Assessment of progressive changes in exercise performance in patients with a systemic right ventricle following the atrial switch repair.

There is a high prevalence of right ventricular dysfunction and reduced exercise performance in survivors of atrial switch repair for transposition of the great arteries. However, it is not known whether the impairment in exercise performance is progressive. We performed paired comparison of exercise performance in 28 patients who underwent two serial incremental exercise tests at an interval of 5.0 +/- 1.4 years between the two tests (age 11.5 +/- 3.7 years at first test, 16.4 +/- 3.6 years at second test). There was no change in the chronotropic response between the two tests. However, there was a reduction in both the peak VO2 (32.5 +/- 8.3 vs 29.6 +/- 5.7 ml/kg/min, p = 0.05) and anerobic threshold (22.1 +/- 5.1 vs 18.3 +/- 4.2 ml/kg/min, p < 0.01) with time. Furthermore, there was a decline in the O2 pulse (oxygen uptake/beat) at anaerobic threshold (% predicted value 95 +/- 23% vs 82 +/- 23%, p =.02), O2 pulse at a heart rate of 140 (% predicted value 100 +/- 30% vs 85 +/- 19%, p = 0.02), and the maximum O2 pulse (z value -0.27 +/- 1.31 vs -1.27 +/- 1.16, p < 0.01) when compared to growth-related normal values. We conclude that there is a progressive reduction in aerobic response to exercise in patients with a systemic right ventricle. The maintenance of chronotropic response suggests that the stroke volume response of the systemic right ventricle during exercise does not increase commensurate with somatic growth.

Myocardial flow reserve in long-term survivors of repair of anomalous left coronary artery from pulmonary artery.

OBJECTIVES: This study sought to evaluate regional myocardial flow reserve in long-term survivors of repair of anomalous left coronary artery from pulmonary artery (ALCAPA) and to relate the flow abnormalities to the patients' exercise performance. BACKGROUND: Patients with ALCAPA usually present during infancy with severe ischemic cardiomyopathy. The left ventricular function recovers after surgical repair. However, the extent of recovery of myocardial blood flow (MBF) and its potential physiologic significance in long-term survivors are unknown. METHODS: We evaluated MBF (ml/g per min) at baseline and during maximal coronary vasodilation by adenosine in 11 patients after ALCAPA repair (median age 17 years, range 7 to 22) using nitrogen-13 ammonia and dynamic positron emission tomographic imaging. Patients also underwent an incremental exercise test with metabolic monitoring. In each patient, MBF was quantified in the three major vascular territories: the left anterior descending and left circumflex coronary artery territories and the right coronary artery (control region) territory. RESULTS: Basal MBF was mildly reduced in the left coronary territories versus the control region (0.79 +/- 0.14 vs. 0.85 +/- 0.19, p = 0.05). During hyperemia, flow in the left coronary territories was significantly lower than that in the control region (2.1 +/- 0.5 vs. 2.6 +/- 0.5, p < 0.001). As a result, myocardial flow reserve was lower in the left coronary territories than in the control region (2.6 +/- 0.7 vs. 3.2 +/- 0.7, p < 0.001). Exercise performance was impaired in patients when compared with age-matched control subjects. Maximal oxygen consumption correlated linearly with maximal hyperemic flows in the left coronary artery territories (r = 0.73, p = 0.03). CONCLUSIONS: Long-term survivors of ALCAPA repair demonstrate regional impairment of myocardial flow reserve. This may contribute to impaired exercise performance by limiting cardiac output reserve.

Determinants of aerobic capacity during exercise following complete repair of tetralogy of Fallot with a transannular patch.

Exercise capacity and the causes of its limitation following repair of tetralogy of Fallot have been studied in heterogeneous populations. Study populations have been grouped together regardless of the type of repair and residual hemodynamic abnormalities. To better understand the factors limiting aerobic exercise capacity in patients repaired with a transannular patch, 37 patients with a transannular patch and no residual pulmonary stenosis underwent resting spirometry and treadmill exercise testing. Maximal oxygen consumption and oxygen consumption at anaerobic threshold were measured in all patients to assess aerobic capacity. Patients were subdivided by gender. Resting spirometry measurements tended to be lower in both genders compared to healthy controls but did not correlate with any measurement of aerobic capacity. Maximal oxygen consumption and anaerobic threshold were significantly less in the female than the male population. A quadratic relation between maximal oxygen consumption and age at exercise testing existed for both genders but peaked at an earlier age and was significantly less in the female population. There was a significant negative correlation between maximal oxygen consumption and echocardiographically estimated right ventricular inflow volume index in the female population only. These data suggest that in patients with tetralogy of Fallot repaired with a transannular patch aerobic capacity is limited primarily by cardiac function, but that gender differences are due to noncardiac causes.

Enhanced resting left ventricular filling in patients with successful coarctation repair and exercise-induced hypertension.

M-mode and Doppler echocardiographic analyses of left ventricular (LV) shortening and filling were performed in 50 patients who underwent coarctectomy (median follow-up 9.5 years) and in 16 athletes in a control group before an exercise stress test with upright bicycle ergometry was performed. Thirty-two of 50 patients and 18 of 50 patients had a normotensive and hypertensive response to exercise, respectively. Preexercise echocardiographic data were compared among the control, normotensive, and hypertensive patient groups. LV peak filling rates (dD/dt, diastole) were increased in the hypertensive group (18.3 +/- 3.5) compared with those in the normotensive group (14.4 +/- 3.2; p < 0.001) and the control group (13.6 +/- 2.8; p < 0.001). LV shortening was enhanced in the coarctectomy group compared with that in the control group. A higher aortic isthmus Doppler gradient at peak exercise was not found in the hypertensive group compared with that in the normotensive group. Therefore patients with successful coarctectomy in childhood have enhanced LV shortening and relaxation at rest. Demonstration of enhanced LV peak filling rates may help identify patients at risk for exercise-induced hypertension.

Exercise capacity and incidence of myocardial perfusion defects after Kawasaki disease in children and adolescents.

OBJECTIVES: This study evaluated exercise performance and myocardial perfusion during exercise in patients with Kawasaki disease who had a broad spectrum of residual coronary abnormalities. BACKGROUND: Reports of exercise performance after Kawasaki disease have generally included a small number of patients evaluated by various protocols, frequently with incomplete data. Myocardial perfusion studies have usually been limited to those using pharmacologically induced coronary vasodilation. Therefore, to our knowledge there has not been a large study directly correlating exercise performance, electrocardiographic (ECG) changes and myocardial perfusion imaging. METHODS: Forty-six patients were classified into three groups on the basis of coronary artery status: group 1 (n = 27) had no objective evidence of coronary artery lesions; group 2 (n = 11) had resolved aneurysms; group 3 (n = 8) had persistent coronary aneurysms. All patients underwent exercise testing with monitoring of ECG changes and oxygen consumption. Single-photon emission computed tomographic imaging was performed at rest and during peak exercise using technetium-99m sestamibi. RESULTS: Maximal oxygen consumption was within normal limits and was similar for all three groups. Five patients had mild ST segment changes at peak exercise. Two of these patients had stress-induced perfusion defects. Myocardial perfusion defects were present in 37% of patients in group 1, 63% in group 2 and 100% in group 3. Perfusion defects corresponded to the coronary artery lesion site in all but three patients. CONCLUSIONS: Maximal oxygen consumption is normal after Kawasaki disease regardless of coronary artery status. Stress-induced perfusion defects are frequent even in the absence of coronary abnormalities and are common in the absence of ST segment changes suggestive of ischemia.

Cardiopulmonary performance at rest and exercise after repair of total anomalous pulmonary venous connection.

Although long-term evaluations of patients after repair of total anomalous pulmonary venous connection have generally shown them to be clinically asymptomatic, assessment of their cardiovascular and pulmonary systems have been limited. Residual cardiopulmonary abnormalities undetected at rest may result in impaired function during exercise. To evaluate this hypothesis 9 patients underwent exercise testing after repair of total anomalous pulmonary venous connection. Pulmonary function testing was performed before exercise. Patients exercised using a 1-minute incremental bicycle or treadmill protocol monitoring heart rate, oxygen consumption, carbon dioxide production and minute ventilation. Compared with healthy children, the study patients had reduced maximal oxygen consumption and reduced oxygen consumption at ventilatory anaerobic threshold. Chronotropic response was impaired in 5 patients. Resting pulmonary functions showed evidence of mild restrictive lung disease. Breathing reserve was within normal limits. It is concluded that (1) aerobic capacity is mildly reduced after repair of total anomalous pulmonary venous connection, (2) chronotropic impairment is a common occurrence, and (3) pulmonary testing suggests mild restrictive lung disease that does not compromise exercise performance.

Carcinomatous meningitis: antibody-guided therapy with I-131 HMFG1.

Seven patients with carcinomatous meningitis were administered intrathecal I-131 labelled monoclonal antibody HMFG1. Clinical responses were seen in two patients, with a long term survivor at 32 months. Aseptic meningitis occurred in 4/7 patients, but more serious toxicity was observed in the form of seizures (2/7 patients) and myelosuppression (3/7 patients). Partial obliteration of the subarachnoid space was identified as a potential problem in patients with advanced disease.

Clinical, pathologic, and microbiologic findings of foot abscess in neonatal pigs.

A longitudinal study was undertaken in a swine herd with an ever-present problem of foot abscess in suckling pigs reared on a woven-wire floor. Of 3,322 4-day-old pigs, 199 (6%) developed abscess lesions involving claws and accessory digits before weaning. Lesions were first detected in 4-day-old pigs; median and mean ages at onset were 10 and 11.3 days, respectively. At first detection, most pigs had only a single claw affected, but 39 pigs had at least 2 claws with abscesses. Hind limbs had more affected claws (140) than forelimbs (96). In the hind limbs, medial claws were most likely to have lesions, whereas the reverse was true for the forelimbs. Gross and microscopic examinations of affected claws indicated necrotic pododermatitis, with severe osteomyelitis, arthritis, and tenosynovitis. Bacteria isolated from foot abscess lesions included Actinomyces pyogenes, Staphylococcus spp, beta-hemolytic Streptococcus spp, Actinobacillus spp, Escherichia coli, Fusobacterium spp, Bacteroides spp, and Peptostreptococcus spp.

HMFG1 antigen: a new marker for carcinomatous meningitis.

Carcinomatous meningitis is a devastating metastatic complication of systemic carcinoma, which may occur insidiously, accompanied by a confusing spectrum of clinical symptoms and signs. In the absence of reliable diagnostic tumour markers, the diagnosis is established by the demonstration of malignant cells within the cerebrospinal fluid (CSF). Cytological techniques requiring skillful interpretation are occasionally negative in the presence of established disease, and when positive may indicate leptomeningeal malignancy of such advanced nature that effective palliation is difficult. Biochemical tumour marker technology offers the potential of reliable diagnosis in early disease states, prior to the appearance of exfoliated malignant cells. In a series of 100 patients, we assayed for an epithelial associated glycoprotein (HMFGI antigen) in CSF obtained at lumbar puncture. In 18 of 20 patients with carcinomatous meningitis, this high-molecular-weight glycoprotein was detectable in the CSF. The antigen was also present in 2 patients with neoplastic meningitis complicating lymphoma and medulloblastoma, but was not detected in the CSF of the remaining 78 patients.

Evaluation of the Minitek system for characterization of Bacillus species.

Minitek (BBL Microbiology Systems, Cockeysville, Md.) substrate disks were evaluated as alternatives to conventional tests for the characterization of Bacillus species. Results were compared for 10 reference isolates and 87 isolates from food sources. The overall agreement of results between the Minitek and conventional tests was 92% for reference strains and 86% for food isolates.

Rapid death of infant rhesus monkeys injected with Clostridium difficile toxins A and B: physiologic and pathologic basis.

Clostridium botulinum can colonize and produce botulinal toxin in the human infant intestine, which the toxin then permeates to cause generalized flaccid paralysis, and occasionally, sudden death. This study was undertaken to test the hypothesis that toxins produced by other intestinal clostridia, e.g., C. difficile, might also cause systemic illness and sometimes death in infants (J Pediatr 100:568, 1982). Because this hypothesis could not be evaluated clinically until the systemic manifestations of C. difficile toxins in primates were known, infant rhesus monkeys were given 6 to 11 micrograms/kg of the recently purified C. difficile toxins A or B, either intravenously or intraperitoneally. The animals showed no abnormalities for several hours, but then developed lethargy, hypotonia, hypothermia, and, shortly before death, sudden elevation of serum concentrations of potassium, magnesium, and phosphorus and of enzymes that derived mainly from skeletal muscle, heart and brain. Five of six animals died quietly 3.5 to 8.0 hours after onset of symptoms. Death appeared to result from cessation of breathing, after which the sinus tachycardia then deteriorated to a flat ECG. Necropsy findings were insufficient to explain the cause of death. It appears that in infant monkeys microgram amounts of C. difficile toxins A and B can produce a rapid quiet death, the cause of which is undetectable at necropsy, a situation pathologically reminiscent of crib death in human infants, although the possible clinical identity of these two conditions has yet to be established.

Enzyme-linked immunosorbent assay for Clostridium difficile toxin A.

Antibodies against Clostridium difficile toxin A were purified by affinity chromatography from antiserum prepared against crude C. difficile toxin preparations. The affinity-purified antibody preparation was free of detectable amounts of antibodies to other C. difficile antigens, as demonstrated by crossed immunoelectrophoresis, and specifically neutralized the cytotoxicity of toxin A. An indirect enzyme-linked immunosorbent assay (ELISA) was subsequently developed using the antibody preparation for the specific detection of toxin A. The ELISA, which could detect 1 ng (5 ng/ml) of toxin A, was used to quantitate the toxin in the culture supernatant fluids of strains of C. difficile. The ELISA values for toxin A closely correlated with the toxin A and B cytotoxic titers of the supernatant fluids. In addition, toxin A was detected by ELISA in human fecal specimens from persons with antibiotic-associated colitis, demonstrating that this toxin is produced during C. difficile colitis.

Investigation of an outbreak of antibiotic-associated colitis by various typing methods.

During an outbreak of diarrheal disease due to Clostridium difficile in a surgical ward, 16 C. difficile isolates were cultured from fecal samples of 15 patients. Agarose gel electrophoresis for the detection of plasmid DNA, crossed immunoelectrophoresis for the detection of extracellular antigens and toxins, polyacrylamide gel electrophoresis for analyses of soluble proteins, assays for cytotoxicity, and a comparison of susceptibility to antimicrobial agents were employed. At least 12 of the 16 isolates were shown to be phenotypically the same strain. These findings suggest that in a hospital setting, diarrhea and pseudomembranous colitis caused by C. difficile can be of nosocomial origin and that they can spread from patient to patient.

Purification and characterization of toxins A and B of Clostridium difficile.

Toxin preparations were obtained by growing Clostridium difficile VPI strain 10463 in 2-liter brain heart infusion dialysis flasks at 37 degrees C for 3 days. The initial step of the purification scheme involved ultrafiltration through an XM-100 membrane filter. Two toxic activities, designated toxins A and B, were separated by ion-exchange chromatography on DEAE-NaCl gradients. Toxin A was purified to homogeneity by an acetic acid precipitation at pH 5.5. Other separation techniques, including CM Sepharose CL-6B, (NH4)2SO4 and acetic acid precipitations, and hydrophobic interaction chromatography, were examined in attempts to further purify toxin B. Although these methods failed to increase the specific activity of toxin B, they provided additional evidence that the two toxins are distinct molecules. The toxins are acid and heat labile and are inactivated by trypsin and chymotrypsin, but not by amylase. The molecular weight of toxin A, as estimated by gel filtration and gradient polyacrylamide electrophoresis, ranged from 440,000 to 500,000. The estimated molecular weight of toxin B was 360,000 to 470,000.

Inactivation of cephalosporins by Bacteroides.

We investigated the relationship between beta-lactamases of Bacteroides fragilis organisms and their resistance to cephalosporins. Timed killing curves were used to study the in vitro activity of three cephalosporins, cephalothin, cefazolin, and cefamandole, and a semisynthetic cephamycin, cefoxitin. Measurements of residual antibiotic concentrations in culture supernatants were made, and they were compared with the beta-lactamase activity of the microorganism. A cephalosporin-susceptible strain was rapidly killed by cephalothin, cefazolin, cefamandole, and cefoxitin. Four cephalosporin-resistant strains were not killed by cephalothin, cefazolin, or cefamandole but were killed by cefoxitin. An inoculum effect was noted with cefazolin and not with cefoxitin. The resistant strains of Bacteroides inactivated the three cephalosporins, but there was no inactivation of cefoxitin. A constitutive beta-lactamase was detected in all the isolates of the B. fragilis group that were resistant to the cephalosporins. There was no distinction of the species based on isoelectric focusing of the enzyme. These data suggest that inactivation by beta-lactamase may be the mechanism for resistance of B. fragilis to the cephalosporins and would explain the enhanced in vitro activity of cefoxitin.

Argon detector: alternative detection system for gas-liquid chromatographic analysis of short-chain organic acids.

Two detection systems for gas-liquid chromatography were compared for the identification of metabolic end products (short-chain organic acids) from anaerobic bacteria. Argon and flame ionization detectors were connected in series with inert argon as the carrier gas for analysis of 35 stock strains and 148 clinical isolates. There was an excellent correlation between the argon and flame ionization chromatograms, and both were readily comparable to the thermal conductivity detector tracings published in the Virginia Polytechnic Institute manual. The linear response of the argon detector was examined by analyzing twofold serial dilutions of the short-chain organic acids and comparing the results to the very linear flame ionization detector. The argon detector was found to react with sufficient linearity within the organic acid concentration range normally obtained from anaerobic bacterial broth cultures. The argon detector, therefore, appears to be a viable alternative to the flame ionization and thermal conductivity detector systems in the identification of anaerobic organisms.

Practical aerobic membrane filtration blood culture technique: development of procedure.

The advantages of a membrane filter system for blood culturing have been realized for many years. Lysing of the blood prior to filtration is a convenient way to proceed, but previously described lysing procedures result in loss of certain organisms, particularly gram-negative bacilli. Four concentrations of Triton X-100 and sodium carbonate were studied in vitro, and their lysing and antibacterial properties were observed. A solution of 0.08% Na2CO3 and 0.005% Triton X-100 was found to have the least antibacterial effect and gave consistently good lysis and filtration times (under 3 min). An 8.3-ml amount of blood added to 190 ml of this concentration of lysing solution, filtered through three 47-mm membrane filters (0.45-mum pore size), led to recovery of 85% or more of various aerobic and facultative organisms in studies of artificially seeded blood.