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This study represents the first sequence analysis of an amyloid fibril protein from a patient with cystic fibrosis. Although chronic infections are a hallmark of cystic fibrosis, secondary amyloidosis is a rare complication, and during the past 20 years, only 16 cases of amyloidosis in patients with cystic fibrosis have been reported. We examined amyloid fibrils isolated from the spleen of a 25-year-old man who had a history of a chronic cough since infancy and a diagnosis of cystic fibrosis at age 6 years. After solubilization in 6 mol/L guanidine and purification by gel filtration, the major component of the amyloid fibrils was a homogeneous 8000 dalton protein that reacted positively with antiserum to human amyloid A (AA) protein. Complete protein sequence analysis was carried out by using the whole protein and fragments obtained by treatment of the protein with cyanogen bromide, lysyl endopeptidase, and carboxypeptidase. The protein contained 76 residues and showed minor heterogeneity when compared with other AA protein sequences. The cystic fibrosis AA protein represents a product of the SAA-specific cDNA clone now known to be the alpha-allelic form of SAA1 in which valine is present at position 52 and alanine is at position 57.

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We retrospectively reviewed the clinical and radiographic findings in patients with pneumatosis intestinalis (PI), who were identified among 441 patients with cystic fibrosis. Since 1944, the age at onset and the incidence of PI have increased. Pneumomediastinum, pneumothorax, or pulmonary interstitial emphysema was found in 95% of patients with PI compared with 62% of patients without PI. The type, distribution, and severity of PI often changed with time. PI is correlated with the development of obstructive pulmonary disease, which facilitates air dissection into interstitial spaces. Dissection of air is often clinically silent and tends to be self-perpetuating.

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The authors report the pathologic features of three cases of amyloidosis associated with cystic fibrosis. Renal biopsy led to the diagnosis (case 1) or suspicion (case 2) of amyloidosis in patients who were 23 and 21 years old, respectively. The third patient died at age 22 years, and amyloidosis was not discovered until autopsy. Immunohistochemical staining and potassium-permanganate pretreatment of histologic sections in all three cases provided evidence that the amyloid seen in these patients is of the secondary (AA) type. Congo red staining in each case and electron microscopy in case 1 confirmed the initial diagnosis of amyloidosis. A markedly elevated serum amyloid A protein (160 micrograms/mL; normal less than 1 microgram/mL) in case 1 indicated the presence of large quantities of the precursor protein from which the AA fibrils of secondary amyloid are derived. The kidneys, spleen, and liver contained amyloid deposits in autopsy material from all three cases. Involvement of other organs by amyloid was variable. Review of autopsy material in Boston from 23 additional cystic fibrosis patients with long-term survival did not reveal any evidence of amyloidosis. It appears that secondary amyloidosis is emerging as a significant, although rare, complication of cystic fibrosis as greater numbers of these patients survive into adulthood.

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We report five children who had transient elevations in sweat electrolyte values in association with environmental deprivation. The high electrolyte values were not always associated with malnutrition, and normalized more rapidly than weight. The reason for these abnormalities is unknown. In as much as elevated sweat electrolytes are rarely associated with environmental deprivation, repeat studies are recommended before diagnosing cystic fibrosis in such children.

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This study determined the relationship between vocational and educational plans, work values, vocational choice, awareness of occupational requirements, intelligence, self-esteem, and clinical severity of patients with cystic fibrosis and their school and vocational status six years after hospital clinical evaluation. Initially, 52 adolescents were tested on the Goldberg Vocational Development Scale, the Army General Classification Test, Tennessee Self-Concept Scale, and the Shwachman-Kulczycki System of Clinical Evaluation. Six years later each patient was sent a questionnaire to determine current school and employment. All data were subjected to intercorrelations (Pearson and biserial r) and analysis of variance. Eighteen survived and 15 responded. Ten were working in a variety of professional, semi-professional, and clerical jobs, two were unemployed due to cystic fibrosis, and three were still attending college. Of the 15, eight had graduated from college, nursing, or graduate school; one graduated from high school; three were full time students; and three were parttime students. The best predictors of school status were severity of illness (r = -0.55, p less than 0.01), and higher self esteem (r = 0.43, p less than 0.05). No single measure predicted work status. In a two-way analysis of variance using clinical severity and the average vocational development score, the main effect for severity (F = 4.19, p less than 0.05) was significant for student, but not for work status. It was concluded that the most powerful predictor of current student status was mild severity.

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Amyloidosis appears to be a rare complication of cystic fibrosis. We discuss three patients with amyloidosis complicating cystic fibrosis to add to the six patients previously recorded. The presenting problem was proteinuria in five patients, thyromegaly in three patients, and hepatosplenomegaly in one patient. The progression of proteinuria to nephrotic syndrome and edema occurred in eight of nine patients and portended a very poor prognosis. The kidneys, adrenal glands, spleen, thyroid gland, liver, heart, and bowel were most frequently involved. Renal involvement is a frequent and devastating complication of amyloidosis in patients with cystic fibrosis.

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Meconium ileus is the initial clinical manifestation of cystic fibrosis. Once the intestinal obstruction is corrected either medically or surgically the course of disease is that of cystic fibrosis. It is suggested that babies with this disease should be treated in specialized pediatric cystic fibrosis centers to prevent early death or some avoidable complications. Genetic counseling for affected families is recommended when a baby is born with this condition. Usually such infants are born at full term and there is no sex predilection. Prognosis is uncertain and the outlook depends, as it does in cystic fibrosis, on the degree and rate of progression of the pulmonary involvement. This paper presents a series of unusual patients with meconium ileus who have reached adulthood, thus, offering hope that a satisfactory life beyond adolescence is possible in this formerly fatal disease of infancy.

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The increased longevity of patients with cystic fibrosis has resulted in a concomitant increase in the frequency with which pneumothorax is seen. While several approaches to this problem have been available from both a medical and surgical standpoint, unsettled questions remain regarding the efficacy of various modalities of therapy. A review of our own experience with 170 episodes of pneumothorax has provided a basis for proposing what appears to be a reasoned approach to therapy. During the past 12 years, 65 patients ages 5 to 32 years experienced 170 episodes of pneumothorax. Of the 211 trials of treatment, all yielded a high rate of initial resolution (70% to 100%) but rates of recurrence were high. The recurrence rates were: observation 60%, thoracentesis 79%, trochar thoracotomy 63%, tetracycline sclerosis 86%, and silver nitrate 43%. Quinacrine sclerosis yielded an acceptable recurrence rate of 12.5% and partial pleurectomy had no recurrence. There was no statistical difference in the pulmonary function parameters determined before pneumothorax and after chemical pleurodesis or partial pleurectomy. Based upon the data obtained in this review, we recommend that initial management of the pneumothorax include evacuation of the pneumothorax using a chest tube and then chemical pleurodesis using quinacrine sclerosis. In those cases where this pleurodesis fails, upper-partial pleurectomy with obliteration of pleural blebs via a limited thoracentesis is the treatment of choice. An occasional patient requires a concomitant lobectomy.

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Patients with cystic-fibrosis (CF) often have low plasma concentrations of vitamin A. We have measured dark-adapted scotopic thresholds of 56 patients with CF, ages 4 to 34 years, either with a two-alternative forced-choice procedure or as the final threshold after a full dark-adaptation curve. Fasting plasma vitamin A alcohol (retinol) was measured in 34 of the 56 patients. The average thresholds were higher and retinol values lower in patients than in controls. In two patients with very low (less than 7 micrograms/dl) initial retinol levels and elevated thresholds, decreased rhodopsin densities were observed; rhodopsin density and thresholds returned to normal after treatment with oral vitamin A. Rhodopsin density and log sensitivity were linearly related. Only marked decreased in plasma retinol were associated with elevations of dark-adapted threshold and decreases in rhodopsin density, suggesting that the tissues of patients with CF sequester vitamin A to maintain retinal function.

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Thirty-one children and young adults who had been severely malnourished in infancy due to intestinal disease, were compared with sibling controls for psychometric intelligence, academic performance as judged by teacher ratings, and developmental history as judged by parental questionnaires. Older members of the sample were also examined on the Lincoln-Oseretzky Motor Development Scale and by a brief psychiatric interview. There were no significant differences between patients and controls on any outcome measure. Furthermore, previously malnourished individuals were performing at or above age equivalent norms on all psychological tests. The findings suggest that the adverse behavioral effects of severe infantile malnutrition observed in children below the age of 5 yr are, to a large extent, compensated during development when the children are raised in supportive home and school environments.

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We reviewed our experience over the past 12 years to determine the best method of management, to determine the morbidity and the physiologic outcome of medical vs surgical treatment of pneumothorax complicating CF, and to assess the influence of age, sex, and Shwachman scores on survival. Sixty-five patients, ages ranging from 5 to 32 years (mean 18 years). Shwachman scores ranging from 25 to 87 (mean 57), and a male-female ratio of 1:1, experienced 170 pneumothoraces, 93 first episodes, and 77 recurrences, requiring 211 trials of management. All methods of management except needle aspiration resulted in a fair rate of resolution (70 to 100%), but recurrence rates were high for observation (60%), needle aspiration (79%), trocar thoracotomy (63%), tetracycline sclerosis (86%), and silver nitrate sclerosis (43%). The recurrence rates were 12.5% for quinacrine sclerosis and 0% for parietal pleurectomy. Quinacrine sclerosis and parietal pleurectomy were the most effective methods of management. There was no significant difference in pulmonary function before pneumothorax and after pleural sclerosis or parietal pleurectomy. Age, sex, and severity of pulmonary disease were all independent variables influencing prognosis. Severity of disease, rather than the occurrence of a pneumothorax, appears to be the major cause of death. We recommend that quinacrine sclerosis should be considered for management of the first pneumothorax, and parietal pleurectomy if it fails.

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In view of the reported enhanced sensitivity to iodide-induced hypothyroidism in patients with cystic fibrosis, studies were carried out to determine the possible mechanism of this abnormality. The intrathyroid organification of iodide, as assessed by the iodide-perchlorate discharge test, was normal in patients with cystic fibrosis, strongly suggesting that an organification defect was not present. The serum TSH response to TRH was not significantly different from the response in normal children and adolescents. Serum T4 concentration was normal whereas that of T3 was decreased in patients with cystic fibrosis, strongly suggesting decreased peripheral conversion of T4 to T3, as commonly occurs in nonthyroid illness. Our findings do not delineate the mechanism whereby patients with cystic fibrosis develop iodide-induced hypothyroidism.

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A rapid and simple screening test for detecting cystic fibrosis, described in 1956, has been used routinely for 21 years; the results during a 15-month period are compared with those using the quantitative pilocarpine iontophoresis sweat test. In the chloride agar plate test the concentration of chloride on the finger tips is evaluated accordingly to the intensity of the imprint. Readings of 2+ or less excluded cystic fibrosis in 1589 cases with only two doubtful instances, whereas 4+ readings were recorded in 198 cases of cystic fibrosis and 3+ readings in 15 cases of cystic fibrosis. In doubtful cases 4 individuals had 4+ readings and 11 had 3+ readings. This screening test does not replace the quantitative pilocarpine iontophoresis test but it does identify an individual who is likely to have the disease and who requires further tests. It is not reliable for infants aged under 2 months.

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Directors of cystic fibrosis centers in the United States have noted an increasing number of patients with histories of either false-positive or false-negative sweat tests. These inaccuracies were attributed to the use of rapid test methods which avoided actually weighing the sweat collected. These rapid tests have inherent difficulties which, theoretically at least, could lead to mistaken diagnoses. To evaluate methods of performing the sweat test, the National Cystic Fibrosis Foundation organized a combined study comparing the older Quantitative pilocarpine iontophoretic test (QPIT) method of performing the test with two newer and more rapid methods, the Orion skin electrode, and the Medtherm conductivity apparatus. Five cystic fibrosis centers participated in the study. Although two centers obtained considerably more accurate results with the Orion and the Medtherm than did the other three centers, the combined results of the study indicate that these procedures can be considered to be little more than screening tests.

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Severe bronchial hemorrhage in 13 patients with cystic fibrosis was treated by catheter embolization of bronchial arteries. Indications were either excessive bleeding persisting for several days, or bleeding serious enough to interfere with pulmonary drainage and recurring over weeks or months. In follow-up ranging from one to 30 months, cessation of major bleeding was achieved in 12 of 13 patients (93%), although 5 of 13 patients (40%) did have recurrence of minor hemoptysis. No neurologic or other major complications were encountered. However, there are potential risks and this approach at present should be limited to patients with life-threatening bleeding and carried out only by experienced angiographers.

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