearly normal ventricular wall thickening and motion, intact metabolic and biochemical function, and no tissue hemorrhage. However, reperfusion after 30 and 120 minutes of ischemia was associated with ventricular wall thickening and failure to resume systolic and diastolic wall motion. Furthermore, adverse metabolic and biochemical alterations and reperfusion zone hemorrhaging increased proportionally with the duration of ischemia. These findings suggest critical myocardial damage occurring between 15 and 30 minutes of ischemia in an animal model without preexisting coronary collateral circulation. The observed metabolic and biochemical changes are consistent with irreversible cell membrane defects, allowing calcium ion accumulation and thus adversely affecting diastolic relaxation and systolic thickening.

Left atrial abnormality as an electrocardiographic criterion for the diagnosis of left ventricular hypertrophy in the presence of right bundle branch block.

Left atrial (LA) abnormality determined from precordial lead V1 was assessed by 2 observers as a criterion of left ventricular (LV) hypertrophy in the presence of right bundle branch block (BBB) in 23 patients. The presence of LV hypertrophy was confirmed from a postmortem cardiac partition technique and defined at 2 levels of confidence: probable and definite hypertrophy. Observers reliably differentiated between the hypertrophied and normal-sized ventricle in the presence of right BBB by using LA abnormality as an electrocardiographic criterion. When defined as definite hypertrophy, observer 1 correctly identified LV hypertrophy in 78% of the cases and observer 2 in 67% of the cases. False-positive results were present in 21% of cases by observer 1 and 14% by observer 2. Comparable results were achieved when a definition of probable hypertrophy was used. Observer performance of recognition of LA abnormality in this study was satisfactory with 91% agreement between observers. Our results are comparable and in some instances superior to conventional criteria commonly recommended to diagnose LV hypertrophy on the electrocardiogram without right BBB.

Efficacy of propafenone compared with quinidine in chronic ventricular arrhythmias.

A double-blind, randomized study was designed to evaluate the efficacy of oral propafenone and oral quinidine in suppressing premature ventricular complexes (PVCs). Twenty-five men were studied for 3 weeks. Twelve were randomized to the quinidine group and 13 to the propafenone group. Small doses of the drugs were administered for 1 week (200 mg of quinidine every 6 hours or 300 mg of propafenone every 12 hours) and large doses were administered for another week (400 mg of quinidine every 6 hours or 300 mg of propafenone every 8 hours). Strict criteria were used to define responders to antiarrhythmic therapy. For more than 85% reduction in total PVCs per hour: During the low-dose week, 36% in the quinidine group and 50% in the propafenone group were responders (difference not significant [NS]), while during the high-dose week 33% and 64% were responders (NS). For more than 95% reduction of ventricular couplets per hour: During the low-dose week, 45% in each group were responders, while during the high-dose week, 56% and 60% were responders (NS). For 100% abolition of ventricular tachycardia (VT) beats per 24 hours: During the low-dose week, 60% in the quinidine group and 56% in the propafenone group were responders (NS); during the high-dose week 80% and 67% were responders (NS). There was no significant difference in the 2 groups in incidence of side effects. This study shows comparable efficacy and tolerance of propafenone and quinidine for the control of ventricular arrhythmias in ambulatory patients with diverse forms of heart diseases.

Five-year effect of medical and surgical therapy on resting left ventricular function in stable angina: Veterans Administration Cooperative Study.

The effect of coronary artery bypass grafting (CABG) and medical therapy on 5-year resting left ventricular (LV) function was studied in 194 randomized patients with stable angina in the Veterans Administration Study of Coronary Artery Bypass Surgery. LV ejection fraction (EF) was determined in a central laboratory. The 92 medical and 102 surgical patients were comparable at entry with respect to historic, angiographic and electrocardiographic prognostic indicators. Twenty-eight percent of the medical and 30% of the surgical patients had a baseline EF of less than 50%. There was no significant change in mean EF between baseline and 5-year values in either treatment group. The baseline and 5-year values were 56 and 58% in each treatment group. Intervening myocardial infarction (MI) had an adverse effect in medically treated patients (59 to 46%, p less than 0.01) and in surgically treated patients with late MI (58 to 47%, difference not significant). Perioperative MI was not associated with a decrease in EF (56 to 58%, difference not significant). These findings extend the similar results of previous short-term studies of the effect of coronary bypass surgery on resting LV function to 5 years, and provide data in a comparable medical control group.

QRS voltage measurements in autopsied men free of cardiopulmonary disease: a basis for evaluating total QRS voltage as an index of left ventricular hypertrophy.

Use of total 12-lead QRS electrocardiographic voltage as a criterion for left ventricular (LV) hypertrophy has been of recent interest. Although upper and lower limits of QRS voltage for individual electrocardiographic leads have been reported in clinically healthy men and women, the upper limit of total 12-lead QRS voltage has not been established in adults free of cardiopulmonary disease by clinical and necropsy criteria. Therefore, the total QRS voltage from all 12 electrocardiographic leads was determined in 30 autopsied men known to be free of cardiopulmonary disease by clinical assessment and by a special cardiac examination using postmortem coronary angiography and chamber partition determination of LV weight. Gross heart weight, LV weight and total QRS voltage are reported. Comparisons were made between disease-free patients and previously reported patients with aortic valve stenosis, aortic regurgitation and cardiac amyloidosis with respect to total QRS voltage and gross heart weight. Total QRS voltage and gross heart weight were significantly greater in patients with severe aortic stenosis (mean 245 mm) and severe aortic regurgitation (mean 274 mm) than in our patients (mean 127 mm). Total QRS voltage was significantly less, whereas gross heart weight was significantly greater in patients with cardiac amyloidosis (mean 101 mm) than in our normal subjects (mean 127 mm). These data provide a basis for evaluating the total 12-lead QRS voltage as a criterion for LV hypertrophy.

Altered refractory periods in patients with short P-R intervals and normal QRS complex.

To evaluate the refractory periods of the atrioventricular (A-V) conducting system in patients with a short P-R interval and normal QRS complex, 57 patients with a P-R interval of 110 to 280 msec were studied with His bundle recording and premature atrial stimulation at similar cycle lengths of 660 to 720 msec. In 13 patients with a short P-R interval (120 msec or less) the mean value for the functional refractory period of the A-V node was 368 plus or minus 36 msec (standard deviation), which was significantly lower (P smaller than 0.01) than the mean value of 415 plus or minus 50 msec in 36 patients with a normal P-R interval (between 120 and 200 msec) and the mean value of 492 plus or minus 57 msec in 8 patients with an increased P-R interval (200 msec or greater). Patients with a short P-R interval had a mean value for the effective refractory period of the A-V conducting system of 247 plus or minus 26 msec, which was significantly lower (P smaller than 0.01) than the mean values of 297 plus or minus 51 msec in patients with a normal P-R interval and 369 plus or minus 87 msec in patients with an increased P-R interval. The results identify a characteristic conduction abnormality that is compatible with a partial A-V nodal bypass or dual A-V nodal conduction pathways. The relation between the duration of the P-R interval and the regractory period may aid understanding of the clinical significance of the scalar electrocardiogram.

Effect of propafenone on left ventricular ejection fraction.

The effects of orally administered propafenone on ejection fraction (EF) determined by radionuclide angiography were studied in 2 groups of patients receiving different dosing regimens. Fourteen group A patients had no clinical evidence of left ventricular (LV) dysfunction and were not receiving digoxin therapy. In this group a mean daily dosage of 879 mg resulted in a decrease in resting LVEF from 52 +/- 9% to 48 +/- 11% (p less than 0.05). Eight group B patients had clinical radionuclide evidence of LV dysfunction and were receiving digoxin therapy. In this group, a daily dosage of propafenone of 600 mg/day resulted in no significant change in LVEF. No clinically significant effects on cardiac compensation were evident in either group. These data suggest a negative inotropic effect that is either related to propafenone dosage or at least partially attenuated by digoxin therapy. Further studies are necessary to define precisely the effects of propafenone on LV function.

Digoxin-quinidine interaction. Changes in canine tissue concentration from steady state with quinidine.

Tissue concentrations of tritiated digoxin inthe dog are altered by simultaneous administration of quinidine. Serum levels rise as tissue concentration decreases significantly in all tissue except brain tissue, where an increase of 51 percent is noted over that of the control digitalized state. The digitalis toxicity associated with digoxin-quinidine interaction appears to be associated with rising brain levels of digoxin and falling levels in the myocardium. These findings suggest a neurally mediated form of toxicity with this interaction related to a change in the space of distribution. The question of possible loss of inotropic effect associated with diminished myocardial digoxin concentration requires further study.

Descriptive characteristics of the electrocardiogram from autopsied men free of cardiopulmonary disease--a basis for evaluating criteria for ventricular hypertrophy.

Most measurements establishing standard values for the normal electrocardiogram have been derived from a healthy population, whereas many electrocardiographic interpretations are necessary in hospitalized or seriously ill patients. Therefore, the characteristics of the electrocardiogram were described from 48 autopsied men known to be free of cardiopulmonary disease by clinical assessment and by a special cardiac examination using postmortem coronary angiography and a chamber partition technique. Highest values, mean and standard deviation, and the upper 97.5 percentile or lower 2.5 percentile when appropriate were noted for QRS voltage, QRS axis and duration, and intrinsicoid deflection in V5 or V6. Any ST-segment and T-wave changes were noted as well as left and right atrial abnormalities. Twenty-eight electrocardiographic criteria recommended to detect left ventricular hypertrophy and 10 recommended to detect right ventricular hypertrophy were evaluated for percentage of false-positive results and the 97.5 percentile value for each criterion was developed from the present data base. The data in this study can be used as a standard for comparing electrocardiographic variation in middle-aged men with specific relevance for electrocardiographic criteria of ventricular hypertrophy.

Sensitivity of electrocardiographic criteria for left ventricular hypertrophy according to type of cardiac disease.

The sensitivity of 30 electrocardiographic criteria for left ventricular (LV) hypertrophy, isolated or combined, was examined to determine the relation to the underlying disease. Patients with coronary artery disease (CAD), systemic hypertension, valvular heart disease and cardiomyopathy were evaluated. A cardiac partition technique was used to define ventricular hypertrophy. Single electrocardiographic criteria often showed high sensitivity for 1 disease state, but not for others. Precordial voltage criteria were most sensitive for those with hypertensive and valvular disease. A QRS axis of more than -30 degrees occurred most often in patients with CAD. Both left atrial abnormality and abnormal T-wave inversion of more than 1 mm in V6 occurred with a high sensitivity in general; however, T-wave inversion of more than 1 mm in V6 had a low sensitivity in cardiomyopathy. Methods using combinations of various electrocardiographic criteria improved sensitivity. Using these methods, sensitivity of the electrocardiogram for LV hypertrophy was excellent for patients with systemic hypertension and valvular heart disease and acceptable by usual standards for patients with CAD and cardiomyopathy. Because the use of a single criterion is often ineffective, methods using multiple electrocardiographic criteria to detect LV hypertrophy are recommended when the patients under study have diverse cardiac diseases.

Reevaluation of electrocardiographic criteria for left, right and combined cardiac ventricular hypertrophy.

Cardiac chamber weight was determined at necropsy in 323 men to develop correlative studies of electrocardiographic criteria for ventricular hypertrophy. Thirty recommended criteria for left ventricular (LV) hypertrophy, 10 for right ventricular (RV) hypertrophy, and combinations of both criteria for combined hypertrophy were evaluated. Four methods for electrocardiographic diagnosis of LV hypertrophy were derived: (1) a modification of the Romhilt-Estes point system; (2) the presence of any 1 of 3 criteria: (a) S V1 + R V5 or V6 greater than 35 mm, (b) left atrial abnormality, or (c) intrinsicoid deflection in lead V5 or V6 greater than or equal to 0.05 second; (3) a combination of any 2 criteria or of 1 criterion (above) plus at least 1 of the following 3 additional criteria: (a) left-axis deviation greater than -30 degrees, (b) QRS duration greater than 0.09 second, or (c) T-wave inversion in lead V6 of 1 mm or more; and (4) the use of a single criterion--left atrial abnormality. Sensitivity varied from 57 to 66% and specificity from 85 to 93% among these 4 methods. Myocardial infarction increased sensitivity of the foregoing methods, but the specificity was reduced. Method 2 is preferred for the electrocardiographic diagnosis of LV hypertrophy. Two methods were useful for right ventricular (RV) hypertrophy: (1) the use of any 1 of 4 criteria: (a) R/S ratio in lead V5 or V6 less than or equal to 1; (b) S V5 or V6 greater than or equal to 7 mm; (c) right-axis deviation of more than +90 degrees, or (d) P pulmonale; and (2) use of any 2 combinations of the foregoing criteria. Sensitivity ranged from 18 to 43% and specificity from 83 to 95%. Combined hypertrophy was best diagnosed using left atrial abnormality as the sole criteria of LV hypertrophy, plus any 1 of 3 criteria of RV hypertrophy: (a) R/S ratio in lead V5 or V6 less than or equal to 1, (b) S V5 or V6 greater than or equal to 7 mm, or (c) right axis deviation greater than +90 degrees.(ABSTRACT TRUNCATED AT 250 WORDS)