Chaim Springer

Clinical and Genetic Risk Factors for Cystic Fibrosis-related Liver Disease

Objective. The aim of this study was to define the role of possible risk factors for the development of cystic fibrosis (CF)-related liver disease and to analyze the association between liver disease and the different genotypes present in the Israeli CF patient population. Patients and Methods. All patients followed at the seven CF centers in Israel were included in this study. Liver disease was determined by persistently elevated serum liver enzymes and/or bilirubin, and/or significant ultrasonographic changes suggestive of chronic liver disease. The following clinical parameters were evaluated: ethnic origin, age at assessment of liver function, sex, history of meconium ileus, pancreatic function, history of distal intestinal obstruction syndrome, pulmonary function, and cystic fibrosis transmembrane conductance regulator mutation analysis. Results. Of the 288 patients screened, 80 (28%) had liver disease. Of the 256 patients with pancreatic insufficiency, 80 (31%) had liver disease compared with none of the 32 patients with pancreatic sufficiency. Genotype-phenotype correlation was performed on 207 patients carrying identified mutations that were previously classified according to phenotype severity. Liver disease was found in 56 (32%) of 173 patients carrying mutations associated with a severe phenotype and in 6 (38%) of 16 patients carrying at least one mutation associated with a variable genotype (G85E and/or 5T allele). None of the 18 patients carrying the 3849+10kb C->T mutation had liver disease. Prevalence of liver disease increased with age. No correlation was found between liver disease and severity of lung disease, nutritional status, history of meconium ileus, or distal intestinal obstruction syndrome. Conclusion. CF patients who have pancreatic insufficiency and carry mutations associated with a severe or a variable genotype are at increased risk to develop liver disease.

Oxygen uptake and heart rate responses during hypoxic exercise in children and adults

Control of ventilation and heart rate during exercise appears to undergo maturation, while aerobic metabolism (VO2) may not. Since we had previously found that hypoxia during exercise produced different ventilatory responses in children (C) compared to adults (A), we hypothesized that VO2 and heart rate kinetics during exercise would show similar maturational responses to hypoxia. To test this hypothesis, we examined the responses during progressive (ramp) and constant work rate tests in children and adults breathing either room air or hypoxic gas (FiO2 = 0.15). When corrected for body weight, children and adults had similar values for lactic acidosis threshold (LAT) (C: 29.1 +/- 5.0 ml.min-1.kg-1; A: 27.9 +/- 4.3) and VO2max (C: 40.7 +/- 8.6 ml.min-1.kg-1; A: 45.2 +/- 6.7) during normoxia. Hypoxia significantly lowered LAT (C: 27.5 +/- 5.4 ml.min-1.kg-1; A: 23.2 +/- 3.8; both P less than 0.05) and VO2max (C: 37.7 +/- 8.3 ml.min-1.kg-1; A: 40.1 +/- 5.3; both P less than 0.05) in both children and adults. Metabolic efficiency (delta VO2/delta work rate) and the VO2-heart rate relationship (delta VO2/delta HR/kg) were similar in the two groups and unaffected by hypoxia. During the constant work rate exercise, VO2 kinetics (time constant during phase 2 of the response (pi 1) and the O2 deficit) were similar between children and adults and were significantly slowed by hypoxia, consistent with current understanding of the control of oxidative metabolism. Finally, heart rate was increased at rest and during exercise with hypoxia, while the time to reach 75% of the end-exercise response was delayed significantly, in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino-Terminal Pro-Brain-Type Natriuretic Peptide: Heart or Lung Disease in Pediatric Respiratory Distress?

Objectives. The aim of this study was to determine whether plasma levels of amino-terminal pro-brain natriuretic peptide (N-BNP) could differentiate between heart failure and lung disease among infants with acute respiratory distress. In addition, our aim was to determine whether plasma levels of N-BNP could be used to monitor the effects of treatment among infants with heart failure. Methods. Infants (age range: 1–36 months; median age: 10 months) who presented with respiratory distress underwent physical examination, plasma N-BNP measurement, and echocardiography within 24 hours after admission. Seventeen infants were finally diagnosed with acute heart failure and 18 with acute lung disease. Thirteen healthy infants served as a control group. Results. Plasma N-BNP levels were significantly higher for the infants with heart failure (median: 18452 pg/mL; range: 5375–99700 pg/mL) than for the infants with lung disease (median: 311 pg/mL; range: 76–1341 pg/mL). Among the infants with heart failure, there was a significant difference in plasma N-BNP levels before and after congestive heart failure treatment. Conclusion. Among infants with respiratory distress, plasma N-BNP measurements can differentiate between acute heart failure and lung disease and can be used to monitor the effects of treatment for infants with heart failure.

Are obese children truly unfit? minimizing the confounding effect of body size on the exercise response

To test the hypothesis that obese children are unfit (i.e., have abnormal responses to exercise testing consistent with reduced levels of habitual physical activity), we used new analytic strategies in studies of 18 obese children performing cycle ergometry. The subjects weight (mean +/- SD) was 168 +/- 24% that predicted by height, and the age range was 9 to 17 years. Size-independent measures of exercise (e.g., the ratio of oxygen uptake (VO2) to work rate during progressive exercise and the temporal response of VO2, carbon dioxide output (VCO2), and minute ventilation (VE) at the onset of exercise) were used. The ability to perform external mechanical work was corrected for VO2 at unloaded pedaling (change in maximum oxygen uptake (delta VO2max) and in anaerobic threshold (delta AT). On average, obese childrens responses were in the normal range: delta VO2max, 104 +/- 41% (+/- SD) predicted (by age); delta AT, 85 +/- 51%; ratio of change in VE to change in VCO2, 111 +/- 21% and ratio of change in VO2 to change in work rate, 100 +/- 24%, but six of the obese children had values of delta VO2max or delta AT that were more than 2 SD below normal. In addition, obese children did not have increased delta VO2max or delta AT with age as observed in nonobese children. Although the response time of VO2 was normal (99 +/- 32% of predicted), those for both VCO2 and VE were prolonged. We conclude that the finding of obesity in a child is not a reliable indicator of poor fitness but that testing cardiorespiratory responses to exercise can be used to identify subjects with serious impairment and to individualize therapy.

Doxapram in the treatment of idiopathic apnea of prematurity unresponsive to aminophylline

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Natural history of five children with surfactant protein C mutations and interstitial lung disease

Interstitial lung diseases in infants and children are uncommon and may be caused by specific inborn errors of surfactant metabolism. Five children with open lung biopsy diagnosed interstitial lung disease were followed (mean of 27.2 years) and evaluated for surfactant protein gene mutations. Four of the children were originally diagnosed as desquamative interstitial pneumonitis and one as chronic interstitial pneumonitis. All had good response to chloroquine or hydroxychloroquine treatment for periods of 7–38 months. Lung function tests, incremental exercise tests, and rentgenological studies were performed in the children. Surfactant protein gene mutations were searched in all the patients and in part of their families.

Effect of hypoxia on ventilatory control during exercise in children and adults.

ABSTRACT: Little is known about maturation of peripheral chemoreceptor tone (PCT) during growth. We recently demonstrated that the increase in PCT was 49% greater during hypoxic (15% O2) exercise in children compared to adults. As the PCT is a major determinant of ventilatory (VE) response at the onset of exercise (measured by the time constant γ), we hypothesized that hypoxia would affect γVE (and γVCO2) to a greater extent in children. Nine healthy children (6-10 y old) and nine healthy adults (18- 40 y old) performed multiple transitions from rest to constant work rate on the cycle ergometer. Studies were done breathing 21% O2 and 15% O2. Hypoxic breathing quickened the VE responses in all of the adults and children, but the magnitude of the hypoxic effect did not differ between the two groups (in children, γVE was 50.9 ± 9.9 s during 21% O2 breathing and 32.6 ± 6.9 s during hypoxia; in adults, γVE was 69.4 ± 17.6 s, which fell to 50.9 ± 18.4 s during hypoxia). The hypothesized greater ventilatory response to hypoxia in children compared to adults during exercise was not observed. During 21% O2 breathing, the data demonstrated that children stored relatively less CO2 (by 49%) than did adults in the transition between rest and exercise, possibly explaining the faster ventilatory kinetics. We speculate that there must be additional respiratory control differences between adults and children such that for a given increase in PCT-induced by hypoxia, the VE response at the onset of exercise is less in children than in adults.

Pharmacology of trimethoprim-sulfamethoxazole in newborn infants

The pharmacokinetic parameters of sulfamethoxazole and trimethoprim were measured in 12 newborn infants of less than 3 days postnatal age, following a single or repeated intravenous injection. The mean half-lives for SMZ and TMP were 16.5 hours and 19.0 hours, respectively. The mean volumes of distribution were SMZ 0.48 L/kg and TMP 2.7 L/kg. The mean drug clearances were SMZ 0.65 ml/minute and TMP 3.31 ml/minute. From these data the recommended loading dose is SMZ 10 mg/kg with TMP 3 mg/kg, and the maintenance dose is SMZ 3 mg/kg with TMP 1 mg/kg twice daily. No adverse side effects were seen during treatment, and the bilirubin-binding capacity of albumin were not changed at therapeutic concentrations of the antimicrobial drugs.

Decline in asthma prevalence and severity in Israel over a 10-year period.

Background: The prevalence of asthma has increased in western countries towards the end of the last century, but recently seems to have stabilized. Objective: To evaluate trends in the prevalence and severity of asthma that occurred in Israel over the past decade. Methods: The medical records of 17-year-old boys, eligible for national service, between 1999 and 2008 were reviewed. National annual hospitalization and death rates for asthma were extracted. Results: Three hundred thousand medical records were reviewed. During the study period, lifetime asthma prevalence decreased from 9.7 to 8.1% (p = 0.002). The point prevalence of moderate-to-severe and mild persistent asthma decreased significantly from 0.88 and 3.41% to 0.36 and 2.44%, respectively, during this period. The prevalence of intermittent asthma and asthma in clinical remission for more than 3 years did not change significantly. The annual hospitalization rate for asthma decreased from 13.0 to 7.5 per 10,000 population (p < 0.0001), whilst the annual death rate due to asthma decreased between 1999 and 2008 from 2.1 to 1.4 per 100,000 population (p = 0.003). Conclusions: The prevalence of asthma in Israeli teenage boys decreased significantly over the last decade. In addition, asthma hospitalization and asthma-related death rates in the total population also decreased.

Poly-lactic-glycolic Acid Microspheres: A Biodegradable Marker for the Diagnosis of Aspiration in Hamsters

Aspiration is a major cause of lung disease in infants and young children. As the symptoms and signs of aspiration are not specific, the diagnosis is delayed due to a low index of suspicion and low sensitivity and specificity of the available diagnostic tests. In the present study, we evaluated the utility of microspheres composed of a degradable polymer, polylactic glycolic acid (PLGA), as a marker to diagnose aspiration in hamsters. Thirty hamsters underwent direct tracheal instillation of 0.1 mL of a suspension of PLGA. Eighteen other animals served as controls and underwent tracheal instillation of 0.1 mL of saline. Three animals served as naive controls and had no tracheal instillation. Five animals from the PLGA group and three from the saline group underwent whole-lung lavage (WLL) on days 1, 8, 15, 29, 43, and 58. PLGA microspheres were easily identified under light microscopy inside the alveolar macrophages obtained from WLL in all PLGA-instilled animals during all studied days. The number and size of PLGA microspheres within the alveolar macrophages decreased gradually with time with a 90% rate of disappearance of about 36 d. There was a marked neutrophilic response in lung lavage and a mild peribronchial neutrophil infiltration on the first day after tracheal instillation of PLGA which subsequently disappeared. We conclude that PLGA microspheres are a sensitive and specific marker for aspiration in hamsters. The usefulness of this test in diagnosing aspiration in humans should be further evaluated in clinical studies.