Colonic strictures in children with cystic fibrosis

PURPOSE: To determine the radiographic, clinical, surgical, and histologic findings in children with cystic fibrosis who develop strictures of the colon. MATERIALS AND METHODS: Ten children (five boys, five girls; age range, 2.5-9.0 years; mean age, 5.5 years), who were treated at the practices of the authors, were retrospectively identified and their medical records reviewed. RESULTS: Radiographic manifestations of the colonic disease included mucosal irregularity and spiculation with nodular thickening of the colonic wall and loss of normal colonic haustration. Luminal narrowing involved long segments of the colon. Longitudinal shortening of the colon was also a prominent feature. The decrease in caliber of the bowel ranged from mild narrowing to complete occlusion of the lumen. Histologic examination revealed severe submucosal fibrosis and fatty infiltration with transmural extension of the fibrosis to involve the serosa in some cases. Unlike in Crohn disease, however, acute inflammatory changes were minimal or absent. CONCLUSION: Colonic stricture in children with cystic fibrosis is due to irreversible and frequently progressive narrowing of the colonic lumen.     

Fibrosing colonopathy in children with cystic fibrosis

PURPOSE: Fibrosing colonopathy is a newly described entity seen in children with cystic fibrosis. The radiological hallmarks are foreshortening of the right colon with varying degrees of stricture formation. High-dose enzyme therapy has been implicated as the cause of this process. The purpose of this study is to review the author's experience with evaluation and treatment of these patients. METHODS: There are currently 380 patients being treated at our CF center. Fifty-five of these patients have been treated with high-dose enzyme therapy (> 5,000 units of lipase/kg). The medical records of these patients, who are at risk for developing fibrosing colonopathy, were reviewed for the presence of recurrent abdominal complaints, and the work-up and treatment of these symptoms. RESULTS: Chronic complaints of abdominal pain, distension, change in bowel habits, or failure to thrive were present in 24 of the 55 patients treated with high-dose enzymes. So far, 18 of these 24 patients have been evaluated by contrast enema. Thirteen of eighteen have been found to have fibrosing colonopathy characterized by foreshortening and strictures of the colon. Additional findings included focal strictures of the right colon (7 of 13), long segment strictures (5 of 13), and total colonic involvement (1 of 13). Nine patients with the most severe symptoms have undergone colon resection, including five segmental right colectomies, three extended colectomies (ileo-sigmoid anastomosis), and one subtotal colectomy with end-ileostomy. Pathological evaluation has shown submucosal fibrosis, destruction of the muscularis mucosa, and eosinophilia. No postoperative complications or deaths occurred. All nine postoperative patients have noted marked symptomatic improvement. Contrast enema follow-up results are available for six patients, and have documented no recurrent strictures to date. Three of four nonoperative patients have less severe symptoms and are currently being treated conservatively. The other family has refused surgery and the patient is being treated symptomatically. CONCLUSION: High-dose lipase replacement has been implicated as the etiology for FC and was present in all of our patients. Our cystic fibrosis center now routinely limits lipase to 2,500 U/kg per dose. We recommend the use of the contrast enemas to evaluate at-risk patients who have chronic abdominal complaints or who present with recurrent bowel obstruction. Colon resection should be performed in those with clinically and radiographically significant strictures with the expectation of a good outcome.     

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.     

Lower respiratory illness in infants and young children with cystic fibrosis: evaluation of treatment with intravenous hydrocortisone

The enzyme-linked immunosorbent assay (ELISA) using HLA class I molecules purified from pooled platelets has the potential to detect HLA antibodies with increased efficiency without sacrificing sensitivity or specificity. This test, which was originally developed in our institution, has been independently validated by recent studies and is now commercially available. We now present evidence of its usefulness as a routine HLA antibody screening test for renal transplant patients. A total of 515 patients were tested monthly by ELISA (13.9 tests/patient) and by antiglobulin-enhanced panel reactivity (6.3 tests/patient). In patients found to be unsensitized, the incidence of false-positive results was less for ELISA than for the panel studies. In patients who were highly sensitized, both tests performed equally well, whereas discordant results were registered mainly in cases of mild sensitization. Because 66% of our patients were not sensitized, the ELISA was effective in reducing the number of more involved tests aimed at characterizing the antibodies. These results provide a foundation to use the pooled platelet HLA ELISA on a routine basis for HLA antibody screening.     

Personality structure in children with cystic fibrosis studied using Rorschach test

BACKGROUND AND AIMS: The recent positive evolution in the development of cystic fibrosis, resulting in the current prospect of survival, has led to the formation of a new population of chronic patients. The characteristics of the disease and treatment (hereditary, early onset, affecting the alimentary tract and airways) may interfere with personality structuring processes. The aim of the study was to identify the psychopathological risk. METHODS: The study was performed using the Rorschach test in a population of children with cystic fibrosis monitored by the Pneumology Division of the Ospedale Infantile Regina Margherita in Turin: 20 children aged between 7 and 13 years old were included in the study, most of whom had been diagnosed before the age of 2. The analysis of tests was focused on the use of thought, interior resources, instincts and interpersonal relations. A study of the contents was also made using a self-representational grid. RESULTS: The results obtained highlight an inhibitory attitude which cannot be attributed to intellectual insufficiency, but rather to the failed attempt to invest in the intellectual sphere, typical of this age range, owing to the intensity of anguish. Children with cystic fibrosis appear to be at an earlier stage of development, marked by emotive coarctation and the use of adult-type defensive methods, tending towards rationalisation. CONCLUSIONS: Oh the basis of this study, it is possible to detect a danger of disharmonious organisation in the personality structuring process of these children. The hospital must therefore offer adequate psychological support for their psychic evolution.     

Retrospective review of the effects of rhDNase in children with cystic fibrosis

Bone densitometry is characterized by high sensitivity and specificity in osteoporosis, and new generations of densitometers enable measurements with improved intra- and inter-assay precision. The clinical potential of bone densitometry is well documented and the technique is widely used in clinical practice. It does not, however, allow for measurement of "true" bone density; instead it measures so called serial density (expressed in g/cm2) which is the distribution of bone mass over the flat projection of the skeleton. Limitations of densitometric techniques can be overcome by applying other methods, i.e. quantitative computed tomography (QCT) and ultrasound (US). QCT enables separate measurements of compact and trabecular bone density (expressed in g/cm3), as well as calculation of Strength-Strain Index (SSI), reflecting the mechanical resistance of bone to fracture. US is a non-invasive technique, providing information of fracture risk and bone tissue quality. Both techniques seem very promising and have been extensively studied recently; they are expected to move from clinical research to clinical practice soon.     

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.     

Effects of feeding on protein turnover in healthy children and in children with cystic fibrosis

In 24 patients presenting with 55 renal lesions (mean size, 20.8 mm), single-breath-hold (SBH) fast spin-echo (FSE) techniques allowing T1 and T2 images to be produced within 20 and 23 sec, respectively, were compared with routine non-breath-hold (NBH) spin-echo (SE) T1 and NBH-FSE T2 sequences. Contrast-to-noise ratios (CNRs) measured from SBH-FSE T1 images were an average of 97% higher than their NBH counterparts (P = .0001) and allowed an improved lesion conspicuity in 80% of the cases (P = 0.0001). For T2 imaging, SBH-FSE and NBH-FSE sequences were not statistically different with respect to lesion conspicuity (P = .55) and CNR values (P = .19). This was observed despite a 35% average decrease in CNR of SBH-FSE compared to NBH-FSE images. By reducing respiratory motion artifacts while preserving SE-like image contrast, SBH-FSE techniques have the potential to replace routine NBH sequences for an optimal diagnosis of renal masses.     

Determinants of the tension-time index of inspiratory muscles in children with cystic fibrosis

1. Hypertension secondary to renal disease was studied in non-pregnant and pregnant ewes to determine whether there were any changes in arterial pressure and the distribution of cardiac output and, in particular, whether uteroplacental blood flow was affected. 2. In six non-pregnant, chronically catheterized, uninephrectomized ewes, a reduction in renal blood flow (RBF) to 40-50% of control caused hypertension within 3 h. This was maintained for as long as RBF was reduced (72 h) and returned to control 24 h after the occluder around the renal artery was released. When this experiment was repeated in 16 uninephrectomized pregnant ewes (118-134 days gestation) hypertension occurred within 3 h and was sustained for as long as RBF was reduced (between 24 and 72 h). Arterial pressure returned to control within 24-72 h of restoring RBF. 3. Compared with non-pregnant ewes, pregnant ewes had similar arterial pressures, higher cardiac outputs (CO; P < 0.001) and heart rates (HR; P < 0.001), lower total peripheral resistances (TPR; P < 0.001) and similar blood flows to brain, ovary, pancreas, kidney and spleen. Splenic vascular resistance (VR) was greater (P = 0.006), gut blood flow was greater (P < 0.05) and gut VR was less (P < 0.05). Myoendometrial blood flow/g was greater (P < 0.005) and myoendometrial VR was less (P = 0.006). 4. In pregnant sheep with renal clip hypertension, there was no change in CO and HR, but TPR increased (P < 0.01), as did plasma renin activity. Gut, brain, pancreatic and myoendometrial VR were increased as long as RBF was reduced; in addition, myoendometrial VR remained high for the rest of the experiment. Placental blood flow was unchanged at 3 h; 24-72 h later it was reduced (P < 0.05) and remained low. Placental VR was increased 24-72 h after RBF was restored when ewes were again normotensive. 5. Thus, one-clip, one-kidney renal hypertension in the pregnant ewe was due to increased TPR associated with a fall in uteroplacental blood flow that persisted even when RBF was restored and ewes were normotensive. This reduction in uteroplacental blood flow could account for the high foetal morbidity and mortality that occurs in pregnant women with renovascular hypertension.     

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.     

The effect of 12 months'' treatment with eicosapentaenoic acid in five children with cystic fibrosis

BACKGROUND: The use and indications for laparoscopy have been increasing. As part of this trend, a new algorithm may emerge for pediatric trauma in which laparoscopic techniques are used in hemodynamically stable patients with suspected hollow viscus perforation. CASE REPORT: We present a case in which laparoscopy was successfully used in a pediatric trauma patient as a diagnostic and therapeutic modality. A 4-year-old boy was a back-seat passenger in a head-on collision motor vehicle accident. He was restrained by a lap seat belt. He sustained a concussion, a large forehead laceration and a seat belt abdominal injury. On admission, he complained of abdominal pain. Physical examination revealed a soft, non-distended abdomen with moderate diffuse tenderness. He was hemodynamically stable. Computerized tomography of the abdomen revealed free fluid in the pelvis. No abnormalities were detected in the liver or spleen. Because of clinical deterioration and suspected intestinal perforation, diagnostic laparoscopy was utilized instead of proceeding directly to celiotomy. At laparoscopy a jejunal perforation was found and successfully repaired laparoscopically. Large hematomas were seen in the mesentery, as well as an unsuspected splenic laceration. No active bleeding was found. The patient recovered uneventfully and was discharged 5 days following the surgical procedure. CONCLUSION: This case illustrates the efficacy of using early laparoscopy in children with abdominal trauma when diagnosis is difficult and hollow viscus injury is suspected.     

Impedance cardiography accurately measures cardiac output during exercise in children with cystic fibrosis

Pro-inflammatory cytokines produced in the central nervous system (CNS) have been suggested to have a role in the anorexia and cachexia of disease. In the present study, the effects of chronic exposure of the CNS to interleukin-1beta (IL-1beta) on several indicators of cachexia were studied. Rats were prepared with an intracerebroventricular (i.c.v.) cannula and an osmotic minipump that delivered vehicle or 1.56 ng/h recombinant murine IL-1beta for 4 days. Food intake and body weight were determined daily during the 4-day infusion period and plasma IL-6 and corticosterone concentrations were determined from plasma collected postinfusion. Chronic i.c.v. infusion of IL-1beta resulted in a chronic reduction in food intake. Rats infused i.c.v. with IL-1beta ate less food each day compared to vehicle controls and, at the end of the 4-day infusion period, consumed an average of 17.2 g less. Intracerebroventricular infusion of IL-1beta also caused an immediate and substantial loss of body weight that was sustained throughout the infusion period. In addition, rats infused with IL-1beta had plasma levels of IL-6 double those of vehicle controls (401 pg/ml vs. 185 pg/ml). Plasma corticosterone concentrations were similar between treatments. These results suggest that chronic exposure of the CNS to cytokines such as IL-1beta may be sufficient to induce anorexia and cachexia.     

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.     

Lung disease in mice with cystic fibrosis

The leading cause of mortality and morbidity in humans with cystic fibrosis is lung disease. Advances in our understanding of the pathogenesis of the lung disease of cystic fibrosis, as well as development of innovative therapeutic interventions, have been compromised by the lack of a natural animal model. The utility of the CFTR-knockout mouse in studying the pathogenesis of cystic fibrosis has been limited because of their failure, despite the presence of severe intestinal disease, to develop lung disease. Herein, we describe the phenotype of an inbred congenic strain of CFTR-knockout mouse that develops spontaneous and progressive lung disease of early onset. The major features of the lung disease include failure of effective mucociliary transport, postbronchiolar over inflation of alveoli and parenchymal interstitial thickening, with evidence of fibrosis and inflammatory cell recruitment. We speculate that the basis for development of lung disease in the congenic CFTR-knockout mice is their observed lack of a non-CFTR chloride channel normally found in CFTR-knockout mice of mixed genetic background.     

Lipid levels in adults with cystic fibrosis

The systemic treatment of soft tissue sarcomas is difficult due to the limited availability of active cytotoxic drugs. Combinations of cytotoxic drugs at standard doses do increase toxicity but do not improve response rates or survival. All combinations are limited by myelosuppression, mainly leukocytopenia. For at least two of the four active drugs (doxorubicin and ifosfamide) studies have shown a clear dose-response relationship. Recent studies have focused on increasing dose-intensity by increasing dosages or shortening treatment intervals, which is only possible by the use of hematological growth factors. This review will focus on the latter concept.