Complement mediated cell death is associated with DNA fragmentation.

In this study, we demonstrate for the first time that complement attack of target cells, in the presence of suitably high levels of serum, can induce the oligonucleosomal DNA fragmentation characteristic of apoptosis. This phenomenon requires membrane permeabilisation induced by formation of the complete membrane attack complex and relies on physiologically relevant levels of serum. TUNEL analysis detected complement mediated DNA fragmentation as early as 30 min after the addition of serum and electron microscopy confirmed that chromatin became condensed after complement attack. Various experiments implicate serum DNase I as the mediator of this DNA fragmentation. Intriguingly, membrane permeability induced by melittin gave rise to similar serum dependent DNA fragmentation. The implications of these results for the study of apoptosis in vitro and in vivo are discussed.

Plasma corticoids in the respiratory distress syndrome and in normal infants.

Serial plasma samples for corticoid determination were obtained during the neonatal period in 16 infants with RDS (eight of whom died) and 44 healthy babies. The median corticoid level in the eight infants with RDS who was considerably higher than that of patients with RDS who survived, or the normal babies. The median corticoid level in the surviving RDS infants was statistically greater than that of the normal controls, but the actual difference was only 1.9 mug/100 ml. Simultaneous pH, PCO2, PO2, HCO3- and corticoid measurements were obtained serially in five patients with fatal RDS. However, the correlation between plasma corticoids and the acid-base determination was poor in all but one infant. It is concluded that infants are able to respond to severe physical stress in the neonatal period with an appropriate rise in plasma corticoid concentration, but lesser degrees of illness may cause only minimal changes in corticoid levels.

Phenotypic heterogeneity in cystic fibrosis.

We have confirmed heterogeneity in CF using a different combination of primary clinical variables than those used in previous studies. Subgroupings of individuals with similar levels of sweat chloride were independent of the clustering based on level of pancreatic enzyme supplementation and degree of pulmonary involvement. Data from families with multiple CF children are consistent with the hypothesis that the genetic etiology of CF involves two or more genes that modify the expression of the primary gene defect.

Correlation of phenotypic and genetic heterogeneity in cystic fibrosis: variability in sweat electrolyte levels contributes to heterogeneity and is increased with the XV-2c/KM19 B haplotype.

We have reinvestigated a classification of clinical heterogeneity among cystic fibrosis (CF) patients that we previously reported and investigated the possible relationship of the identified CF subgroups to haplotypes around the CF gene and to HLA-DR haplotypes. Age-corrected values for sweat electrolytes, rate of progression of lung disease as assessed by Brasfield chest x-ray scores, and severity of pancreatic insufficiency as assessed by daily supplemented enzyme dosage were obtained for 55, 59, and 59 patients, respectively. XV-2c and KM19 RFLPs were determined by hybridization to TaqI and PstI digests of human genomic DNA, respectively, and analysis of mutations by PCR amplification followed by allele-specific oligo-deoxynucleotide hybridization was performed for 29 patients. HLA-DR restriction fragment length polymorphisms (RFLPs) were determined by hybridization of cDNA beta 1 and genomic DQ alpha probes to TaqI digests of human genomic DNA. The results show that the previous subdivision on the basis of age-corrected levels of sweat electrolytes, as well as measures of severity of lung disease and pancreatic disease, is valid. In addition, the C and D haplotypes are associated with lower age-corrected sweat sodium level. No significant relationship between CF haplotypes and the other two disease variables or between HLA-DR haplotypes and any of the clinical variables was found.

Spirometry and chest roentgenographic appearance in adults with cystic fibrosis.

The pathophysiologic manifestations of cystic fibrosis are continually evolving as more patients survive into their adult years. Although the correlation between chest roentgenographic appearance and pulmonary function testing is well described in children with cystic fibrosis, to our knowledge, there are no data that evaluate this relationship in adults. We analyzed 66 paired studies of chest roentgenographic appearance (Brasfield score) and spirometry in 27 adults with cystic fibrosis between the ages of 18 and 40 years. There was a very good correlation between spirometry and the Brasfield score in adults with cystic fibrosis. The strongest correlation was between the percent predicted FEV1 and the Brasfield score (r = 0.68, p less than 0.001). These correlations were found to remain significant in the patients in whom longitudinal data were available. The FEV1 declined 104 +/- 26 ml/yr in 11 patients who were followed up for a mean duration of 5.8 +/- 0.5 years. The decline in FEV1 per year in adults with cystic fibrosis was significantly greater than in nonsmoking or smoking adults of similar age.

Vitreous fluorophotometry in rats with streptozocin-induced diabetes.

Vitreous fluorophotometry (VF) has been used to study the blood-retinal barrier in rats with streptozocin-induced diabetes. Subsequent investigations have shown that many variables other than diabetes influence VF values. With the use of a commercially available fluorophotometer, we assessed VF measurements in diabetic rats while simultaneously measuring other variables, including plasma fluorescein level, free plasma fluorescein level, and blood pH. Mean total plasma fluorescein concentration, mean free plasma fluorescein concentration, and mean midvitreous fluorescein concentration were significantly decreased in diabetic animals. The mean ratio of midvitreous fluorescein concentration to total plasma fluorescein concentration was significantly increased in diabetic animals. In comparison with nondiabetic animals, the diabetic animals showed no significant difference in blood pH or mean ratio of free plasma fluorescein concentration to total plasma fluorescein concentration. Our findings confirm an early derangement of the blood-retinal barrier in diabetic rats.

Apnea in newborn infants: approach to management.

Approximately 25% of infants with birth weights less than 1800 g or infants of about 34 weeks gestational age have an apneic episode. This, and the known high incidence of apneas in infants who subsequently are victims of sudden infant death syndrome, has led to aggressive attempts at early identification of newborns with abnormal cardio-respiratory patterns. We have found the pneumocardiogram to be effective in detecting cardio-respiratory abnormality in the newborn, and a very useful tool in the assessment of the effectiveness of pharmacologic therapy of neonatal apnea. Infants who are discharged on a home apnea monitor should be managed, utilizing a coordinated multidisciplinary team approach, that includes 24 h availability of a physician, technician, community health nurse, social worker and, when possible, a member of a parent support group. This paper presents a review of neonatal apnea and our institutional approach to its evaluation and management.

A new in vivo and in vitro B cell lymphoma model, pi-BCL1.

We report a new variant of the BCL1 syngeneic mouse B-cell lymphoma model, which we have called pi-BCL1. pi-BCL1 can be established as a syngeneic tumor in BALB/c mice. Tumors can be removed, prepared and easily grown in liquid culture and subsequently transferred back successfully as syngeneic tumors. As a syngeneic tumor pi-BCL1 behave more like a lymphoma with solid tumor masses, than a chronic lymphocytic leukaemia of the original BCL1 model. The immunophenotype and the growth characteristics of the pi-BCL1 and BCL1 tumors appear very similar. Cytologically, pi-BCL1 appears to be a transformation from a small lymphocytic lymphoma to a more diffuse large cell centroblast-like higher-grade lymphoma. We are not aware of any previous reports of such transformation events in a syngeneic animal model of B cell lymphoma. We believe pi-BCL1 provides a useful new tool for the study of B cell lymphoma in vitro and in vivo and enables reduced numbers of tumor passage in mice.

Transition program from pediatric to adult care for cystic fibrosis patients.

A survey of adolescents and young adults with cystic fibrosis (CF) attending an adult CF center was conducted to evaluate a transition program as a means of transferring care from pediatric to adult setting. A total of 40 patients completed a self-administered questionnaire of whom 13 (32.5%) went through the transition program, and 21 (52.5%) received their care at the University of Michigan Cystic Fibrosis Center. Fourteen patients (35.0%) were cared for at other pediatric CF centers, and five (12.5%) were first diagnosed as adults. All those in the transition program approved of having the visit with the internal medicine physician in the pediatric clinic. Most thought that the transition program made the change from pediatric to adult care easier. All patients were comfortable leaving the pediatric clinic after the transition period. Of the 40 patients, 17 (42%) recommended that other patients go through the transition program, although 9 of these 17 patients did not themselves go through the transition program. Twenty-six patients (65%) preferred the adult program. These findings suggest that adolescents with CF should be encouraged to transfer their medical care to an adult CF Center once they have reached an agreed-upon age. This process should be smooth and should occur as part of the regular CF care. This is possible through a well-structured and well-organized transition program with committed pediatric and adult staff.

Reducing tobacco smoke in the environment of the child with asthma: a cotinine-assisted, minimal-contact intervention.

Children with asthma who are exposed to environmental tobacco smoke are at increased risk for adverse health consequences. An experimental design was used to evaluate a minimal-contact intervention aimed at modifying parents' smoking behavior in their homes. All subjects received counseling on the health effects of passive smoking and advice to quit smoking inside the home. Treatment subjects were also mailed the results of a urine cotinine test on their child and a self-help manual. More treatment (35%) than control (17%) subjects reported smoking outside their homes at posttest (and their children's cotinine levels were lower), but this difference was not statistically significant.

Clinical scoring does not accurately assess hypoxemia in pediatric asthma patients.

Management of acute asthma in the pediatric population is based almost entirely on clinical evidence of severity. Although pulmonary function testing has been advocated to improve evaluation, it is difficult in the pediatric patient and not routinely practiced. A clinical scoring system has been devised to help standardize evaluation, but has not been validated by comparison of the results of clinical scoring with those of arterial blood oxygen levels as determined by blood gas analysis. This study was undertaken to compare clinical scoring of pediatric asthma patients with the results of arterial blood gas analysis. Thirty-eight children between the ages of 2 and 13 having 42 episodes of acute asthma were evaluated. The average age was 5.4 years. The average clinical score was 2.62; arterial blood for analysis was obtained in 37 (88%), with an average PaO2 of 81.7 mm Hg. None of the children had CO2 retention. There was no correlation between the clinical score of the children on presentation and the severity of hypoxia (correlation coefficient = -0.149). Comparison of age and arterial oxygen tension revealed a trend toward worsening hypoxemia with diminishing age from 6 to 2 years, which was not identified by clinical scoring. We conclude that clinical scoring is inaccurate for the assessment of hypoxemia in the pediatric age group. Arterial blood gas determination should be used to assess the severity of hypoxemia in the emergency treatment of pediatric asthma patients.

Morphine administration to pregnant rabbits: effect on fetal growth and lung development.

Morphine was injected subcutaneously in doses of 2.5 to 10 mg/kg every 6 hours into pregnant rabbits from early pregnancy until delivery by hysterotomy on the 27th, 28th or 29th day. Pregnant control animals received 0.9% NaC1 injections. Abortions occurred in 34% of the morphine-treated does as a doserelated effect and in 6.5% of the controls. In preserved pregnancies the prevalence of intrauterine death was identical in both samples. Fetuses of treated animals weighed significantly less than those of the controls.However, the normally present effect of intrauterine position on fetal growth was not altered in fetuses of treated animals, so that growth-retarded as well as normal fetuses weighed more when located in the ovarium rather than the cervical portion of the uterus. The fetal lungs were inflated to 35 cm H2O and the remaining air at a deflation pressure of 10 cm H2O (V10) was determined as a measure of lung stability. There were no differences in this indicator of fetal lung maturity between fetuses of treated and control animals. It was found that the lecithin/sphingomyelin (L/S) ratio in the amniotic fluid of rabbits does not correlate with lung maturity; there were no differences between fetuses of treated and control animals. Morphine, when administered to pregnant rabbits does not accelerate fetal lung development. Therefore, the observed reduction in the incidence of respiratory distress syndrome in infants of heroin-addicted women has no direct equivalent in this animal model.

Passive smoking in childhood. Respiratory conditions and pulmonary function in Tecumseh, Michigan.

The relationship of passive smoking to respiratory conditions and pulmonary function was assessed using a cross-sectional design in the defined population of Tecumseh, Michigan. The study population was made up of 3,482 children who were 0 to 19 yr of age at the 1962-1965 examination and for whom questionnaire information was available for both parents. Nearly 62% of children in this age group were exposed at the time of examination to at least 1 parent who smoked. Passive exposure to cigarette smoke was associated with an elevated prevalence of phlegm, wheeze, asthma, and chest colds among males and wheeze, bronchitis, and chest colds among females. Using logistic regression, offspring were shown to be 1.5 to 2.0 times more likely to have a respiratory condition if both their parents currently smoked than if both parents never smoked. FEV1, and FVC among males and Vmax50 among females were significantly lower by 5% in nonsmokers 10 to 19 yr of age whose parents were current smokers compared with similar offspring of never smoking parents. Respiratory conditions were generally more frequent and the level of lung function was generally lower for males from households where only mothers smoked compared with males from households where only fathers smoked, although sample size was limited. In females similar relationships were less consistent. Differences tended to be larger and more often significant for males than for females when respiratory symptoms and illnesses were examined.(ABSTRACT TRUNCATED AT 250 WORDS)

An index of risk for obstructive airways disease.

Predictors of obstructive airways disease (OAD) have been identified, and models for estimating risk of developing OAD have been derived for the adult population of Tecumseh. Men and women 16 to 64 yr of age when first studied were reexamined after an average interval of 15 yr. Incidence rates of OAD increased with age and were higher in men than in women more than 45 yr of age. Incidence rates were significantly higher in men and women with low degrees of lung function initially, and in cigarette smokers, especially those who continued to smoke. Other risk factors included a physician's diagnosis of chronic bronchitis, or asthma, a history of cough, wheeze, shortness of breath, frequent upper or lower respiratory tract infections, bronchitis or pneumonia, leanness, and familial chronic bronchitis. Multiple logistic regression analyses identified combinations of risk factors that placed 70% of the male and 73% of the female incidence cases in the top 10% of the risk distribution. The excess risk of obstructive airways disease associated with cigarette smoking and reduced lung function and the benefits of stopping smoking are clearly apparent. For example, the risk of developing obstructive airways disease in the next 15 years is about 1 in 200 for a 45-yr-old male nonsmoker whose Vmax50 equals to 100% of predicted, if he doesn't take up smoking. The risk for a man of the same age who smokes 40 cigarettes a day and whose Vmax50 equals 80% of predicted is 1 in 5 or 6 if he doesn't cut down on his smoking and about 1 in 15 if he stops smoking.

Comparison of gastrointestinal pH in cystic fibrosis and healthy subjects.

The primary objective of this study was to define the pH conditions under which supplemental pancreatic enzyme preparations must function in the upper gastrointestinal tract. The hypothesis was that normal or greater acid output in patients with cystic fibrosis (CF), combined with low pancreatic bicarbonate output, results in an acidic duodenal pH, compromising both dosage-form performance and enzyme activity. Gastrointestinal pH profiles were obtained in 10 CF and 10 healthy volunteers under fasting and postprandial conditions. A radiotelemetric monitoring method, the Heidelberg capsule, was used to continuously monitor pH. Postprandial duodenal pH was lower in CF than in healthy subjects, especially in the first postprandial hour (mean time greater than pH 6 was 5 min in CF, 11 min in healthy subjects, P less than 0.05). Based on the dissolution pH profiles of current enteric-coated pancreatic enzyme products, the duodenal postprandial pH in CF subjects may be too acidic to permit rapid dissolution of current enteric-coated dosage forms. However, the pH was above 4 more than 90% of the time on the average, suggesting that irreversible lipase inactivation in the duodenum is not likely to be a significant limitation to enzyme efficacy. Overall results suggest that slow dissolution of pH-sensitive coatings, rather than enzyme inactivation, may contribute to the failure of enteric-coated enzyme supplements to normalize fat absorption.