Cystic fibrosis (CF) is the most common genetic disease within the Caucasian population and leads to premature respiratory failure. Approximately 60,000 individuals are currently living with CF in North America and Europe, 40% of whom are adults. The life span of these patients has increased from approximately 2 to 32 yr of age over the last three decades. Bone disease has emerged as a common complication in long-term survivors of CF. Some studies have observed that 50-75% of adults have low bone density and increased rates of fractures. Prevention and treatment of CF-related bone disease must address the myriad risk factors (decreased absorption of fat-soluble vitamins due to pancreatic insufficiency, altered sex hormone production, chronic lung infection with increased levels of bone-active cytokines, physical inactivity, and glucocorticoid therapy) for poor bone health. This review is a condensed and updated summary of the Guide to Bone Health and Disease in Cystic Fibrosis: A Consensus Conference, a statement that evolved from a meeting convened by the Cystic Fibrosis Foundation in May 2002 to address the pathogenesis, diagnosis, and treatment of bone disease in CF. The goal of this conference was to develop practice guidelines for optimizing bone health in patients with CF.

SUMMARY Rationale In cystic fibrosis (CF), conventional antibiotic susceptibility results correlate poorly with clinical outcomes. We hypothesized that biofilm testing would more accurately reflect the susceptibilities of bacteria infecting CF airways. Methods A multi-center randomized pilot trial was conducted to assess the efficacy and safety of using biofilm susceptibility testing of Pseudomonas aeruginosa sputum isolates to guide antibiotic regimens for chronic airway infections in clinically stable adolescent and adult CF patients. Thirty-nine participants were randomized to biofilm or conventional treatment groups; 14-day courses of two antibiotics were selected according to an activity-based algorithm using the corresponding susceptibility results. Results Of the agents tested, meropenem was most active against biofilm-grown bacteria, and was included in regimens for about half of each study group. For nineteen of 39 randomized participants, randomization to the other study group would not have changed the antibiotic classes of the assigned regimen. Study groups were comparable at baseline, and had similar mean decreases in bacterial density, measured in log10 colony forming units per gram of sputum (biofilm, -2.94 [SD 2.83], versus conventional, -3.27 [SD 3.09]), and mean increases in forced expiratory volume in one second, measured in liters (0.18 [SD 0.20] versus 0.12 [SD 0.22]). Conclusions In this pilot study, antibiotic regimens based on biofilm testing did not differ significantly from regimens based on conventional testing in terms of microbiological and clinical responses. The predictive value of biofilm testing may nonetheless warrant evaluation in an adequately powered clinical trial in younger CF patients or those experiencing acute pulmonary exacerbation.

Cystic fibrosis is a common inherited fatal disease. As the life expectancy of affected individuals continues to increase with advances in disease management, this disease is no longer limited to the pediatric population. Currently, 40% of patients with cystic fibrosis are adults. In addition, patients may not present until adulthood and frequently have extrapulmonary symptoms. Abdominal manifestations are common and affect multiple organ systems. Hepatobiliary manifestations include fatty infiltration of the liver, gallbladder abnormalities, bile duct abnormalities, focal biliary fibrosis, and multinodular cirrhosis. Manifestations in the pancreas include acute pancreatitis, fatty replacement, calcifications, cysts, duct abnormalities, and carcinoma. Gastrointestinal manifestations include gastroesophageal reflux, peptic ulceration of the gastric and duodenal mucosa, distal intestinal obstruction syndrome, intussusception, appendicitis, fibrosing colonopathy, pneumatosis intestinalis, rectal mucosal prolapse, malignancies, and pseudomembranous colitis. Renal manifestations include nephrolithiasis, as well as secondary renal complications such as interstitial nephritis due to antibiotic therapy and amyloidosis. Awareness of these manifestations is important to successfully guide management of cystic fibrosis in adult patients.

Chronic hypoxia produces pulmonary hypertension, in part because of hypertrophy and hyperplasia of pulmonary artery smooth muscle cells (PA SMC). Platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) have been shown to stimulate SMC proliferation and may be involved in these vascular changes. Both factors cause a rise in intracellular pH (pHi) in systemic vascular SMC through stimulation of the Na+/H+ exchanger, an event that has been thought to be permissive, allowing cell proliferation in response to the growth factor. The present studies examined the possibility that the activation of Na+/H+ exchange is involved in the PA SMC mitogenic response to these growth factors. Na+/H+ exchange activity was assessed by monitoring pHi in cultured cells using the pH-sensitive dye, 2'7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF). PDGF (60 ng/ml) exposure led to a marked activation of Na+/H+ exchange, evidenced by a rise in pHi (mean +/- SEM) of 0.20 +/- 0.03 pH units (n = 5, P < 0.05). EGF (60 ng/ml) exposure produced a rise in pHi of 0.27 +/- 0.03 pH units (n = 5, P < 0.05). Dimethyl amiloride (DMA, 50 microM), a competitive inhibitor of Na+/H+ exchange, blocked the pH response to PDGF and EGF. PA SMC showed a proliferative response when exposed to PDGF and EGF which was attenuated by 50 microM DMA (n = 6). Thus, activation of the Na+/H+ exchanger may be important in pulmonary cell signaling in response to growth factors as it has been found to be in systemic vessels.

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