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.

Infant health care utilization predicted by pattern of prenatal care.

STUDY OBJECTIVE: The objective of this study was to examine the relationship between patterns of prenatal care and subsequent infant health care use in a sample of inner-city women and their infants. In testing this relationship we controlled for several sociodemographic, economic, and psychological factors. DESIGN: This case-control study examined medical records of 148 infants born to mothers previously enrolled in a 9-month study of prenatal care and use or nonuse of illicit drugs. Cases (N = 62) were defined as infants born to women who first registered for prenatal care after 28 weeks' gestation or completed fewer than four prenatal visits. Controls (N = 86) were all other infants matched by date of birth. Data on maternal health and sociodemographic factors were obtained from a maternal interview and medical record review. Maternal drug use was defined as the use of illicit drugs at any time during the pregnancy based on maternal interview and/or a positive maternal or neonatal urine toxicology screen obtained within 48 hours of delivery. RESULTS: Infants of case mothers had significantly lower birth weight and gestational age, increased number of protective service referrals, and lower completion rate of three or more health supervision visits by 9 months of age. Multiple logistic regression analysis revealed that adequate prenatal care was significantly associated with adequate use of infant health care independent of maternal drug use, educational level, marital status, and number of previous living children. CONCLUSIONS: Patterns of infant health care use can be predicted before birth based on the mother's pattern of prenatal care use.

Airway hyperreactivity in cystic fibrosis. Clinical correlates and possible effects on the course of the disease.

To evaluate whether increased airway reactivity affected the course of patients with cystic fibrosis (CF), we categorized 40 CF patients as to methacholine sensitivity and then evaluated their disease activity and natural history. Twenty methacholine reactors had more severe lung disease (lower S-K clinical scores and more impairment of pulmonary function) than did 16 nonreactive patients, and acute bronchodilator response was greater in the methacholine reactors. Thirty-four patients were followed prospectively over a 17- to 24-month period. Among 19 methacholine reactors, there were more pulmonary exacerbations and a more rapid decline in FEV1. In general, increased obstruction was associated with increased reactivity. Although the data are subject to differing interpretations, they are consistent with the hypothesis that in patients with CF, airway hyperreactivity occurs secondary to bronchial damage, age, is associated with more rapid pulmonary deterioration, and is an unfavorable prognostic finding.

Homogeneity of bronchopulmonary distribution of 99mTc aerosol in normal subjects and in cystic fibrosis patients.

We characterized the bronchopulmonary distribution of a 0.9 percent saline aerosol (1.12 microM) labelled with 99mTc sulfur colloid in nine normal subjects and five patients with CF. Homogeneity of distribution was quantified using indices derived from computerized analysis of Anger camera pulmonary images including skew (a measure of distribution asymmetry) and kurtosis (a measure of distribution range). Aerosol clearance in 97 minutes (a measure of large, central airway deposition) was also assessed. Values of skew and kurtosis were reproducible for the patients with CF and were significantly elevated compared to the normal subjects. Reproducibility of skew and kurtosis were not studied in the normal subjects. Clearance was not significantly different in the two groups. We conclude that the bronchopulmonary distribution of this radioaerosol is nonuniform in patients with CF, compared to normal subjects, and clearance may be impaired in patients with CF who are severely ill.

Use of oral contraceptives in women with cystic fibrosis.

Oral contraceptive pills (OCP) represent the most common contraceptive method among teenagers and young adults. Because many women with cystic fibrosis (CF) are now surviving into childbearing age and are at risk for the complications of pregnancy in CF, oral contraceptive use may be indicated. However, it has been suggested that OCP use by CF patients may be associated with deterioration in pulmonary function. Ten adolescent and young adult women with CF and moderate-to-severe obstructive lung disease were studied while taking a combination oral contraceptive pill (Ovral 28). No significant deterioration was found in clinical status or pulmonary function. Careful follow-up should nevertheless be continued to monitor for other adverse effects of oral contraceptive use in CF, such as cholelithiasis.

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.

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.

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.

Evaluation of the culture of safety: survey of clinicians and managers in an academic medical center.

BACKGROUND: Despite the emphasis on patient safety in health care, few organizations have evaluated the extent to which safety is a strategic priority or their culture supports patient safety. In response to the Institute of Medicine's report and to an organizational commitment to patient safety, we conducted a systematic assessment of safety at the Johns Hopkins Hospital (JHH) and, from this, developed a strategic plan to improve safety. The specific aims of this study were to evaluate the extent to which the culture supports patient safety at JHH and the extent to which safety is a strategic priority. METHODS: During July and August 2001 we implemented two surveys in disparate populations to assess patient safety. The Safety Climate Scale (SCS) was administered to a sample of physicians, nurses, pharmacists, and other ICU staff. SCS assesses perceptions of a strong and proactive organizational commitment to patient safety. The second survey instrument, called Strategies for Leadership (SLS), evaluated the extent to which safety was a strategic priority for the organization. This survey was administered to clinical and administrative leaders. RESULTS: We received 395 completed SCS surveys from 82% of the departments and 86% of the nursing units. Staff perceived that supervisors had a greater commitment to safety than senior leaders. Nurses had higher scores than physicians for perceptions of safety. Twenty three completed SLS surveys were received from 77% of the JHH Patient Safety Committee members and 50% of the JHH Management Committee members. Management Committee responses were more positive than Patient Safety Committee, indicating that management perceived safety efforts to be further developed. Strategic planning received the lowest scores from both committees. CONCLUSIONS: We believe this is one of the first large scale efforts to measure institutional culture of safety and then design improvements in health care. The survey results suggest that strategic planning of patient safety needs enhancement. Several efforts to improve our culture of safety were initiated based on these results, which should lead to measurable improvements in patient safety.

Prenatal care and drug use in pregnant women.

This case-control study tested the hypothesis that pregnant inner-city women with low utilization of prenatal care are likely to be frequent drug users. Cases registered consecutively for prenatal care at > or = 28 weeks gestation or had < 4 prenatal visits. Controls were matched to cases by date of delivery. 24/81 (30%) cases and 16/128 (12%) controls were frequent drug users (adjusted odds ratio = 2.5; 95% CI, 1.2-5.4). Drug use (P = 0.01) and socioeconomic status (P = 0.001) were significantly correlated with prenatal care utilization. Self-report alone failed to note as many drug users as toxicology screen alone. Both substance use history and toxicology screen are advisable in women with low utilization of prenatal care.

What is a cystic fibrosis diagnosis?

Cystic fibrosis (CF) should be considered in patients with a wide variety of clinical presentations and of diverse racial and ethnic backgrounds. In most cases the diagnosis is suggested by manifestations of chronic sinopulmonary disease and exocrine pancreatic insufficiency, and then confirmed by a positive sweat test result. Patients may, however, present with pancreatic sufficiency or other atypical clinical features, sometimes in association with normal or borderline sweat test results. In such cases, the ability to detect CF mutations and to measure transepithelial bioelectric properties can be diagnostically useful. Mutation analysis can also be used for carrier screening, prenatal diagnosis, and newborn screening.

Misdiagnosis of cystic fibrosis. Need for continuing follow-up and reevaluation.

A retrospective review was conducted of the charts of 271 patients with a diagnosis of cystic fibrosis (CF) who were evaluated over a 15-year period at the Johns Hopkins Hospital. Among these patients, eight were encountered in which the diagnosis of CF was made on the basis of a compatible clinical picture and at least two positive quantitative pilocarpine iontophoresis sweat tests but who were subsequently documented to have normal sweat electrolyte concentrations. Six of the eight patients had recurrent episodes of cough and wheezing without evidence of suppurative pulmonary disease. Our experience suggests that variability in sweat electrolyte concentrations may occur more commonly than is generally appreciated. In those patients who do not follow a typical course, it is crucial to repeat sweat tests, even if the initial diagnosis was based on two or more positive quantitative pilocarpine iontophoresis sweat tests performed in a CF referral center.

Moxalactam-tobramycin-resistant Pseudomonas aeruginosa isolates in patients with cystic fibrosis.

In vitro studies have shown synergistic killing activity against Pseudomonas aeruginosa (PA) with the combination of an aminoglycoside and moxalactam, a new beta-lactam agent. We describe three patients with cystic fibrosis (CF) with PA isolates that were resistant to all single-agent antibiotics, but sensitive to the combination of moxalactam-tobramycin. Initially, all patients had a good clinical response to this combination. However, during a second course of therapy, there was clinical deterioration coincident with the rapid emergence of moxalactam-tobramycin-resistant PA isolates.