Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis.

In a subset of patients with cystic fibrosis (CF), nonsense mutations (premature stop codons) disrupt production of full-length, functional CF transmembrane conductance regulator (CFTR). Ataluren (PTC124) allows ribosomal readthrough of premature stop codons in mRNA. We evaluated drug activity and safety in patients with nonsense mutation CF who took ataluren three times daily (morning, midday and evening) for 12 weeks at either a lower dose (4, 4 and 8 mg·kg(-1)) or higher dose (10, 10 and 20 mg·kg(-1)). The study enrolled 19 patients (10 males and nine females aged 19-57 yrs; dose: lower 12, higher seven) with a classic CF phenotype, at least one CFTR nonsense mutation allele, and an abnormal nasal total chloride transport. Both ataluren doses were similarly active, improving total chloride transport with a combined mean change of -5.4 mV (p<0.001), and on-treatment responses (at least -5 mV improvement) and hyperpolarisations (values more electrically negative than -5 mV) in 61% (p<0.001) and 56% (p = 0.002) of patients. CFTR function was greater with time and was accompanied by trends toward improvements in pulmonary function and CF-related coughing. Adverse clinical and laboratory findings were uncommon and usually mild. Chronic ataluren administration produced time-dependent improvements in CFTR activity and clinical parameters with generally good tolerability.

Treatment of ovalbumin-induced experimental allergic bronchitis in rats by inhaled inhibitor of secretory phospholipase A(2).

BACKGROUND: The pathophysiology of asthma involves the action of inflammatory/allergic lipid mediators formed following membrane phospholipid hydrolysis by phospholipase A(2) (PLA(2)). Cysteinyl leukotrienes are considered potent inducers of bronchoconstriction and airway remodelling. Ovalbumin (OVA) induced bronchoconstriction in rats is associated with increased secretory PLA(2) (sPLA(2)) activation and cysteinyl leukotriene production, together with suppression of cytosolic PLA(2) and prostaglandin E(2). These processes are reversed when the animals are pretreated systemically with an extracellular cell impermeable sPLA(2) inhibitor which also suppresses the early allergic reaction to OVA challenge. In this study we examine the capacity of the sPLA(2) inhibitor to ameliorate inflammatory and allergic manifestations (early and late bronchoconstriction) of OVA induced allergic bronchitis in rats when the inhibitor was administered by inhalation to confine it to the airways. METHODS: Rats sensitised with OVA were treated with the sPLA(2) inhibitor hyaluronic acid-linked phosphatidyl ethanolamine (HyPE). The rats were divided into four groups (n = 10 per group): (1) naïve controls (no sensitisation/no treatment); (2) positive controls (sensitisation + challenge with OVA inhalation and subcutaneous injection of 1 ml saline before each challenge; (3) sensitisation + challenge with OVA and HyPE inhalation before every challenge; and (4) sensitisation + challenge with OVA and treatment with subcutaneous dexamethasone (300 mug) before each challenge as a conventional reference. Another group received no treatment with HyPE during the sensitisation process but only before or after challenge of already sensitised rats. Pulmonary function was assessed and changes in the histology of the airways, levels of cysteinyl leukotrienes in BAL fluid, and the production of nitric oxide (No) and tumour necrosis factor alpha (TNFalpha) by BAL macrophages were determined. RESULTS: Inhalation of HyPE markedly suppressed OVA induced early and late asthmatic reactions as expressed by bronchoconstriction, airway remodelling (histology), cysteinyl leukotriene level in BAL fluid, and production of TNFalpha and NO by BAL macrophages. OVA induced bronchoconstriction in sensitised non-pretreated rats was also inhibited by inhalation of HyPE either before or after the challenge. CONCLUSIONS: These findings confirm the pivotal role of sPLA(2) in the pathophysiology of both the immediate allergic response and the inflammatory asthmatic process. Control of airway sPLA(2) may be a new therapeutic approach to the treatment of asthma.

Corticosteroid therapy reversed progressive chronic granulomatous lung disease following deterioration on interferon-gamma treatment.

We describe a patient who suffered from chronic progressive granulomatous lung disease. He had no clinical or microbiological evidence of infection. After failure of treatment with interferon-gamma and trimethoprim-sulfamethoxazole, he responded dramatically to corticosteroids.

The prevalence of gastroesophageal reflux in children with tracheomalacia and laryngomalacia.

OBJECTIVE: We conducted a retrospective study to determine the relationship between gastroesophageal reflux (GER) and large airways malacia in infancy. METHODS: One hundred sixteen children referred for chronic respiratory problems who were between the ages of 3 and 28 months were investigated. All of them underwent flexible bronchoscopy and chest radiography. Eighteen children had laryngomalacia, 13 had tracheomalacia, and 23 had combined laryngotracheomalacia. During bronchoscopy, BAL was performed. An analysis of macrophages in the BAL fluid for lipid content was performed. Fifty-four children with laryngomalacia and tracheomalacia constituted the study group, and 62 children were in the control group. Reflux studies were obtained for 40 children from the study group and 41 from the control group. RESULTS: In the study group, 28 children (70%) had GER documented by reflux studies compared with 16 children (39%) in the control group (p < 0.01). In the control group, GER was found mainly among those with recurrent bilateral pneumonia. The lipid-laden macrophage score was correlated with the documented GER. CONCLUSION: GER is prevalent among infants with large airways malacia, and treatment of this group with antireflux therapy should be considered.

The clinical course of bronchiolitis associated with acute otitis media.

BACKGROUND: Acute otitis media (AOM) is the most common bacterial co-infection of viral bronchiolitis. AIMS: To evaluate the influence of AOM on the clinical course of bronchiolitis. SUBJECTS: 150 children younger than 24 months old, diagnosed with bronchiolitis, hospitalised between December 1997 and May 1999. METHODS: Body temperature, respiratory rate, oxygen saturation, and the need for oxygen supplementation were recorded on admission and daily throughout hospitalisation. Complete blood count, erythrocyte sedimentation rate, and assay for respiratory syncytial virus were performed on admission. All children were examined daily for the appearance of AOM. The clinical course of children with bronchiolitis and AOM was compared to those without AOM. RESULTS: AOM was diagnosed in 79/150 (53%) children with bronchiolitis. Most were diagnosed within the first two days of hospitalisation. No significant difference was found in the clinical and laboratory findings on admission and on daily follow up between children with and without AOM. CONCLUSIONS: This 2.5 year prospective study showed no difference in the course of bronchiolitis, whether an ear infection was present or not.

[Evaluation of asthmatic children presenting at the emergency room at Barzilai Hospital].

Bronchial asthma in the pediatric age group has become prevalent recently. Many children who suffer from asthma arrive at the emergency room (ER) with exacerbations which did not respond to medical treatment at home. Between July and December 1997, 136 children 8 months to 14 years of age (61% below 3 years), were studied in our pediatric ER. Investigation included physical examination and pulse oximetry, which were used as guidelines for scoring the children on arrival and post-treatment. Spirometry was done in those who could cooperate. For each patient a detailed questionnaire about medical and sociodemographic factors was filled. Primary pediatricians used mainly beta-agonist and corticosteroid inhalators, while pediatric pulmonologists used mainly inhaled steroids. There was no relationship between severity of attack on arrival at the ER, mode of treatment and speed of recovery in the ER. More children treated by a general pediatrician more were admitted to hospital. Low parental education and paternal smoking were risk factors for recurrent hospital admissions. Our results indicate that parents must be educated to stop smoking, especially those with asthmatic children, and primary pediatricians should be updated with regard to proper treatment and follow-up of asthma.

Gallbladder and pancreatic involvement in hepatitis A.

Gallbladder (GB) abnormalities are rarely reported in children, but involvement of the GB has been demonstrated in various inflammatory disorders. Thirty-nine children hospitalized with hepatitis A virus infection were evaluated by ultrasound. Pseudosurgical gallbladder wall of 10 mm or more with striation was found in 10. Pathological echographic findings were found in the pancreas of three patients, one with frank pancreatitis. Ascitic fluid was noted in eight. Pediatricians and pediatric surgeons alike should be familiar with this gallbladder and pancreatic involvement, which might avoid unnecessary procedures or surgery.

Treatment with hypertonic saline versus normal saline nasal wash of pediatric chronic sinusitis.

BACKGROUND: Chronic sinusitis (CS) is a common disease in children, especially those with allergies, that is caused by impaired drainage from the sinuses. Hypertonic NaCl solution has been shown to increase mucociliary clearance and ciliary beat frequency. OBJECTIVE: We performed a randomized double blind study to compare the effect of nasal wash with hypertonic saline (HS) (3.5%) versus normal saline (NS) (0.9%) on CS. METHODS: Thirty patients with CS aged 3 to 16 years were studied. They were randomly divided into two treatment groups matched by age and severity of the disease. Each individual was treated with either HS or NS for 4 weeks. All patients were evaluated by two clinical scores (cough and nasal secretions/postnasal drip [PND]) and by a radiology score at the beginning of the study and after 4 weeks. RESULTS: The HS group improved significantly in all scores (average +/- SD): cough score, from 3.6 +/- 0.51 to 1.6 +/- 0.74; nasal secretion/PND score, from 2.86 +/- 0.35 to 1.6 +/- 0.74; and radiology score, from 8.06 +/- 1.28 to 2.66 +/- 1.04. The NS treatment group showed significant improvement only in the PND score (from 2.66 +/- 0.49 to 1.53 +/- 0.83) but no significant change in both the cough score (from 3.53 +/- 0.52 to 3.33 +/- 0.49) and the radiology score (from 8.13 +/- 1.25 to 7.86 +/- 0.91). Clinical observation 1 month after the end of the study showed no change compared with the end of the study in both groups. CONCLUSION: HS nasal wash is an efficient treatment of CS.

[Sudden death from asthma in childhood, is it preventable?].

Sudden death from asthma is rare but occurs in the young age group. We recently faced this rare situation when 3 asthmatic children were dead on arrival at the local emergency room. All 3 had been treated with beta-2 agonist inhalation on a regular basis, without anti-inflammatory treatment, 2 of the children died while inhaling the beta-2 agonist. It is important that there be clear guidelines and full education about the management of asthma, during and between exacerbations, to prevent such deaths.

[Pediatric flexible bronchoscopy].

Between 1993-1996, 200 pediatric flexible bronchoscopies were performed. Indications were: chronic cough (158 children), persistent pulmonary infiltrates (89), recurrent stridor (28), suspected tracheobronchial foreign body (20), suspected tuberculosis (17) and hemoptysis (3). Some children had more than 1 indication. 124 patients were boys (mean 4.18 +/- 2.86 years; range 1 month-15 years) and 76 were girls (mean 4.39 +/- 2.7 years; range 4 months-15 years). The procedure included direct vision recorded by video-camera and bronchoalveolar lavage; the lavage fluid was sent for culture, Gram and Ziehl-Nielsen strains and for cytology. There were a few minor side effects: mild stridor which resolved within a few hours (10 children) and transient fever (3). This simple, flexible instrument was effective and helpful in the diagnosis and treatment of children with respiratory symptoms in a secondary hospital facility.

Epidemiology of childhood tuberculosis in the Ashkelon region in Israel, 1958-1994.

The incidence rates of tuberculosis (TB) in Israel decreased steadily up to 1984, but rose again between 1985 and 1991, mainly due to immigration waves from Ethiopia. The epidemiology of TB in children was surveyed in the Ashkelon region. The regional TB register of Barzilai Medical Centre, kept since 1958, was used as the source for our data. Two hundred and fifty TB cases in children were reported between 1958 and 1994, constituting 9.7% of the total 2565 cases reported in the whole population of Israel's southern Mediterranean coast. While in the late 1950s and early 1960s the majority of reported cases occurred in children of North African origin, reflecting the large wave of immigration from North Africa at that time, in 1985-94 at the time of the Ethiopian immigration wave, Ethiopian children constituted the majority of the patients. They were diagnosed up to 9 years after arrival. None of the reported cases was HIV-positive.

Inspiratory pressures with CO2 stimulation and weaning from mechanical ventilation in children.

Maximal transdiaphragmatic (Pdimax) and airway occlusion pressures (PaOmax) have been used to predict weaning from mechanical assisted ventilation in adults, but criteria for weaning are still based on trial and error in infants and young children. Because infants and young children cannot cooperate, crying Pdi and PaOmax against an occlusion have been used, but these may not yield maximal values. We hypothesized that breathing CO2 would achieve better Pdimax and PaOmax values by maximizing respiratory drive and help in establishing weaning criteria. To test this, we measured tidal breathing and occluded Pdi and PaOmax in 27 patients (mean age, 15.0 +/- 31.5 SD months) who required prolonged assisted mechanical ventilation and had failed previous weaning attempts. Measurements were performed while patients were breathing spontaneously 100% O2 and 5% and 7% CO2 in O2. The patients achieved higher Pdimax breathing 5% CO2 (73.2 +/- 24.4 cm H2O) than in O2 (61.6 +/- 24.4 cm H2O; p < 0.0001) or in 7% CO2 (69.1 +/- 23.4 cm H2O; p < 0.0001). They also achieved higher PaOmax in 5% CO2 (81.7 +/- 23.5 cm H2O) than with the other gases (69.9 +/- 25.5 in O2, and 77.5 +/- 24.1 in 7% CO2; p < 0.001); 19 patients (70%) were weaned from assisted ventilation within 3.2 +/- 1.9 wk. In 5% CO2, all patients who were weaned achieved Pdimax > 60 cm H2O and could sustain > 60% Pdimax for more than five successive occluded breaths (100% sensitivity; 100% specificity; p < 0.0005).(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral chemoreceptor function in children with the congenital central hypoventilation syndrome.

In children with the congenital central hypoventilation syndrome (CCHS), some patients require mechanical ventilation during sleep, whereas others need respiratory assistance even when awake. The cause of this disparity is unclear. We hypothesized that differences in peripheral chemoreceptor response (PCR) could provide an explanatory mechanism for this disparity in clinical manifestations. PCR was measured in five children with CCHS and five sex- and age-matched controls by measuring the ventilatory responses induced by 100% O2 breathing, five tidal breaths of 100% N2, and vital capacity breaths of 5% and 15% CO2 in O2 and 5% CO2-95% N2. Tidal breathing of 100% O2 resulted in similar ventilatory responses in CCHS patients and controls with various changes dependent on the method of analysis of response used. Acute hypoxia by N2 tidal breathing resulted in a 39.2 +/- 22% increase in respiratory rate in CCHS patients and a 15.1 +/- 11.1% increase in controls (P < 0.05), with similar increases in minute ventilation (VE) of 124 +/- 69% and 85 +/- 11%, respectively. Vital capacity breaths of each of the CO2-containing gas mixtures induced similar increases in VE in CCHS patients and controls. The changes in VE obtained with 15% CO2-85% O2 and with 5% CO2-95% N2 were significantly greater than those with 5% CO2-95% O2, suggesting a dose-dependent response as well as additive effects of hypercapnic and hypoxic stimuli. We conclude that the PCR, when assessed by acute hypoxia, hyperoxia, or hypercapnia, is present and intact in CCHS children who are able to sustain adequate ventilation during wakefulness.(ABSTRACT TRUNCATED AT 250 WORDS)

A 15-year study of the role of Aeromonas spp. in gastroenteritis in hospitalised children.

During a 15-year period, 146 strains of Aeromonas spp. were isolated from 32810 faecal specimens from 13,820 hospitalised patients up to 13 years of age. These isolates constituted 4% of all the pathogenic bacterial strains cultured. For the years 1978-1988, the files of children with gastro-enteritis revealed 81 whose faeces yielded Aeromonas spp. Most of them (94%) were < 3 years of age, 78% < 1 year old. The peak incidence was at 2-6 months, involving severe morbidity including dehydration and vomiting with acidaemia and azotaemia; the mean duration of illness and length of hospitalisation at this age were longer than at other ages. Bloody diarrhoea was found in 7% of the children. Almost all the strains of Aeromonas were resistant to ampicillin. We conclude that Aeromonas spp. are of aetiological significance in gastro-enteritis in small children; culture for this pathogen should be routine in the bacteriological examination of faeces.