Correlates of well-being in mothers of children and adolescents with cystic fibrosis

The phytoestrogen, genistein, is a naturally occurring isoflavone found in soy products. On a biochemical basis, genistein is a competitive inhibitor of tyrosine kinases and the DNA synthesis-related enzyme, topoisomerase-II (topo-II). Exposure of mammalian cells to genistein results in DNA damage that is similar to that induced by the topo-II inhibitor and chromosomal mutagen, m-amsa. In order to determine the potential genotoxicity of genistein, human lymphoblastoid cells which differ in the functional status of the tumor suppressor gene, p53, were exposed to genistein and the induction of micronuclei quantified by microscopic analysis. In addition, the mutant fraction at the thymidine kinase (tk) locus (both the normal-growth and slow-growth phenotypes) was determined by resistance to trifluorothymidine (TFT) and at the hypoxanthine phosphoribosyl transferase (hprt) locus by resistance to 6-thioguanine (6-TG). Flow cytometric analysis of the percentage of viable, apoptotic and degenerating cells was utilized to determine the rate and kinetics of cell death after genistein exposure. The detection of micronuclei in both cell lines indicated that genistein-induced damage had occurred in both AHH-1 tk+/- and L3. Linear regression analysis detected a significant increase in the number of 6-TG-resistant clones in both AHH-1 tk+/- (p53+/-) and L3 (p53+/+). A comparison of slopes revealed no difference between the lines. In contrast, a significant, concentration-dependent increase in the number of TFT-resistant clones with the slow-growth phenotype was detected in AHH-1 tk+/- (mutant p53), but not in L3 (wild-type p53). Cell death occurred primarily by apoptosis in both cell lines; however, a concentration-dependent decrease in the percentage of viable cells was detected immediately after exposure in L3, but not until 32 h after exposure in AHH-1 tk+/-. A comparison of the slopes of the concentration-response curves for the percentage of viable cells revealed no difference between the cell lines in the effect of genistein on cell viability. Our results may be interpreted that genistein is a chromosomal mutagen and that p53 functional status affects the recovery of chromosomal mutants, possibly by signalling cells into the apoptosis pathways.     

Pregnancy in patients with cystic fibrosis

With increasing life span of patients with CF, more women with CF are becoming pregnant and others are seeking information about the risks involved during pregnancy and delivery. A striking limitation of the available information is the lack of large prospective studies of pregnant patients with CF matched for age and disease severity compared with their non-pregnant cohorts. A study investigating the effect of pregnancy on morbidity and mortality is being completed by the Cystic Fibrosis Foundation. We recommend that all women with CF be offered contraceptive measures and counseling on the maternal and fetal risks of pregnancy, including the genetic risks for the child. The issue of who will raise the child in the event of subsequent morbidity or maternal mortality should ideally be prospectively discussed.     

Osteoporosis in patients with cystic fibrosis

Decreased bone density and increased risk of fractures are seen in patients with cystic fibrosis. Suboptimal vitamin D levels, nutrition problems, hypogonadism, inactivity, corticosteroid use, and cytokines may contribute to the low bone mass seen in these patients. Treatment recommendations must be individualized and may include nutrition, vitamin D, estrogen or testosterone, and exercise. In high-risk patients calcitonin or growth hormone could be considered.     

Glucose tolerance in patients with cystic fibrosis

In order to define prevalence and incidence of diabetes mellitus in cystic fibrosis, we followed 191 unselected patients above two years of age (median 13.6) in a five-year prospective study with annual oral glucose tolerance tests. The prevalence of diabetes increased from 11 to 24% during the study period with an annual age-dependent incidence rate of 4-9%. Diabetes was diagnosed at a median age of 21 years (range 3-40). At diagnosis of diabetes, hyperglycaemia, fasting hyperglycaemia (> or = 7.8 mmol/l), and increased haemoglobin Alc levels (> 6.4) were present in 33%, 16% and 16% of the diabetic patients, respectively. Impaired glucose tolerance implied a higher risk than normal glucose tolerance for the development of diabetes (odds ratio 5.6). In 58% of cases with impaired glucose tolerance, however, glucose tolerance was normalised at the next annual test. Normal glucose tolerance was found in only 37% of the patients at all five tests. Within this group of patients, median fasting and two-hour post-load plasma glucose concentrations and haemoglobin Alc levels increased by 6-8% during five years. Thus, the prevalence and incidence of diabetes in patients with cystic fibrosis is very high and increases with age. Since symptoms of hyperglycaemia and increased fasting plasma glucose and haemoglobin Alc levels are inconstant findings in newly diagnosed diabetic cystic fibrosis patients, we recommend annual oral glucose tolerance tests in all cystic fibrosis patients above the age of 10 years.     

Pharmacokinetics of famotidine in patients with cystic fibrosis

Famotidine pharmacokinetics were studied in 13 patients with severe cystic fibrosis (CF) ranging from 10 to 47 years of age and 25 to 72 kg in weight. Patients were randomized to first receive famotidine either 20 mg intravenously or 40 mg orally. Twelve patients were crossed over to the alternate treatment. Repeated blood samples were obtained over 12 hours after intravenous and oral administration and urine was collected over 24 hours for quantitation of famotidine by means of high-performance liquid chromatography (HPLC). A compartment model-dependent approach was used to characterize the disposition of famotidine. From the intravenous data, the mean +/- standard deviation elimination half-life (t1/2) was 2.11 +/- 0.75 hours, the total clearance (Cl) was 0.79 +/- 0.41 L/kg/hr, the renal clearance was 0.57 +/- 0.26 L/kg/hr, the fraction eliminated unchanged in the urine was 83% +/- 16%, and the apparent volume of distribution (Vdss) was 1.33 +/- 0.53 L/kg. The bioavailability determined from comparison of intravenous and oral area under the curve data was 71% +/- 27%. Results of this study support an initial famotidine dose of 20 mg intravenously or 40 mg orally every 12 hours in patients with CF who are older than 9 years of age.     

Composition of nasal secretion in patients with cystic fibrosis

Quantitative examination of nasal secretion in patients with cystic fibrosis revealed a significantly greater than normal concentration of calcium, a finding in keeping with the hypothesized importance of this ion in the pathophysiology of the disease.     

Infections in patients with cystic fibrosis following lung transplantation

BACKGROUND: There is controversy over whether colonization with drug-resistant organisms is a contraindication to lung transplantation. METHODS: We undertook a retrospective review of the results of lung transplantation for patients with cystic fibrosis (CF) at Duke University Medical Center. RESULTS: As of May 1996, 21 patients with CF underwent bilateral lung transplantation. The first patient died within 24 h of transplantation from sepsis due to Stenotrophomonas maltophilia. Of the remaining 20 patients, 17 (85%) are alive and in stable condition. The three deaths were related primarily to bronchiolitis obliterans at 4 and 18 months in two patients and to cytomegalovirus pneumonitis at 5 months in the other patient. The 17 surviving patients have been followed up for a mean of 13 months (range, 0.5 to 34 months). Most of them were colonized and infected with multidrug-resistant organisms before transplantation. Following transplantation, 11 patients had complications from infections. One patient had bacteremia due to a panresistant Burkholderia cepacia and was treated successfully. Two patients had bacteremia and wound infection due to Burkholderia gladioli, previously thought to be pathogenic only in plants. Both patients were treated successfully. Of the six patients with Aspergillus fumigatus isolated from cultures before transplantation, only one had invasive disease following transplantation and responded to treatment. CONCLUSION: The organisms present before transplantation were not the primary cause of mortality in our patient population. Our findings suggest that lung transplantation should be considered in CF patients infected with multidrug-resistant organisms.     

Neutrophil collagenase in sputum from patients with cystic fibrosis

The potential role of neutrophil elastase in causing lung damage and exacerbating the inflammatory response in cystic fibrosis (CF) has received considerable attention. Although another potent neutrophil-derived enzyme, collagenase, is implicated in tissue destruction in several interstitial lung disorders, there has been no reference to this enzyme in CF. The objective of this study was to determine whether neutrophil collagenase is present in active form in CF sputum and, if so, whether it is related to disease severity. High levels of active collagenase were detected in sputum from patients with CF, and the majority of the enzyme present was of neutrophil origin. In a group of 16 patients with CF, negative relations between sputum collagenase activity and Shwachman score (r = -0.55, p < 0.05) and FEV1 (r = -0.59, p < 0.02) were noted, indicating an association between high collagenase activity and severity of disease. A positive correlation was observed between sputum collagenase and elastase activity (r = 0.62, p < 0.05). These results suggest that both neutrophil elastase and collagenase may play a significant role in lung destruction in CF.     

Pharmacokinetics of once-daily amikacin dosing in patients with cystic fibrosis

PURPOSE: To report the injection of tissue plasminogen activator into a retinal vein to treat central retinal vein occlusion. METHODS: An 81-year-old woman with visual loss of the right eye secondary to central retinal vein occlusion developed central retinal vein occlusion and visual loss in her left eye. Treatment of her left eye with topical ocular hypotensive medications, pentoxifylline, and laser chorioretinal anastomosis was without benefit. Thereafter, she underwent vitreoretinal surgery, including tissue plasminogen activator injection into a branch retinal vein of her left eye. RESULTS: The patient reported subjective improvement in the vision of her left eye. Ophthalmoscopic and fluorescein angiographic improvement were also noted. CONCLUSION: The feasibility of cannulating a retinal vein for treatment has been demonstrated.     

Efficiency of two pancreatic extracts in patients with cystic fibrosis

Mechanical cell damage was studied in vitro with three types of prostheses: Starr-Edwards, Kay-Shiley and Bj?rk-Shiley valves. Mechanical cell damage was found to be closely related to the flow characteristics in the prosthesis. Considering valves of similar orifice diameter, Bj?rk-Shiley valves produced the lowest rate of haemolysis. This is due to the improved haemodynamic characteristics of the valve which resulted from the laminar type of flow. With Starr-Edwards valves, smaller sizes produced unacceptably high rates of haemolysis. Increasing the mean forward flow across the valve resulted in a disproportionate rise in the energy loss and the rate of haemolysis when compared with Bj?rk-Shiley valves of similar annulus diameters.     

Severe Clostridium difficile-associated colitis in young patients with cystic fibrosis

We report four patients with cystic fibrosis and fulminant Clostridium difficile-associated colitis: two died, and one required hemicolectomy. Three of four patients carried the N1303K mutation. Severe and fatal C. difficile colitis can occur in cystic fibrosis patients, possibly with a genotype-specific predilection (i.e., N1303K/other). Because cystic fibrosis patients may have a wide spectrum of gastrointestinal symptoms, disease caused by C. difficile must be considered when these patients have acute abdominal pain, diarrhea, or severe leukocytosis.     

Enhanced oxidative damage in cystic fibrosis patients

Antioxidant depletion and increased free radical production by inflammatory cells have been described in cystic fibrosis (CF) patients. To evaluate oxidative damage intensity, we measured plasma concentrations of malondialdehyde, hydroperoxides and protein carbon groups as markers of oxidative injury to lipids and proteins in a group of 101 CF patients free of acute exacerbation, and in 43-112 controls. Moreover, we estimated antioxidant function by measuring activities of erythrocyte superoxide dismutase, glutathione reductase and vitamin E concentrations. In CF patients, malondialdehyde and hydroperoxide plasma levels were significantly higher than in controls (p < 0.001). Increased lipid peroxidation was documented by these two markers. Parallel rises in protein carbonyls in plasma of CF patients were observed (p < 0.0001). These patients presented biochemical but not clinical vitamin E deficiency. Glutathione reductase and superoxide dismutase activities were significantly higher than in controls. These results show a serious imbalance of CF patients between oxidant-antioxidant status leading to oxidative stress.     

Exercise limitations and training for patients with cystic fibrosis

Exercise has much to offer to cystic fibrosis patients. Overcoming the limits of decreased pulmonary function by increasing fitness has a considerable potential to improve patients' quality of life; decreased breathlessness allows greater mobility and participation with peers in social and sporting activities, improves confidence and self-esteem and creates a greater pleasure in life for the individual patient. There are also immediate therapeutic gains and potentially long-term gains with improved survival. Above all, cystic fibrosis patients enjoy and prefer exercise as a therapeutic option to most other forms of therapy.     

Mutations of the cystic fibrosis gene in patients with chronic pancreatitis

BACKGROUND: The pancreatic lesions of cystic fibrosis develop in utero and closely resemble those of chronic pancreatitis. Therefore, we hypothesized that mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene may be more common than expected among patients with chronic pancreatitis. METHODS: We studied 134 consecutive patients with chronic pancreatitis (alcohol-related disease in 71, hyperparathyroidism in 2, hypertriglyceridemia in 1, and idiopathic disease in 60). We examined DNA for 22 mutations of the CFTR gene that together account for 95 percent of all mutations in patients with cystic fibrosis in the northwest of England. We also determined the length of the noncoding sequence of thymidines in intron 8, since the shorter the sequence, the lower the proportion of normal CFTR messenger RNA. RESULTS: The 94 male and 40 female patients ranged in age from 16 to 86 years. None had a mutation on both copies of the CFTR gene. Eighteen patients (13.4 percent), including 12 without alcoholism, had a CFTR mutation on one chromosome, as compared with a frequency of 5.3 percent among 600 local unrelated partners of persons with a family history of cystic fibrosis (P<0.001). A total of 10.4 percent of the patients had the 5T allele in intron 8 (14 of 134), which is twice the expected frequency (P=0.008). Four patients were heterozygous for both a CFTR mutation and the 5T allele. Patients with a CFTR mutation were younger than those with no mutations (P=0.03). None had the combination of sinopulmonary disease, high sweat electrolyte concentrations, and low nasal potential-difference values that are diagnostic of cystic fibrosis. CONCLUSIONS: Mutations of the CFTR gene and the 5T genotype are associated with chronic pancreatitis.     

Atypical presentation of Clostridium difficile colitis in patients with cystic fibrosis

OBJECTIVE: This report describes the unusual presentation of Clostridium difficile colitis in five patients with cystic fibrosis and the role of CT in first suggesting the correct diagnosis in this group of patients. Because of the absence of watery diarrhea and the presence of abdominal bloating and decreased stooling, cystic fibrosis patients with C. difficile colitis will be treated for stool impaction, meconium ileus equivalent, or distal intestinal obstruction syndrome. CT of the abdomen, performed in these five patients because of their lack of improvement after standard therapy for stool impaction, showed an extensive pancolitis later confirmed to be caused by C. difficile infection. CONCLUSION: In patients with cystic fibrosis, imaging findings of a pancolitis should raise the possibility of C. difficile colitis despite the lack of watery diarrhea. Anticlostridial treatment can be initiated before bacteriologic confirmation is obtained.     

Chloride conduction of nasal fibroblasts in polyposis patients with cystic fibrosis and in patients without cystic fibrosis. Relevance for the ENT physician]

Cystic fibrosis (CF) is a complex systemic disease that has pathological alterations in the upper airways, including the recurrent formation of nasal polyps. Although the fibroblast is the predominant cell type in nasal stroma and nasal polyps, little is known about the electrophysiological properties of nasal fibroblasts. We investigated whether fibroblasts possess a cAMP-regulated chloride conductance which is impaired in patients with CF. Thus far the few studies concerning conductance in fibroblasts have been performed on skin fibroblasts using indirect methods and have yielded conflicting results. Therefore we studied chloride conductance in fused nasal fibroblasts by employing conventional microelectrodes. We have demonstrated that a cAMP-regulated chloride conductance is present in fibroblasts. However, this chloride conductance cannot be activated in fibroblasts from CF-patients. Thus, we present direct evidence that the impairment of the cAMP-regulated chloride conductance in CF is not confined to epithelial cells but also affects the fibroblast. We discuss how this conductance might modulate fibroblast proliferation to produce polyp formation.     

Totally implantable venous access devices in adult patients with cystic fibrosis

Between September 1987 and April 1995, 33 totally implantable venous access devices (TIVADs) were implanted at the Cardiff Adult Cystic Fibrosis Centre, U.K., for the purpose of intermittent antibiotic therapy, including 22 PORT-A-CATH (Simcare Ltd.) devices (PCs) to 18 patients, and 11 P.A.S.PORT (Simcare Ltd.) devices (PPs) to nine patients. There were 50 complications during 25 824 days of catheter function which were severe enough to lead to removal of the devices in eight patients (six PCs and four PPs). Overall, patients' acceptance of these devices was excellent. Despite a shorter functional time and a higher rate of complications in PPs compared with PCs, PPs were preferred by many patients for cosmetic reasons. Totally implantable venous access devices provide safe, effective and convenient means of venous access in cystic fibrosis patients requiring intermittent antibiotic therapy.     

Anaesthesia for liver transplantation in cystic fibrosis patients

INTRODUCTION: Cystic fibrosis (CF) is a disease caused by an inherited genetic defect. While pulmonary and pancreatic abnormalities predominate the clinical spectrum, other organ involvement is common, including liver. The severity of liver disease does not appear to be related to the severity of exocrine pancreatic or lung function. We discuss anaesthesia in four CF patients undergoing liver transplantation. METHODS: We studied haemodynamic and oxygenation modifications during anaesthesia in four patients affected by CF with end-stage liver disease and mild to moderate pulmonary abnormalities. The patients received pancreatic enzyme prior to transplantation and two had insulin-dependent diabetes mellitus. All patients were treated with broad-spectrum antibiotic therapy. After a waiting time ranging one week to three months, all patients were successfully transplanted. General anaesthesia was induced with fentanyl, thiopental and pancuronium, and maintained with isoflurane supplemented by fentanyl in O2:air. Haemodynamic and oxygenation evaluations were made during the main phases of the transplant. After the intubation and at the end of the procedure all patients received a broncho-alveolar toilet through fiberoptic bronchoscopy. RESULTS: During anaesthesia for liver transplantation, PaO2 increased proportionally to the decreasing of Qs/Qt. In postoperative follow-up, Fev1 and FVC improved from preoperative time in all patients. In conclusion, even if cystic fibrosis is a multisystem disease, liver transplantation can be offered to CF patients with endstage liver disease and mild to moderate pulmonary function abnormalities. The four patients are still alive, enjoying good health. The improved respiratory function and quality of life of these children is remarkable.