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Biomedical subjects

B J Rosenstein

Publications and source records attributed to B J Rosenstein.

At least 19 recordsLinked to original sources
PubMed1992

Correlation of intestinal lactulose permeability with exocrine pancreatic dysfunction.

Increased intestinal permeability to lactulose has been reported in patients with cystic fibrosis (CF). To determine whether this finding is unique to CF or whether it is related to accompanying exocrine pancreatic dysfunction, we evaluated 31 patients with CF and 10 with Shwachman syndrome who had variable degrees of pancreatic dysfunction, together with 17 healthy control subjects. There was no significant difference in the mean urinary lactulose excretion, expressed as the percentage of dose recovered, between CF and non-CF patients with pancreatic insufficiency (2.1% +/- 1.2% and 1.9% +/- 0.8, respectively) or between CF and non-CF patients with pancreatic sufficiency (0.6% +/- 0.5% and 0.6% +/- 0.3%, respectively). However, there was a significant difference in mean lactulose excretion between the pancreatic-insufficient and the pancreatic-sufficient patients (both CF and non-CF groups; p less than 0.001 and p less than 0.013, respectively). We further analyzed the results from 26 of the 41 patients (16 patients with CF and 10 non-CF patients) with pancreatic dysfunction who had previously undergone quantitative pancreatic function testing. A nonlinear, inverse relationship was found between urinary lactulose excretion and exocrine pancreatic function determined by duodenal trypsin output. These data confirm a direct relationship between intestinal lactulose permeability and the degree of exocrine pancreatic dysfunction, unrelated to the cause of the pancreatic disease.

Adolescent↗
PubMed1992

Radioaerosol assessment of lung improvement in cystic fibrosis patients treated for acute pulmonary exacerbations.

We compared bronchopulmonary distribution homogeneity of a radioaerosol before and after hospitalization in 20 patients with cystic fibrosis (CF) with pulmonary exacerbations in order to assess lung improvement. Deposition homogeneity was quantified in terms of skew (an index of distribution symmetry), derived from frequency distribution histograms generated from gamma camera images of the lungs following radioaerosol inhalation. Lower skew values indicate enhanced distribution homogeneity. Right lung skew (RLS) was significantly reduced following therapy (1.00 +/- 0.49 to 0.84 +/- 0.47), whereas skew in the left lung was unchanged (0.95 +/- 0.38 to 0.87 +/- 0.40). The reduction in RLS was significant in patients with Shwachman-Kulczycki (SK) clinical scores less than 50 (1.27 +/- 0.53 to 0.90 +/- 0.42), but not in patients with scores greater than 50 (0.81 +/- 0.38 to 0.80 +/- 0.52). These results indicate that treatment affected the right lung more than the left lung, particularly in patients with SK scores less than 50, and suggests that radioaerosol lung imaging may be valuable in identifying sites of impairment to be targeted during treatment. Statistically, skew was less sensitive an indicator of acute change than several other clinical indices that improved following hospital treatment.

Acute Disease↗
PubMed1992

Passive smoking among children with chronic respiratory disease.

The purpose of this study was to determine the prevalence and source of passive smoke exposure among children with chronic respiratory diseases and compare these to both a well child and nonrespiratory chronic illness child population. Rates and source of passive smoke exposure were compared among four child groups: asthma, cystic fibrosis, rheumatoid arthritis, and well children using a questionnaire mailed to the parents of the selected children. Twenty percent of respondents reported current smoking with a significantly higher rate among the cystic fibrosis and rheumatoid arthritis groups. One-third of all children surveyed were exposed to passive smoke at home and/or day care on a daily basis. Over 80% of the asthma and cystic fibrosis respondents reported a change in smoking behavior (i.e., smoking outside the home or smoking fewer cigarettes) after the diagnosis of their child's illness as compared with only 40% of the nonrespiratory groups. Health care providers need to inquire about potential sources of passive smoke exposure in their patients, particularly children with chronic respiratory disease.

Adult↗
PubMed1992

Analysis of four diverse population groups indicates that a subset of cystic fibrosis mutations occur in common among Caucasians.

To determine the nature and frequency of non-delta F508 cystic fibrosis (CF) mutations among diverse populations, we have sequenced exons 9-12 and 19-23 of the CF transmembrane conductance regulator (CFTR) gene from 128 CF chromosomes (39 U.S. Caucasian, 27 African-American, 42 Northern Irish, and 20 Israeli chromosomes). These regions were chosen because they encode the two putative ATP-binding folds of CFTR, domains which appear to have functional significance. In addition, CFTR exons 1 and 2 were analyzed in the American patients. Mutations were found on 49 of the 128 CF chromosomes. Nineteen different mutations were observed; six were novel, while the remaining 13 had been reported previously by our group or by other investigators. Six of nine different mutations found in African-American patients were unique to that population. However, the vast majority of the mutations found in U.S. Caucasians (eight of nine), Northern Irish (four of five), and Israelis (three of three) also occurred in other Caucasian groups. The preponderance of previously reported mutations in these three groups suggested that a subset of the non-delta F508 mutations occur in common among Caucasians. A survey of mutation frequencies in other Caucasian groups confirmed this observation. Unfortunately, this subset accounts for less than half of non-delta F508 CF mutations in most groups. These data suggest that screening for delta F508 and this select group of mutations will efficiently and economically maximize the number of CF mutations identified in Caucasian groups. However, it will be difficult to detect more than 90% of mutant CFTR alleles except in ethnically and geographically discrete populations where CF is the result of founder effect.

Amino Acid Sequence↗
PubMed1992

Cystic fibrosis patients bearing both the common missense mutation Gly----Asp at codon 551 and the delta F508 mutation are clinically indistinguishable from delta F508 homozygotes, except for decreased risk of meconium ileus.

The glycine-to-aspartic acid missense mutation at codon 551 (G551D), which is within the first nucleotide-binding fold of the cystic fibrosis transmembrane conductance regulator (CFTR), is the third most common cystic fibrosis (CF) mutation, with a worldwide frequency of 3.1% among CF chromosomes. Regions with a high frequency correspond to areas with large populations of Celtic descent. To determine whether G551D confers a different phenotype than does delta F508, the most common CF mutation, we studied 79 compound heterozygotes for G551D/delta F508, from nine centers in Europe and North America. Each subject was matched, by age and sex, with a delta F508 homozygote from the same center. A retrospective cohort analysis was performed on the following outcome parameters: age at diagnosis, sweat chloride, meconium ileus at birth, height, weight, weight for height, FVC, FEV1, chest X-ray score, pseudomonas colonization, pancreatic sufficiency, and Shwachman clinical score. There was less meconium ileus among the G551D/delta F508 compound heterozygotes (relative risk 0.33; 95% confidence interval .13-.86), as well as a trend toward later age at diagnosis of pancreatic insufficiency. No statistically significant difference was found between the groups for any other parameter. These results suggest that the CF genotype can be a predictor of pancreatic and intestinal phenotype. Prenatal counseling for the two genotype groups should differ only with respect to probability of meconium ileus. Clinical outcome (after survival of meconium ileus) for G551D/delta F508 compound heterozygotes and delta F508 homozygotes is indistinguishable; therefore, prognostic counseling should not differ.

Adolescent↗
PubMed1992

Dermatitis as a presenting sign of cystic fibrosis.

BACKGROUND: Three percent to 13% of patients with cystic fibrosis present with protein-energy malnutrition that is characterized by hypoproteinemia, edema, and anemia and is associated with high morbidity and mortality. Cutaneous manifestations of malnutrition are rare in patients with cystic fibrosis and have been attributed to deficiencies of protein, zinc, and essential fatty acids. OBSERVATIONS: We describe five patients who presented with failure to thrive, hypoproteinemia, edema, and a cutaneous eruption before the onset of pulmonary symptoms and before the diagnosis of cystic fibrosis was made. The rash had a predilection for the extremities (lower > upper), perineum, and periorificial surfaces. In most cases, erythematous, scaling papules developed by 4 months of age and progressed within 1 to 3 months to extensive, desquamating plaques. Alopecia was variable, and mucous membrane or nail involvement was not observed. The rash was associated with malnutrition and resolved in all survivors within 10 days of providing pancreatic enzyme and nutritional supplementation. The pathogenesis of the rash is unclear, but it appears to stem from deficiencies of zinc, protein, and essential fatty acids and may be mediated by alterations in prostaglandin metabolism. CONCLUSIONS: Cystic fibrosis should be included in the differential diagnosis of the red, scaly infant, particularly when failure to thrive, hypoproteinemia, and edema are also present. Recognition of rash as a sign of cystic fibrosis complicated by protein-energy malnutrition will allow earlier diagnosis and treatment of these patients and may improve their outcome.

Cystic Fibrosis↗
PubMed1991

Differences in expression of cystic fibrosis in blacks and whites.

The recent identification of the cystic fibrosis (CF) gene confirms that genetic heterogeneity occurs in CF. A three-base-pair deletion in exon 10 resulting in a loss of the phenylalanine residue at amino acid position 508 of the gene product, termed the CF conductance regulator protein, accounts for 70% of cases of CF in white subjects. However, this gene defect occurs in only 37% of affected blacks. Analysis of CF genes from American blacks has revealed a number of mutations, most of which are unique to that population. We therefore searched for potential differences in expression of CF between 24 black and 48 white patients with CF matched for birth date and gender. Black patients more frequently presented with only respiratory symptoms (38% vs 10%). Black patients had fewer hospitalizations for pulmonary exacerbations (2 vs 6.9), a better mean forced vital capacity (77% vs 62% of predicted), and higher chest roentgenogram scores (18.2 vs 14.4) than white patients. Complication rates were similar except for a higher incidence of hyponatremic dehydration (21% vs 2%) and peptic ulcer disease (13% vs 0%) in blacks. Survival time appeared to be longer in blacks, but the difference was not statistically significant. We conclude that phenotypic differences exist between black and white patients with CF, which may be due to the genetic heterogeneity between these two populations.

Age Factors↗
PubMed1991

Severe deficiency of cystic fibrosis transmembrane conductance regulator messenger RNA carrying nonsense mutations R553X and W1316X in respiratory epithelial cells of patients with cystic fibrosis.

Cystic fibrosis (CF) is the most common, lethal inherited disorder in the Caucasian population. We have recently reported two African-American patients with nonsense mutations in each CF gene and severe pancreatic disease, but mild pulmonary disease. In order to examine the effect of these nonsense mutations on CF gene expression, bronchial and nasal epithelial cells were obtained from one of these patients (no. 246), a compound heterozygote for nonsense mutations R553X and W1316X; a healthy normal individual; a patient (no. 528) homozygous for the common CF mutation (delta F508); and a CF patient (no. 272) who carries the R553X mutation and a missense mutation, S549N. When mRNA from bronchial cells of the normal individual, the delta F508 homozygote, and the S549N/R553X compound heterozygote was reverse transcribed and amplified by polymerase chain reaction using primers derived from the CF gene, DNA fragments of the predicted size were observed. However, patient no. 246 with nonsense mutations in each CF gene has no detectable cystic fibrosis transmembrane conductance regulator (CFTR) messenger RNA, and therefore should have severely diminished, and possibly absent, CFTR protein. Furthermore, less than 2% of the CFTR transcripts in nasal epithelial cells from patient no. 272 (S549N/R553X) were derived from the gene with the nonsense mutation. We conclude that severe reduction in CFTR mRNA causes CF, but can have different consequences in the lung and pancreas.

Adolescent↗
PubMed1991

A controlled trial of long-term bronchodilator therapy in cystic fibrosis.

To evaluate the effect of long-term bronchodilator therapy in CF patients with demonstrated bronchial hyperresponsiveness, we first performed methacholine challenges to determine responsiveness, then entered 27 patients (16 methacholine responders and 11 nonresponders) into a two-month double-blind crossover trial of albuterol, 90 micrograms by inhalation four times a day vs placebo. Among the responders, daily PEFR measures improved significantly more during treatment with albuterol (12 +/- 32 L/min) than with placebo (-0.4 +/- 19 L/min; p less than 0.05). In addition, a clinically important level of improvement in PEFR (15 percent increase) was reached significantly more frequently in the responders. Methacholine nonresponders had no change in PEFR on either albuterol or placebo. Daily symptom scores as well as spirometry measurements at biweekly visits did not show significant changes. We conclude that long-term therapy with inhaled albuterol improves lung function in CF patients, but only in those with bronchial hyperresponsiveness as demonstrated by methacholine challenge.

Administration, Inhalation↗
PubMed1991

Outcomes of emergency room treatment of children with asthma.

Duration of symptoms, medication use and follow-up medical care were examined over an 8-week period in children following emergency room treatment for an acute asthma episode. Two groups of children were compared: Short-course (N = 90) and Continuous Medication Users (N = 46). Over a third of Short-Course Users continued to report symptoms up to 6 weeks following the index episode with 31% reporting medication use at 8 weeks. Relapse, resulting in an emergency room visit, occurred in 26% of all study children. Factors associated with relapse included maternal smoking, female gender, prior hospitalization for asthma, cough, and medication use during the follow-up period.

Asthma↗
PubMed1990

A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein.

The gene responsible for cystic fibrosis (CF) has recently been identified and is predicted to encode a protein of 1,480 amino acids called the CF transmembrane conductance regulator (CFTR). Several functional regions are thought to exist in the CFTR protein, including two areas for ATP-binding, termed nucleotide-binding folds (NBFs), a regulatory (R) region that has many possible sites for phosphorylation by protein kinases A and C, and two hydrophobic regions that probably interact with cell membranes. The most common CF gene mutation leads to omission of phenylalanine residue 508 in the putative first NBF, indicating that this region is functionally important. To determine whether other mutations occur in the NBFs of CFTR, we determined the nucleotide sequences of exons 9, 10, 11 and 12 (encoding the first NBF) and exons 20, 21 and 22 (encoding most of the second NBF) from 20 Caucasian and 18 American-black CF patients. One cluster of four mutations was discovered in a 30-base-pair region of exon 11. Three of these mutations cause amino-acid substitutions at residues that are highly conserved among the CFTR protein, the multiple-drug-resistance proteins and ATP-binding membrane-associated transport proteins. The fourth mutation creates a premature termination signal. These mutations reveal a functionally important region in the CFTR protein and provide further evidence that CFTR is a member of the family of ATP-dependent transport proteins.

Adenosine Triphosphate↗
PubMed1990

Congenital renal abnormalities in infants with in utero cocaine exposure.

To determine the incidence of renal abnormalities among infants exposed to cocaine in utero, we performed ultrasound studies of the genitourinary tract in 100 consecutive infants admitted to the full-term nursery whose mothers had a history of cocaine use during pregnancy and/or a maternal toxicology screen was positive for cocaine. Mean gestational age of the newborns was 38.4 +/- 2.1 weeks. Mean birth weight was 2,846 +/- 561 gm.; 26% of the patients were less than 2,500 gm. and 18% were small for gestational age. Symptoms of drug withdrawal were present in 47 patients. Two newborns had murmurs consistent with a ventricular septal defect. On ultrasonography, 1 newborn had a unilateral multicystic/dysplastic kidney and 1 had kidneys that were 2 standard deviations below normal in size. Based on our results routine renal ultrasound studies do not appear to be indicated in full-term newborns exposed in utero to cocaine.

Abnormalities, Drug-Induced↗
PubMed1989

Effect of pancreatic enzyme supplements on iron absorption.

Iron deficiency has been reported in one third of patients with cystic fibrosis. There are data that suggest that iron absorption is increased with exocrine pancreatic deficiency and that administration of pancreatic enzymes may impair oral iron absorption. We compared oral iron absorption over a 3-hour period in the presence and absence of exogenous pancreatic enzymes in 13 stable young-adult patients with cystic fibrosis and 9 age-matched control patients. Although none of the patients with cystic fibrosis had a hemoglobin level less than 119 g/L, serum ferritin levels were less than 25 micrograms/L in 5 of the 13 patients, and the mean corpuscular volume was significantly lower in the patient group (86.1 +/- 2.7 vs 90.9 +/- 5 fL). Baseline mean serum iron levels were higher in controls (18.9 +/- 5.9 mumol/L) than in patients (11.9 +/- 6.3 mumol/L). There was no difference in iron absorption in the absence of exogenous pancreatic enzymes. Significant impairment of iron absorption was detected in both patients with cystic fibrosis and controls after administration of a preparation of pancreatic enzymes. There was an inverse relationship between iron stores, as measured by serum ferritin, and iron absorption. These findings suggest that long-term consumption of pancreatic enzymes by patients with cystic fibrosis may contribute to iron deficiency.

Adolescent↗