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Biomedical subjects

Eitan Kerem

Publications and source records attributed to Eitan Kerem.

At least 19 recordsLinked to original sources
PubMed2007

A single dose of dexamethasone to prevent postbronchoscopy fever in children: a randomized placebo-controlled trial.

STUDY OBJECTIVE: To assess the effectiveness of one dose of dexamethasone (0.5 mg/kg; maximum, 10 mg) to prevent fever after bronchoscopy with BAL. DESIGN: Randomized, placebo-controlled study. PATIENTS: Immunocompetent nonfebrile children undergoing fiberoptic bronchoscopy with BAL. MEASUREMENTS AND RESULTS: Sixty-nine children were included in the study. Thirty-eight children received saline solution, and 31 children received dexamethasone. The two groups were similar regarding the number of children < 2 years old, the percentage of abnormal bronchoscopic findings, the number of positive BAL culture findings, and the index of lipid-laden macrophages. Twenty-six children (68%) in the saline solution group (SG) had fever, compared to 3 children (9.6%) in the dexamethasone group (DG) [p < 0.001]. Fever after the procedure appeared later (12.3 +/- 5.5 h) in the DG compared to 5.4 +/- 2.7 h in the SG. CONCLUSIONS: One dose of dexamethasone administered prior to performing bronchoscopy with BAL may prevent fever subsequent to the procedure. Further studies are necessary in order to determine the optimal dosing regimen for dexamethasone when used for this purpose.

Bronchoalveolar Lavage↗
PubMed2006

Pregnancy and chronic progressive pulmonary disease.

Progressive pulmonary disease may preclude the option of pregnancy for a number of women in their child-bearing years due to the severity of the disease. For a subset of women with chronic lung disease including cystic fibrosis, pregnancy is possible, but can have a devastating effect both on the prospective mother and fetus. The potential hazards of pregnancy in cystic fibrosis or other progressive pulmonary diseases may trigger a moral conflict between physician and patient. The female patient may argue that her autonomy cannot be circumscribed and that the physician is obliged to assist her reproductive efforts. The physician can counter that his/her participation in potentially harmful interventions is not consistent with professional norms requiring adherence to the principles of beneficence and nonmaleficence. Whenever possible, the ethical conflict between physician and patient should be resolved before initiation of pregnancy. We propose that this best be done through structured negotiations between physician and patient with the goal of constructing an ethical framework for reducing the moral tension between the two. Steps in the negotiating process include defining the therapeutic alliance, information exchange, dialog, and deliberation. As part of the information exchange, it is important to discuss alternatives to pregnancy such as adoption and surrogacy, especially when there are strong contraindications to pregnancy. If negotiations reach a satisfactory conclusion for both sides, there should be a well-delineated consensual agreement to commence the pregnancy with the full support of the medical team.

Chronic Disease↗
PubMed2006

Investigation of unexplained infant deaths in Jerusalem, Israel 1996-2003.

BACKGROUND: Sudden infant death syndrome (SIDS) is a diagnosis of exclusion that may be assigned only after investigations including a forensic autopsy are performed to exclude possible organic and environmental causes of death. Israeli society is influenced by the Jewish and Islamic faiths, which permit autopsy only under selected circumstances. Against this background, we carried out a study to determine what examinations are performed to investigate unexplained infant deaths in Jerusalem, Israel. METHODS: We examined hospital, Ministry of Health and Ministry of Interior records of unexplained infant deaths in the Jerusalem district from the years 1996-2003. RESULTS: Ninety six cases were identified from all sources. Forty nine (51%) infants were brought to a hospital at or near the time of death. Studies to determine the cause of death were performed in 54% of cases for which medical records were available for review. These studies included bacterial cultures (44%), skeletal surveys (12%), computerised tomography (3%) and metabolic studies (3%). Only one forensic autopsy was performed, and in no instance was the death site examined by medical personnel. There was a high rate of retrospective review by district health physicians. The most frequently assigned cause of death was SIDS. CONCLUSIONS: : The capacity of public health officials and forensic pathologists to investigate unexplained infant deaths is strongly affected by the legal, religious and political milieu in which they work. Efforts should be made to develop socially acceptable methods of improving the quality of infant death investigations in Jerusalem.

Autopsy↗
PubMed2006

Mutation specific therapy in CF.

CFTR mutations cause defects of CFTR protein production and function by different molecular mechanisms. The mutations can be classified according to the mechanisms by which mutations disrupt CFTR function. This understanding of the different molecular mechanism of CFTR dysfunction provides the scientific basis for development of targeted drugs for mutation specific therapy of CF. Class I mutations are nonsense mutations that result in the presence of premature stop codon that leads to the production of unstable mRNA or the release from the ribosome of a short truncated protein that is not functional. The aminoglycoside antibiotics can suppress premature termination codons by disrupting translational fidelity and allowing the incorporation of an amino acid, thus permitting translation to continue to the normal termination of the transcript. Class II mutations cause impairment of CFTR processing and folding in the Golgi. As a result the mutant CFTR is retained in the ER and eventually targeted for degradation by the quality control mechanisms. Chemical and molecular chaperons such as Sodium-4-phenylbutyrate can stabilize protein structure, and allow it to escape from degradation in the ER and be transported to the cell membrane. Class III mutations disrupt the function of the regulatory domain. CFTR is resistant to phosphorylation or ATP binding. CFTR activators such as alkylxanthines (CPX) and the flavonoid genistein can overcome the affected ATP binding through direct binding to a nucleotide binding fold. In patients carrying class IV mutations, phosphorylation of CFTR results in reduced chloride transport. Increases in the overall cell surface content of these mutants might overcome the relative reduction in conductance. Alternatively restoring native chloride pore characteristics pharmacologically might be effective. Activators of CFTR at the plasma membrane may function by promoting CFTR phosphorylation, by blocking CFTR dephosphorylation, by interacting directly with CFTR, and/or by modulation of CFTR protein-protein interactions. Class V mutations affect the spicing machinery and generate both aberrantly and correctly spliced transcripts, the level of which vary among different patients and among different organs of the same patient. Splicing factors that promote exon inclusion or factors that promote exon skipping can promote increase of correctly spliced transcripts, depending on the molecular defect. Inconsistent results were reported regarding the required level of corrected or mutated CFTR that has to be reached in order to achieve normal function.

Colforsin↗
PubMed2006

Atypical CF and CF related diseases.

The clinical characteristics of atypical CF are: symptoms that may start in infancy but the disease become clinically significant only after 10 years of age, survival into adulthood, chronic sinopulmonary disease, pancreatic sufficiency, and sweat chloride <60 meq/L. Other patients may present with single organ involvement such as CBAVD, biliary cirrhosis and portal hypertension, chronic or recurrent pancreatitis, giant nasal polyposis or hypochloremic alkalosis. It is recommended to refer such patients for CFTR genotyping, however, absence of known common mutation does not rule out CFTR associated disease, since mutations causing atypical CF are rare and whole genome scan is required for their identification. Nasal PD measurements may be helpful to establish the diagnosis of these patients; however, measurements might be also atypical. Several explanations have been suggested to explain the atypical CF disease.

Cystic Fibrosis↗
PubMed2006

Plastic bronchitis caused by neoplastic infiltrates in a child.

We report on a case of a 7-year-old girl admitted for pneumonia not responding to oral antibiotics. During hospitalization, her pulmonary status deteriorated as a result of significant atelectasis. An extensive workup revealed an anaplastic large-cell lymphoma with neoplastic cells, found in both a biopsied lymph node and pleural fluid aspirate. Bronchoscopic examination showed nearly complete obstruction of the left side by bronchial casts composed of tumor cells, fibrin, and necrotic material, consistent with plastic bronchitis. Neoplastic infiltration of the bronchi should be considered in the differential diagnosis of disease entities causing plastic bronchitis in children.

Bronchitis↗
PubMed2006

Clinical characteristics and outcome of complicated pneumococcal pneumonia in a pediatric population.

The incidence of complicated pneumonia caused by S. pneumoniae is reported to be increasing. This increase may be related to host susceptibility and/or pathogen virulence. The objective of this study was to evaluate clinical and laboratory characteristics associated with complicated pneumococcal pneumonia, and to identify risk factors associated with prolonged fever and hospitalization. The study involved reviewing the records of all children who were hospitalized in four major hospitals in Jerusalem with a confirmed diagnosis of pneumococcal pneumonia during a 12-year period (1986-1997). Demographic, clinical, laboratory, and outcome variables were compared between those with uncomplicated and complicated pneumonia. One hundred and eleven children (median age, 2.2 years) were hospitalized with pneumococcal pneumonia during the study period. Forty-four (39%) of them had complicated pneumonia, characterized by pleural effusion, empyema, pneumothorax, pneumatocele, and/or atelectasis. There was no correlation between the isolation of penicillin-resistant S. pneumonia (16% of cases) and complicated pneumonia. Factors that were significantly associated with complicated pneumonia included weight <or=10% for age, respiratory distress (e.g., tachypnea, dyspnea), anemia, and a white blood cell count (WBC) <15,000/mm(3) at time of admission. Complicated pneumonia and a WBC <15,000/mm(3) on admission increased the risk for prolonged fever and an extended length of hospitalization. Based on these results, it is concluded that host factors such as anemia, low weight, and a low WBC are associated with complicated pneumonia. Both the presence of pulmonary complications and a relatively low WBC in children hospitalized for pneumococcal pneumonia are independent risk factors for protracted fever and extended hospitalization.

Anemia↗
PubMed2006

Long term nutritional rehabilitation by gastrostomy in Israeli patients with cystic fibrosis: clinical outcome in advanced pulmonary disease.

OBJECTIVES: Several studies have shown a linear correlation between nutritional status and pulmonary function in patients with cystic fibrosis. Our study aims were: 1) To evaluate the effect of nutritional supplementation via gastrostomy on nutritional, clinical, and pulmonary parameters, and 2) To identify predicting factors for success of long-term nutritional rehabilitation. METHODS: Twenty-one Israeli patients, aged 8 months to 20 years, underwent gastrostomy insertion from 1992 to 2001. All patients were pancreatic insufficient, and all carried severe mutations (W1282X in 62% of the patients). Anthropometric and clinical data were obtained for each patient: 0-12 months before and 6-12 months and 18-24 months after gastrostomy placement. Standard deviation scores (SDS) for height, weight, and body mass index as well as percent of height-appropriate body weight were calculated. RESULTS: The mean percent-of-predicted forced expiratory volume in 1 second (FEV1) decreased significantly during the first year of gastrostomy feeding (n = 16), from 44.2% +/- 13.9 to 41% +/- 13.3 (P = 0.05). However, during the second year of therapy (n = 10), a trend toward improvement was observed (from 39.4 +/- 12.1 to 41.4 +/- 16.1). Weight, and BMI z-scores as well as weight percent-of ideal body weight increased significantly. Height z-score for age decreased during the first year (from -1.9 +/- 1.3 to -2.1 +/- 1.4), However, a trend toward improvement was observed during the second year. A significant correlation was found between the change in weight z-score and height z-score during the first (r = 0.488, P = 0.016) and the second (r = 0.825, P < 0.001) years. There was no difference between compliers and noncompliers regarding height, weight, and BMI either before or after gastrostomy placement. A significant correlation between age at insertion of gastrostomy and improvement in height z-score (r = 0.52, P = 0.016) was observed. Cystic fibrosis related diabetes (n = 8) did not affect the response to supplemental feeding. CONCLUSIONS: We observed a trend toward improvement of pulmonary disease during the second year, and a significant improvement in weight, height, and BMI z-scores. Compliance, diabetes, and young age prior to tube insertion did not predict success of nutritional rehabilitation.

Adolescent↗
PubMed2006

Aspergillus bronchitis in cystic fibrosis.

Aspergillus fumigatus, a widely distributed spore-bearing fungus, is commonly grown in sputum cultures of patients with cystic fibrosis (CF). A fumigatus may cause allergic bronchopulmonary aspergillosis (ABPA), a complex condition that leads to worsening of airway inflammation and progressive damage and is diagnosed by specific criteria. In this report, we present six CF patients with respiratory deterioration that did not respond to appropriate antibiotic treatment. All had had A fumigatus in sputum cultures but did not fulfill the criteria of ABPA. Treatment with antifungal agents was followed by improvement in clinical condition. We suggest that in patients with CF, A fumigatus should be considered as a pathogen that may directly cause respiratory exacerbations. Antifungal therapy should be considered when deteriorating respiratory function is not responding to antibacterial therapy and A fumigatus is growing in sputum cultures.

Adolescent↗
PubMed2005

Pancreatitis among patients with cystic fibrosis: correlation with pancreatic status and genotype.

OBJECTIVE: Pancreatitis is an infrequent complication among patients with cystic fibrosis (CF). It has mainly been reported for patients with pancreatic sufficiency (PS). Previous studies involved only a small number of patients because they contained data from single centers. The aim of this study was to evaluate the incidence of pancreatitis in a large heterogeneous CF population, to determine the relationship with pancreatic function, and to assess whether pancreatitis is associated with specific CFTR mutations. METHODS: Physicians caring for patients with CF were approached through the CF Thematic Network or through the European Cystic Fibrosis Foundation newsletter. They were asked to provide data on their current patient cohort through a standardized questionnaire and to report how many patients they had ever diagnosed as having pancreatitis. A detailed questionnaire was then sent, to be filled out for all of their patients for whom pancreatitis had ever occurred. We defined pancreatitis as an episode of acute abdominal pain associated with serum amylase levels elevated above the ranges established by each participating center's laboratory. General clinical data included age, genotype, age at diagnosis of CF, sweat chloride concentrations, pancreatic status, biometric findings, and respiratory status. CFTR mutations were also reported according to the functional classification of classes I to V. Patients were categorized as having PS, pancreatic insufficiency (PI), or PI after an initial period of PS. PI was defined as a 72-hour stool fat loss of >7 g/day, fat absorption of <93%, or fecal elastase levels of <200 microg/g feces. Clinical data on pancreatitis included age at the first episode, amylase and lipase levels, possible triggers, and occurrence of relapses or complications. RESULTS: A total of 10071 patients with CF, from 29 different countries, who were undergoing follow-up monitoring in 2002 were surveyed. Among this group, pancreatitis had ever been diagnosed for 125 patients (1.24%; 95% confidence interval [CI]: 1.02-1.46%). There was variability in the reported rates of pancreatitis for different countries. Twenty-six centers in 15 different countries sent detailed clinical data on their patients with pancreatitis and on their whole CF clinic. This involved 3306 patients with CF and 61 cases of pancreatitis, leading to a prevalence of 1.84% (95% CI: 1.39-2.30%). The mean age of the patients with pancreatitis ever was 24.4 years (SD: 10.8 years). The first episode of pancreatitis occurred at a mean age of 19.9 years (SD: 9.6 years). The median serum amylase level at the time of pancreatitis was 746 IU/L (interquartile range: 319-1630 IU/L), and the median lipase level was 577 IU/L (interquartile range: 229-1650 IU/L). The majority of patients had PS (34 of 61 patients, 56%; 95% CI: 43-68%). Pancreatitis occurred for 15 patients with PI (25%; 95% CI: 14-35%). Eight patients developed PI after initial PS. The occurrence of pancreatitis among patients with PS was 34 cases per 331 patients, ie, 10.27% (95% CI: 7.00-13.55%); the occurrence of pancreatitis among patients with PI was 15 cases per 2971 patients, ie, 0.5% (95% CI: 0.25-0.76%). The mean age (in 2002) of the CF cohort with pancreatitis did not differ between the PS and PI subgroups. The forced expiratory volume in 1 second was significantly lower among the patients with PI than among the patients with PS, ie, 65% (SEM: 7%) vs 79% (SEM: 4%). The mean age at the occurrence of pancreatitis and the amylase and lipase levels during pancreatitis were not different for patients with pancreatitis and PI versus PS. In the group with PS, 31 of 34 patients carried at least 1 class IV or V CFTR mutation. In the groups with PI and PI after PS, 5 of 15 patients and 3 of 8 patients, respectively, carried 2 class I, II, or III CFTR mutations. Relapses and/or evolution to chronic pancreatitis occurred for 42 patients. Pancreatitis preceded the diagnosis of CF in 18 of 61 cases. These patients were significantly older than the rest of the cohort, ie, age of 28.4 years (SEM: 3.4 years) vs 22.7 years (SEM: 1.3 years). Their median age at the diagnosis of CF was also significantly greater, ie, 21.5 years (interquartile range: 11.9-31 years) vs 7.6 years (interquartile range: 0.4-17.0 years). However, the ages at the occurrence of pancreatitis were similar, ie, 21.0 years (SEM: 3.0 years) vs 19.5 years (SEM: 1.2 years). CONCLUSIONS: This study of 10071 patients with CF from 29 different countries revealed an estimated overall occurrence of pancreatitis among patients with CF of 1.24% (95% CI: 1.02-1.46%). The incidence of pancreatitis was much higher among patients with PS. However, pancreatitis was also reported for 15 patients with PI from 11 centers in 9 different countries. A correct diagnosis of pancreatitis for the reported patients with PI was supported by amylase and lipase levels increased above 500 IU/L, similar to those for patients with PS and pancreatitis. A correct diagnosis of PI for these patients with pancreatitis was supported by the adequacy of the methods used. We chose the cutoff values used to distinguish between patients with PI and control subjects without gastrointestinal disease. For one half of the patients, the diagnosis of PI was established on the basis of low levels of stool elastase (mean: 97 mug/g stool). With a cutoff value of 200 microg/g stool, this noninvasive test has high sensitivity (>95%) and high specificity (>90%) to differentiate patients with PI from control subjects with normal pancreatic function. For the other one half of the patients with PI in the cohort, the pancreatic status was determined on the basis of the 3-day fecal fat balance, with the widely used cutoff value of >7 g of fat loss per day. The most likely reason for pancreatitis occurring among patients with PI is that some residual pancreatic tissue is present among these patients. Pancreatitis is a rare complication among patients with CF. It occurred for 1.24% (95% CI: 1.02-1.46%) of a large CF cohort. Pancreatitis occurs mainly during adolescence and young adulthood. It is much more common among patients with CF and PS (10.3%), but it can occur among patients with PI (0.5%). Pancreatitis can be the first manifestation of CF. Pancreatitis was reported for patients carrying a wide range of mutations.

Adult↗
PubMed2005

Pharmacological induction of CFTR function in patients with cystic fibrosis: mutation-specific therapy.

CFTR mutations cause defects of CFTR protein production and function by different molecular mechanisms. Mutations can be classified according to the mechanisms by which they disrupt CFTR function. This understanding of the different molecular mechanisms of CFTR dysfunction provides the scientific basis for the development of targeted drugs for mutation-specific therapy of cystic fibrosis (CF). Class I mutations are nonsense mutations that result in the presence of a premature stop codon that leads to the production of unstable mRNA, or the release from the ribosome of a short, truncated protein that is not functional. Aminoglycoside antibiotics can suppress premature termination codons by disrupting translational fidelity and allowing the incorporation of an amino acid, thus permitting translation to continue to the normal termination of the transcript. Class II mutations cause impairment of CFTR processing and folding in the Golgi. As a result, the mutant CFTR is retained in the endoplasmic reticulum (ER) and eventually targeted for degradation by the quality control mechanisms. Chemical and molecular chaperones such as sodium-4-phenylbutyrate can stabilize protein structure, and allow it to escape from degradation in the ER and be transported to the cell membrane. Class III mutations disrupt the function of the regulatory domain. CFTR is resistant to phosphorylation or adenosine tri-phosphate (ATP) binding. CFTR activators such as alkylxanthines (CPX) and the flavonoid genistein can overcome affected ATP binding through direct binding to a nucleotide binding fold. In patients carrying class IV mutations, phosphorylation of CFTR results in reduced chloride transport. Increases in the overall cell surface content of these mutants might overcome the relative reduction in conductance. Alternatively, restoring native chloride pore characteristics pharmacologically might be effective. Activators of CFTR at the plasma membrane may function by promoting CFTR phosphorylation, by blocking CFTR dephosphorylation, by interacting directly with CFTR, and/or by modulation of CFTR protein-protein interactions. Class V mutations affect the splicing machinery and generate both aberrantly and correctly spliced transcripts, the levels of which vary among different patients and among different organs of the same patient. Splicing factors that promote exon inclusion or factors that promote exon skipping can promote increases of correctly spliced transcripts, depending on the molecular defect. Inconsistent results were reported regarding the required level of corrected or mutated CFTR that had to be reached in order to achieve normal function.

Aminoglycosides↗
PubMed2005

Endoscopic findings in children with obstructive sleep apnea: effects of age and hypotonia.

Obstructive sleep apnea (OSA) syndrome is a common disorder among children and is often associated with significant morbidity. The causes of OSA are related to either fixed upper airway abnormalities such as adenotonsillar hypertrophy, or dynamic airway abnormalities such as laryngomalacia and pharyngeal wall collapse. The aim of the present study was to determine the prevalence of dynamic upper airway abnormalities, based on endoscopic findings, in normotonic and hypotonic children with polysomnographically documented OSA. The records of 39 consecutive children with OSA who underwent bronchoscopy (22 with normal tone, and 17 with hypotonia) were reviewed. The prevalence of dynamic defects among children with normal tone decreased with age. All 7 patients less than 1 year old had dynamic abnormalities (isolated or combined fixed/dynamic), compared to only 66% (6/9) of patients between 1-2 years old, and 17% (1/6) of children more than 2 years old. In contrast, dynamic abnormalities were very common among hypotonic children, independent of age. Since children with dynamic defects are less likely to respond to surgical treatments, it would be appropriate to identify these children prior to any intervention. Due to the higher frequency of dynamic defects in both infants (< 1 year) and hypotonic children, it may be appropriate to include endoscopy as part of the diagnostic evaluation of OSA in these subgroups.

Adenoids↗
PubMed2004

A summer outbreak of influenza A virus infection among young children.

In the summer of 2003 in Jerusalem, Israel, 23 children were hospitalized with influenza A virus (A/Fujian/411/02-like virus) infection. The majority were neonates and infants. Clinical manifestations included neonatal fever, bronchitis, bronchiolitis, and pneumonia, and outcomes were favorable. Continued surveillance between epidemic seasons could allow early recognition of influenza strains that will appear in the following influenza season.

Child↗
PubMed2004

Familial concordance of phenotype and microbial variation among siblings with CF.

The clinical spectrum of cystic fibrosis (CF) is influenced by the cystic fibrosis transmembrane conductance regulator (CFTR) genotype. However, variable courses of the disease were demonstrated among patients with identical genotypes. Since siblings share identical CFTR mutations and environmental factors, they can serve as a model to assess the effect of modifier genes on disease expression, and also to evaluate cross-infection. The aim of this study was to compare disease expression among siblings with CF. All sibling pairs treated at 7 CF centers in Israel were included in the study. Data were collected from patients' medical charts. Fifty families with at least 2 siblings were identified. As expected, the second-born sibling was diagnosed at an earlier age compared to the first-born. The mode of CF presentation at diagnosis showed significant familial concordance. In the families where the first sibling presented with gastrointestinal manifestations, 79% of the second siblings also presented with gastrointestinal manifestations. When gastrointestinal manifestations were absent in the first sibling, only 12% of the second siblings presented with gastrointestinal manifestations (P < 0.0001). Likewise, when the first sibling presented with respiratory symptoms, 60% of the second siblings presented with the similar symptoms. However, when the first sibling presented without respiratory symptoms, only 12% of the second siblings presented with respiratory symptoms (P < 0.001). Meconium ileus (MI) was present in 20 patients (21%). In 10 families where the first-born sibling had MI, 8 (80%) of the subsequent siblings had MI. On the other hand, in the 39 families where the first-born sibling did not have MI, only 2 (5%) subsequent siblings had MI (P < 0.001). Pancreatic insufficiency (PI) also had high familial concordance (P < 0.0001). Percentile growth for weights and heights and lung function (FVC, FEV(1), and FEF(25-75)) at ages 7 and 10 years were similar between siblings. P. aeruginosa grew from sputum in 89% of our study patients. When P. aeruginosa was isolated from the first-born patient, 91% of the second siblings were also positive for P. aeruginosa, whereas when the initial sibling was not a carrier of P. aeruginosa, only 50% of subsequent siblings were positive (P < 0.0001). This familial concordance was not observed for S. aureus. By contrast, the age of first isolation of P. aeruginosa and S. aureus was significantly earlier in the second sibling than in the first for the two bacteria: 10.3 +/- 5.1 vs. 7.3 +/- 5.2 years (P < 0.05) for P. aeruginosa, and 11.5 +/- 5.4 years vs. 6.8 +/- 5.1 years (P < 0.05) for S. aureus. CF siblings tend to share similar phenotypes that are not mutation-dependent. The lack of variability between siblings in mode of initial CF presentation, rates of MI, pulmonary function, and nutritional status supports the role of modifier genes in the determination of these factors.

Adolescent↗
PubMed2004

Pharmacologic therapy for stop mutations: how much CFTR activity is enough?

PURPOSE OF REVIEW: The purpose of this review is to summarize the recent approaches using mutation-specific therapy to correct the genetic defect according to the molecular mechanism by which the mutation causes the defects in cystic fibrosis transmembrane conductance regulator (CFTR). Premature stop mutations (class I mutations) account for 5 to 10% of the total mutant alleles in cystic fibrosis patients, and in certain subpopulations the incidence is much higher. RECENT FINDINGS: The aminoglycoside antibiotics can suppress premature termination codons by permitting translation to continue to the normal termination of the transcript. The susceptibility to suppression by aminoglycosides depends on the stop codon itself and on the sequence context surrounding it. In vitro studies in cell lines expressing stop mutations and in mice have shown that aminoglycosides caused a dose-dependent increase in CFTR expression and restored functional CFTR to the apical membrane. Clinical studies also provided evidence that the aminoglycoside gentamicin can suppress these CFTR premature stop mutations in affected patients. A recent double-blind, placebo-controlled, crossover study has demonstrated restoration of CFTR function by topical application of gentamicin to the nasal epithelium of cystic fibrosis patients carrying stop mutations. In 21% of the patients there was a complete normalization of all the electrophysiologic abnormalities caused by the CFTR defect, and in 68% there was restoration of either chloride or sodium transport. Furthermore, immunohistochemical staining to the C-terminal part of the CFTR was demonstrated via peripheral staining for CFTR in scraped nasal epithelial cells of patients carrying stop mutations. Inconsistent results were reported regarding the required level of corrected CFTR that has to be reached to achieve normal function. Achieving CFTR activity of 10 to 35% might be needed to prevent significant pulmonary morbidity. SUMMARY: It is as yet unknown how much corrected mutant CFTR must reach the apical membrane to induce a clinically relevant beneficial effect. The future goal is to maximize the effect of stop-codon supressors on CFTR while minimizing side effects, but further studies must be performed to find a safer compound that may be administered in small children from the time of diagnosis.

Aminoglycosides↗
PubMed2004

Pharyngeal wall collapse and multiple synchronous airway lesions.

Pharyngeal wall inspiratory collapse (PWIC) is a dynamic obstruction of the air column proximal to the glottis during inspiration. Our objectives were to assess PWIC's incidence and its contribution to the symptoms of upper airway obstruction (UAO), and to propose indications for intervention. In a retrospective review of consecutive endoscopic evaluations and clinical data of 108 infants with UAO, PWIC was diagnosed in 50 infants (46%). The most common presenting symptom was apnea (52%). The PWIC was accompanied by 2 to 7 synchronous airway abnormalities, most frequently laryngomalacia (78%). Generalized hypotonia was the most common associated systemic finding (80%). Severe PWIC cases required bi-level positive airway pressure (BiPAP). The severity of PWIC, measured by a newly developed classification, was positively correlated to apnea (p < .05) and the need for BiPAP (p < .054). Spontaneous recovery occurred within 36 months. The incidence of PWIC among infants with UAO is high, and its role in UAO deserves greater recognition. Better diagnosis of PWIC will improve the treatment of UAO.

Airway Obstruction↗