Inhaled dry powder mannitol in children with cystic fibrosis: A randomised efficacy and safety trial.

INTRODUCTION: Inhaled mannitol has beneficial effects on lung function, mucociliary clearance, quality of life and sputum properties. This trial examined the efficacy of inhaled mannitol in children with cystic fibrosis (CF). METHODS: The efficacy of inhaled mannitol in children with CF aged 6-17years was assessed in a phase 2, randomised, placebo-controlled crossover study. Subjects were randomly assigned to mannitol 400mg every 12h or matching placebo for 8weeks, followed by an 8week washout and an 8week period with the alternate treatment. The primary endpoint was the absolute change from baseline in ppFEV1 (percent predicted FEV1). RESULTS: A total of 92 subjects were studied, with a mean age of 12years and mean baseline ppFEV1 of 72.2%. During mannitol treatment ppFEV1 was 3.42% (p=0.004) higher compared to placebo or a 4.97% (p=0.005) relative difference; relative change from baseline FEF25-75 was 10.52% (p=0.013). During mannitol treatment, acute post-treatment sputum weight was higher (p=0.012). In pre-specified subgroups (rhDNase use, age, and disease severity), the treatment differences consistently favoured mannitol. The most common AEs were cough and pulmonary exacerbations. Pulmonary exacerbation AEs were approximately 30% lower in the mannitol group. CONCLUSIONS: In children with CF, inhaled mannitol was associated with significant improvements in lung function and sputum weight, irrespective of rhDNase use, age or disease severity. Inhaled mannitol was well tolerated and was associated with a reduced incidence of pulmonary exacerbation AEs. (Clinical Trials.Gov: NCT 01883531).

Bronchodilatory effects of salbutamol, ipratropium bromide, and their combination: double-blind, placebo-controlled crossover study in cystic fibrosis.

The efficacy of inhaled sympathomimetic and anticholinergic agents on airway obstruction in cystic fibrosis (CF) has been proven in several studies. However, studies comparing combined therapy with monotherapy led to divergent results, probably due to different study designs, different dosages, and the small numbers of patients investigated. Therefore, we wanted to answer the question which inhalation has the best short term effect: a sympathomimetic or an anticholinergic agent, or the combination of both. We investigated 17 patients with CF on 4 successive days in the morning, using pulmonary function testing before and 30 min after inhalation. Each patient received aerosolized salbutamol (SB, maximum dose (max.) 2.5 mg), ipratropium bromide (IB, max. 0.5 mg), the combination of both, or placebo (normal saline) in a randomized, double-blind crossover design. The mean forced expiratory volume in the first second improved significantly (adjusted P-value < 0.017) after each treatment compared to placebo. Analysis of variance showed that SB and combination therapy with SB and IB were superior to IB alone, without significant difference between SB and combination therapy. Response of a patient to combined therapy was usually associated with response to SB. Long-term efficacy and side effects of treatment with bronchodilators still remain to be investigated after this short term study. We conclude that in CF patients bronchodilator therapy with sympathomimetic agents is usually sufficient. Only in cases with proven additional benefit from inhalation by anticholinergics should combination therapy be recommended.

Invasion of human epithelial cells by Pseudomonas aeruginosa involves src-like tyrosine kinases p60Src and p59Fyn.

Pseudomonas aeruginosa plays a major role in respiratory tract infections or sepsis in patients with cystic fibrosis or upon suppression of the immune system. Several P. aeruginosa strains have been shown to be internalized by human epithelial cells; however, the molecular mechanisms of the invasion process are poorly characterized. Here, we show that the internalization of P. aeruginosa into human epithelial cells results in and requires activation of the Src-like tyrosine kinases p59Fyn and p60Src and the consequent tyrosine phosphorylation of several eukaryotic proteins. The significance of Src-like tyrosine kinase activation is shown by an almost complete blockade of P. aeruginosa internalization, but not adhesion, upon inhibition of Src-like tyrosine kinases. Likewise, inhibition of P. aeruginosa binding to CFTR, which has been shown to block P. aeruginosa internalization, prevents Src and Fyn activation, supporting a pivotal role of Src-like tyrosine kinases for invasion by P. aeruginosa.

Acute encephalopathy associated with vigabatrin in a six-month-old girl.

PURPOSE: Vigabatrin (VGB) is a new-generation anticonvulsant used in the treatment of partial seizures and West syndrome. Side effects of VGB treatment in adults and children are well described. Acute encephalopathy with VGB has recently been reported in eight adults. They developed stupor, confusion, and electroencephalographic abnormalities after starting VGB. Does the acute encephalopathy with VGB also occur in childhood? METHODS: We describe a 6-month-old girl with infantile Alexander disease with hydrocephalus who developed similar clinical symptoms with apathia, somnolence, and sopor, as well as slowing of the background activity in EEG, 3 days after starting VGB. After exclusion of shunt dysfunction, encephalitis, metabolic dysfunction, and renal failure, VGB was discontinued. RESULTS: During the next 2 days, symptoms subsided, and after 10 days, EEG background activity returned to the one before starting VGB. CONCLUSIONS: Acute encephalopathy associated with VGB in children seems to be very rare, but should not be ignored.

Congenital bilateral perisylvian syndrome (CBPS): do concomitant esophageal malformations indicate a poor prognosis?

Congenital bilateral perisylvian syndrome (CBPS) is a syndrome of cortical malformation characterized by faciopharyngoglossomasticatory diplegia. We report on two cases of CBPS with associated esophageal malformations and a poor mental and motor development. The association of CBPS and esophageal malformations may indicate a subgroup of patients with a very early prenatal injury, characterised by a bad prognosis due to severe cortical disorganization. However, it can not be excluded that the association of CBPS and esophageal malformation is purely coincidental.

Colonic wall thickness measured by ultrasound: striking differences in patients with cystic fibrosis versus healthy controls.

BACKGROUND: Colonic strictures represent an advanced stage of fibrosing colonopathy in patients with cystic fibrosis. AIMS: To clarify whether ultrasonography can identify patients with an early stage of fibrosing colonopathy and to determine clinical factors that influence bowel wall thickening. PATIENTS: Ninety patients with cystic fibrosis, median age 10 years, and 46 healthy controls, median age 13 years, were investigated. METHODS: Bowel wall thickness was measured by ultrasound in a prospective study. RESULTS: In cystic fibrosis, wall thickness of both small intestine and colon was significantly (p < 0.0001) higher than in controls; 81% of patients with cystic fibrosis had a maximum colon wall thickness at any site of 2 mm or more, a value that was never reached by controls. The maximum colon wall thickness was 6.5 mm. Bowel wall thickness was unchanged at re-examination after one year. There was no progression even with high dose pancreatic supplements. There was no association between bowel wall thickness and clinical features such as previous meconium ileus, intestinal resection, distal intestinal obstruction syndrome, abdominal pain, or pancreatic enzyme dose. CONCLUSIONS: There is genuine intestinal involvement in cystic fibrosis; in a few cases this could lead to fibrosing colonopathy.

Bilateral spastic cerebral palsy--pathogenetic aspects from MRI.

Thirty eight children with bilateral spastic cerebral palsy underwent MRI at the age of 5 years and more. Twenty nine showed correlates of periventricular leucomalacia, which were found especially in preterms (20 out of 21) but also in 9 of 15 fullterms without birth asphyxia. These findings suggest compromising events in the peri- and neonatal period especially in preterms and prenatal 3rd trimenon compromise in most of the fullterms without birth asphyxia.