It has been shown that chronic bronchitis, cigarette smoke, hypoxia, and chronic airways inflamma... more It has been shown that chronic bronchitis, cigarette smoke, hypoxia, and chronic airways inflammation are associated with reduced CFTR function. Primary ciliary dyskinesia (PCD) is characterized by chronic sino-pulmonary disease and chronic bronchiectasis. We have noticed that some patients with PCD have borderline or high sweat chloride test. This may suggest acquired CFTR dysfunction in these patients. Objectives To analyze CFTR function in a large cohort of PCD patients by measuring sweat chloride and nasal potential difference (NPD), and to compare the results with control individuals and patients with CF. Methods 30 PCD patients >6 years treated at our clinic performed sweat test and NPD. For all patients with above normal values in the sweat test and NPD tests, analysis for CFTR mutations or exome analysis was performed. Results The mean (±SD) value of sweat chloride of the 30 PCD patients was 51.5±18.6 mmol/L (normal 60 mmol/L) and 9/30 had normal values. 2/17 patients had abnormal NPD and genetically confirmed PCD. Conclusions PCD patients may have abnormal sweat chloride tests; therefore, it is important to perform NPD in patients with abnormal/borderline sweat test in order to differentiate between PCD and CF and to confirm the diagnosis with genetic analysis. It is suggested that PCD should be added to the list of diseases causing false-positive sweat tests. The significance of this reduced CFTR function needs further investigation since new therapies that augment CFTR function may be beneficial in these patients.
Activation of naive T and B cells occurs only within the context of organized lymphoid tissue. Th... more Activation of naive T and B cells occurs only within the context of organized lymphoid tissue. Thus, the continuous recircula- tion of mature lymphocytes is crucial for the development of primary immune response to foreign Ags. We have previously shown that low levels of IFN- inhibit homing of B cells to the secondary lymphoid organs. In this study, we demonstrate
The Israel Medical Association journal : IMAJ, 2015
Treatment using inhaled bronchodilators for asthma with a metered dose inhaler attached to a spac... more Treatment using inhaled bronchodilators for asthma with a metered dose inhaler attached to a spacer device (MDI+S) was shown to be as efficient as nebulizers. Nevertheless, nebulizers remain the treatment of choice in most hospitals. To implement a policy change to improve asthma treatment in pediatric wards and the pediatric emergency department. The study was performed in the emergency department and pediatric wards of a university medical center. The study group comprised all children admitted with a diagnosis of asthma necessitating treatment. The medical and nursing staff of both the pediatric emergency department and the pediatric wards was trained how to use metered dose inhalers attached to spacers on a regular basis in asthmatic pediatric patients. At a preset date nebulizers were replaced by spacers and their use was monitored by the supervising physician. Salbutamol was administered by a metered dose inhaler (100 μg/puff) attached to a spacer device. The number of puffs w...
Despite the increase in fungal isolates, the significance of chronic Candida albicans airway colo... more Despite the increase in fungal isolates, the significance of chronic Candida albicans airway colonization in CF is unclear. To investigate the impact of C. albicans airway colonization on CF disease severity. Longitudinal analysis of clinical data from CF patients followed during 2003-2009 at our CF center. Patients were stratified based on their C. albicans colonization status - chronic, intermittent, and none. A total of 4,244 cultures were obtained from 91 patients (mean age 19.7 years, range 5-68). The three colonization groups were similar in age, gender,and body mass index (BMI). Compared to the non-colonized group (n = 27, 30%), the chronic C. albicans colonization group (n = 34, 37%), had a significantly lower FEV1 percent predicted (74.3 ± 23.1% vs. 93.9% ± 22.2) with a higher annual rate of FEV1 decline (- 1.9 ± 4.2% vs. 0.7 ± 4.5%). The patients who were intermittently colonized with C. albicans had intermediate values. Chronic respiratory colonization of C. albicans is a...
Population carrier screening (PCS) has been available in Israel since 1999 and universally subsid... more Population carrier screening (PCS) has been available in Israel since 1999 and universally subsidized since 2008. We sought to evaluate its impact. A retrospective review of governmental databanks, the national CF registry and CF centers. CF rate per 100,000 live births has decreased from 14.5 in 1990 to 6 in 2011. From 2004-2011 there were 95 CF births: 22 utilized PCS; 68 (72%) had 2 known CFTR mutations; 37% were pancreatic sufficient. At diagnosis, age was 6 (0-98) months; 53/95 had respiratory symptoms, 41/95 failure to thrive and 19/95 pseudomonas. Thirty-four (36%) were Arabs and 19 (20%) orthodox Jews, compared to 20% and 8% respectively, in the general population. PCS markedly reduced CF birth rates with a shift towards milder mutations, but was often avoided for cultural reasons. As children regularly have significant disease at diagnosis, we suggest a balanced approach, utilizing both PCS and newborn screening.
Repair of injured lungs represents a longstanding therapeutic challenge. We show that human and m... more Repair of injured lungs represents a longstanding therapeutic challenge. We show that human and mouse embryonic lung tissue from the canalicular stage of development (20-22 weeks of gestation for humans, and embryonic day 15-16 (E15-E16) for mouse) are enriched with progenitors residing in distinct niches. On the basis of the marked analogy to progenitor niches in bone marrow (BM), we attempted strategies similar to BM transplantation, employing sublethal radiation to vacate lung progenitor niches and to reduce stem cell competition. Intravenous infusion of a single cell suspension of canalicular lung tissue from GFP-marked mice or human fetal donors into naphthalene-injured and irradiated syngeneic or SCID mice, respectively, induced marked long-term lung chimerism. Donor type structures or 'patches' contained epithelial, mesenchymal and endothelial cells. Transplantation of differentially labeled E16 mouse lung cells indicated that these patches were probably of clonal origin from the donor. Recipients of the single cell suspension transplant exhibited marked improvement in lung compliance and tissue damping reflecting the energy dissipation in the lung tissues. Our study provides proof of concept for lung reconstitution by canalicular-stage human lung cells after preconditioning of the pulmonary niche.
World journal of gastroenterology : WJG, Jan 7, 2015
To investigate the long-term follow-up of distal intestinal obstruction syndrome (DIOS) in Israel... more To investigate the long-term follow-up of distal intestinal obstruction syndrome (DIOS) in Israeli cystic fibrosis (CF) patients. This is a multi-center, comparative, retrospective study in which we reviewed the medical records of all CF patients from three major CF centers in Israel who were treated in the period from 1980 to 2012. Patients diagnosed with DIOS were defined as the study group. The patients were diagnosed with DIOS based on their clinical presentation and typical findings on either abdominal X-ray or computerized tomography scan. For the control group, CF patients with no DIOS were matched to the patients in the study group for age, sex, and cystic fibrosis transmembrane conductance regulator (CFTR) mutations. For both groups, the collected data included age, sex, CFTR genotype, weight, height, and body mass index. Clinical data included respiratory function tests in the last five years prior to the study, respiratory function test immediately before and after the DI...
Asthma is a disease manifested by recurrent episodes of shortness of breath, wheezing or cough th... more Asthma is a disease manifested by recurrent episodes of shortness of breath, wheezing or cough that often require treatment at the emergency department or even hospitalization. These exacerbations are caused by an increased inflammatory process in the airways. This review focuses on the various daily long term control medications used to prevent exacerbations. The pharmacotherapy used to manage asthma is based mainly on inhaled corticosteroids (ICS and leukotriene receptor antagonists. In more severe cases, other drugs can be added, such as long-acting beta 2 agonists lare used only in conjunction with ICS] as well as additional drugs such as slow release theophylline, anti-lgE monoclonal antibodies, and more. The step-up step-down approach is used to decide on the controller medication needed. If the preventive therapy fails, it is essential to assess the adherence to therapy, the technique used, the existence of aggravating factors and the possibility that the cause of the symptom...
The Israel Medical Association journal : IMAJ, 2002
One of the measures adopted in Israel since 1959 as part of the tuberculosis control program was ... more One of the measures adopted in Israel since 1959 as part of the tuberculosis control program was screening children aged 12-13 years old. The screening comprised single-step tuberculin skin testing using the Mantoux method. To assess the efficacy of tuberculin skin screening for TB in schoolchildren in southwestern Israel as well as the compliance to treatment for latent tuberculosis infection. We retrospectively reviewed the records of children in the Ashkelon region who underwent a tuberculin skin test during the period 1995-99. Of the 28,016 eligible children, 27,232 were tested. In 923 children, mostly from the former USSR and Ethiopia, an induration of 10 mm or more was found. Only 52 Israeli-born children tested positive. Tuberculosis was found in seven children with a positive test, five of whom were from Ethiopia. All children who tested positive were referred to the local TB clinic; only 266 children (28.8%) presented. Only 151 completed the recommended treatment of isoniaz...
American journal of respiratory cell and molecular biology, Jan 19, 2015
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder caused by seve... more Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder caused by several distinct defects in genes responsible for ciliary beating leading to defective mucociliary clearance often associated with randomization of left/right body asymmetry. PCD individuals with defective radial spoke heads are difficult to diagnose due to lack of gross ultrastructural defects and absence of situs inversus. Thus far, most RSPH mutations identified are loss-of function mutations, and missense variants have been rarely described. We studied the consequences of different RSPH9, RSPH4A, and RSPH1 mutations on the assembly of the radial spoke complex to improve diagnostics in PCD. We report 21 PCD individuals (16 families) with bi-allelic mutations in RSPH9, RSPH4A and RSPH1 including 7 novel mutations comprising missense variants and performed high-resolution immunofluorescence analysis of human respiratory cilia. Missense variants are frequent genetic defects in PCD with radia...
Asthma treatment per Global Initiative for Asthma (GINA) guidelines targets airway remodeling and... more Asthma treatment per Global Initiative for Asthma (GINA) guidelines targets airway remodeling and achievement of normal lung function. To study inhaled steroid therapy on airway remodeling and achievement of normal lung function. SUBJECTS AND SET UP: Asthmatic patients were followed over 5 years . The children were divided into two groups. Group I (148 children-treated group) consisted of all the children using inhaled steroids on a regular basis and group II (50 children-untreated group) included patients with mild intermittent asthma who did not use inhaled steroids and were treated with bronchodilators as needed. Detailed medication and compliance history were recorded and the children underwent regular pre- and post-bronchodilator spirometry and physician examination. The incidence of airways remodeling as defined by the low FEV1/FVC post-bronchodilator was markedly increased over the 5-year period in the untreated group compared to the treated group. In the treated group the FEV1/FVC ratio post-bronchodilator decreased from 35% to 20.9% (P<0.009%) compared with the untreated group where the number of children with low FEV(1)/FVC post-bronchodilator increased from 10% to 28% by the end of the study period. Patients with mild asthma who do not receive regular inhaled steroids are at increased risk for airway remodeling. Therefore, we recommend that children with mild intermittent asthma undergo regular pulmonary function testing and that if any deterioration is detected in the FEV1/FVC ratio post-bronchodilators; preventative inhaled corticosteroid therapy be initiated.
The treatment of bacterial community-acquired pneumonia (CAP) is based on appropriate antibiotic ... more The treatment of bacterial community-acquired pneumonia (CAP) is based on appropriate antibiotic therapy and supportive care such as intravenous fluids and supplemental oxygen. There is no available data regarding the use of steroids in CAP in children. We present an unusual case of a child with severe respiratory distress, on the brink of mechanical ventilation, due to a rapidly expanding pneumococcal pneumonia. The administration of systemic steroids resulted in a dramatic response with rapid improvement of clinical and radiological abnormalities followed by improvement of laboratory abnormalities. This case report should raise the awareness of the potential benefits of steroids in the treatment of severe pneumonia in children. Prospective randomized trials are needed to confirm the efficacy of steroids in this setting and to determine which patients would benefit most from this.
It has been shown that chronic bronchitis, cigarette smoke, hypoxia, and chronic airways inflamma... more It has been shown that chronic bronchitis, cigarette smoke, hypoxia, and chronic airways inflammation are associated with reduced CFTR function. Primary ciliary dyskinesia (PCD) is characterized by chronic sino-pulmonary disease and chronic bronchiectasis. We have noticed that some patients with PCD have borderline or high sweat chloride test. This may suggest acquired CFTR dysfunction in these patients. Objectives To analyze CFTR function in a large cohort of PCD patients by measuring sweat chloride and nasal potential difference (NPD), and to compare the results with control individuals and patients with CF. Methods 30 PCD patients >6 years treated at our clinic performed sweat test and NPD. For all patients with above normal values in the sweat test and NPD tests, analysis for CFTR mutations or exome analysis was performed. Results The mean (±SD) value of sweat chloride of the 30 PCD patients was 51.5±18.6 mmol/L (normal 60 mmol/L) and 9/30 had normal values. 2/17 patients had abnormal NPD and genetically confirmed PCD. Conclusions PCD patients may have abnormal sweat chloride tests; therefore, it is important to perform NPD in patients with abnormal/borderline sweat test in order to differentiate between PCD and CF and to confirm the diagnosis with genetic analysis. It is suggested that PCD should be added to the list of diseases causing false-positive sweat tests. The significance of this reduced CFTR function needs further investigation since new therapies that augment CFTR function may be beneficial in these patients.
Activation of naive T and B cells occurs only within the context of organized lymphoid tissue. Th... more Activation of naive T and B cells occurs only within the context of organized lymphoid tissue. Thus, the continuous recircula- tion of mature lymphocytes is crucial for the development of primary immune response to foreign Ags. We have previously shown that low levels of IFN- inhibit homing of B cells to the secondary lymphoid organs. In this study, we demonstrate
The Israel Medical Association journal : IMAJ, 2015
Treatment using inhaled bronchodilators for asthma with a metered dose inhaler attached to a spac... more Treatment using inhaled bronchodilators for asthma with a metered dose inhaler attached to a spacer device (MDI+S) was shown to be as efficient as nebulizers. Nevertheless, nebulizers remain the treatment of choice in most hospitals. To implement a policy change to improve asthma treatment in pediatric wards and the pediatric emergency department. The study was performed in the emergency department and pediatric wards of a university medical center. The study group comprised all children admitted with a diagnosis of asthma necessitating treatment. The medical and nursing staff of both the pediatric emergency department and the pediatric wards was trained how to use metered dose inhalers attached to spacers on a regular basis in asthmatic pediatric patients. At a preset date nebulizers were replaced by spacers and their use was monitored by the supervising physician. Salbutamol was administered by a metered dose inhaler (100 μg/puff) attached to a spacer device. The number of puffs w...
Despite the increase in fungal isolates, the significance of chronic Candida albicans airway colo... more Despite the increase in fungal isolates, the significance of chronic Candida albicans airway colonization in CF is unclear. To investigate the impact of C. albicans airway colonization on CF disease severity. Longitudinal analysis of clinical data from CF patients followed during 2003-2009 at our CF center. Patients were stratified based on their C. albicans colonization status - chronic, intermittent, and none. A total of 4,244 cultures were obtained from 91 patients (mean age 19.7 years, range 5-68). The three colonization groups were similar in age, gender,and body mass index (BMI). Compared to the non-colonized group (n = 27, 30%), the chronic C. albicans colonization group (n = 34, 37%), had a significantly lower FEV1 percent predicted (74.3 ± 23.1% vs. 93.9% ± 22.2) with a higher annual rate of FEV1 decline (- 1.9 ± 4.2% vs. 0.7 ± 4.5%). The patients who were intermittently colonized with C. albicans had intermediate values. Chronic respiratory colonization of C. albicans is a...
Population carrier screening (PCS) has been available in Israel since 1999 and universally subsid... more Population carrier screening (PCS) has been available in Israel since 1999 and universally subsidized since 2008. We sought to evaluate its impact. A retrospective review of governmental databanks, the national CF registry and CF centers. CF rate per 100,000 live births has decreased from 14.5 in 1990 to 6 in 2011. From 2004-2011 there were 95 CF births: 22 utilized PCS; 68 (72%) had 2 known CFTR mutations; 37% were pancreatic sufficient. At diagnosis, age was 6 (0-98) months; 53/95 had respiratory symptoms, 41/95 failure to thrive and 19/95 pseudomonas. Thirty-four (36%) were Arabs and 19 (20%) orthodox Jews, compared to 20% and 8% respectively, in the general population. PCS markedly reduced CF birth rates with a shift towards milder mutations, but was often avoided for cultural reasons. As children regularly have significant disease at diagnosis, we suggest a balanced approach, utilizing both PCS and newborn screening.
Repair of injured lungs represents a longstanding therapeutic challenge. We show that human and m... more Repair of injured lungs represents a longstanding therapeutic challenge. We show that human and mouse embryonic lung tissue from the canalicular stage of development (20-22 weeks of gestation for humans, and embryonic day 15-16 (E15-E16) for mouse) are enriched with progenitors residing in distinct niches. On the basis of the marked analogy to progenitor niches in bone marrow (BM), we attempted strategies similar to BM transplantation, employing sublethal radiation to vacate lung progenitor niches and to reduce stem cell competition. Intravenous infusion of a single cell suspension of canalicular lung tissue from GFP-marked mice or human fetal donors into naphthalene-injured and irradiated syngeneic or SCID mice, respectively, induced marked long-term lung chimerism. Donor type structures or 'patches' contained epithelial, mesenchymal and endothelial cells. Transplantation of differentially labeled E16 mouse lung cells indicated that these patches were probably of clonal origin from the donor. Recipients of the single cell suspension transplant exhibited marked improvement in lung compliance and tissue damping reflecting the energy dissipation in the lung tissues. Our study provides proof of concept for lung reconstitution by canalicular-stage human lung cells after preconditioning of the pulmonary niche.
World journal of gastroenterology : WJG, Jan 7, 2015
To investigate the long-term follow-up of distal intestinal obstruction syndrome (DIOS) in Israel... more To investigate the long-term follow-up of distal intestinal obstruction syndrome (DIOS) in Israeli cystic fibrosis (CF) patients. This is a multi-center, comparative, retrospective study in which we reviewed the medical records of all CF patients from three major CF centers in Israel who were treated in the period from 1980 to 2012. Patients diagnosed with DIOS were defined as the study group. The patients were diagnosed with DIOS based on their clinical presentation and typical findings on either abdominal X-ray or computerized tomography scan. For the control group, CF patients with no DIOS were matched to the patients in the study group for age, sex, and cystic fibrosis transmembrane conductance regulator (CFTR) mutations. For both groups, the collected data included age, sex, CFTR genotype, weight, height, and body mass index. Clinical data included respiratory function tests in the last five years prior to the study, respiratory function test immediately before and after the DI...
Asthma is a disease manifested by recurrent episodes of shortness of breath, wheezing or cough th... more Asthma is a disease manifested by recurrent episodes of shortness of breath, wheezing or cough that often require treatment at the emergency department or even hospitalization. These exacerbations are caused by an increased inflammatory process in the airways. This review focuses on the various daily long term control medications used to prevent exacerbations. The pharmacotherapy used to manage asthma is based mainly on inhaled corticosteroids (ICS and leukotriene receptor antagonists. In more severe cases, other drugs can be added, such as long-acting beta 2 agonists lare used only in conjunction with ICS] as well as additional drugs such as slow release theophylline, anti-lgE monoclonal antibodies, and more. The step-up step-down approach is used to decide on the controller medication needed. If the preventive therapy fails, it is essential to assess the adherence to therapy, the technique used, the existence of aggravating factors and the possibility that the cause of the symptom...
The Israel Medical Association journal : IMAJ, 2002
One of the measures adopted in Israel since 1959 as part of the tuberculosis control program was ... more One of the measures adopted in Israel since 1959 as part of the tuberculosis control program was screening children aged 12-13 years old. The screening comprised single-step tuberculin skin testing using the Mantoux method. To assess the efficacy of tuberculin skin screening for TB in schoolchildren in southwestern Israel as well as the compliance to treatment for latent tuberculosis infection. We retrospectively reviewed the records of children in the Ashkelon region who underwent a tuberculin skin test during the period 1995-99. Of the 28,016 eligible children, 27,232 were tested. In 923 children, mostly from the former USSR and Ethiopia, an induration of 10 mm or more was found. Only 52 Israeli-born children tested positive. Tuberculosis was found in seven children with a positive test, five of whom were from Ethiopia. All children who tested positive were referred to the local TB clinic; only 266 children (28.8%) presented. Only 151 completed the recommended treatment of isoniaz...
American journal of respiratory cell and molecular biology, Jan 19, 2015
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder caused by seve... more Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder caused by several distinct defects in genes responsible for ciliary beating leading to defective mucociliary clearance often associated with randomization of left/right body asymmetry. PCD individuals with defective radial spoke heads are difficult to diagnose due to lack of gross ultrastructural defects and absence of situs inversus. Thus far, most RSPH mutations identified are loss-of function mutations, and missense variants have been rarely described. We studied the consequences of different RSPH9, RSPH4A, and RSPH1 mutations on the assembly of the radial spoke complex to improve diagnostics in PCD. We report 21 PCD individuals (16 families) with bi-allelic mutations in RSPH9, RSPH4A and RSPH1 including 7 novel mutations comprising missense variants and performed high-resolution immunofluorescence analysis of human respiratory cilia. Missense variants are frequent genetic defects in PCD with radia...
Asthma treatment per Global Initiative for Asthma (GINA) guidelines targets airway remodeling and... more Asthma treatment per Global Initiative for Asthma (GINA) guidelines targets airway remodeling and achievement of normal lung function. To study inhaled steroid therapy on airway remodeling and achievement of normal lung function. SUBJECTS AND SET UP: Asthmatic patients were followed over 5 years . The children were divided into two groups. Group I (148 children-treated group) consisted of all the children using inhaled steroids on a regular basis and group II (50 children-untreated group) included patients with mild intermittent asthma who did not use inhaled steroids and were treated with bronchodilators as needed. Detailed medication and compliance history were recorded and the children underwent regular pre- and post-bronchodilator spirometry and physician examination. The incidence of airways remodeling as defined by the low FEV1/FVC post-bronchodilator was markedly increased over the 5-year period in the untreated group compared to the treated group. In the treated group the FEV1/FVC ratio post-bronchodilator decreased from 35% to 20.9% (P<0.009%) compared with the untreated group where the number of children with low FEV(1)/FVC post-bronchodilator increased from 10% to 28% by the end of the study period. Patients with mild asthma who do not receive regular inhaled steroids are at increased risk for airway remodeling. Therefore, we recommend that children with mild intermittent asthma undergo regular pulmonary function testing and that if any deterioration is detected in the FEV1/FVC ratio post-bronchodilators; preventative inhaled corticosteroid therapy be initiated.
The treatment of bacterial community-acquired pneumonia (CAP) is based on appropriate antibiotic ... more The treatment of bacterial community-acquired pneumonia (CAP) is based on appropriate antibiotic therapy and supportive care such as intravenous fluids and supplemental oxygen. There is no available data regarding the use of steroids in CAP in children. We present an unusual case of a child with severe respiratory distress, on the brink of mechanical ventilation, due to a rapidly expanding pneumococcal pneumonia. The administration of systemic steroids resulted in a dramatic response with rapid improvement of clinical and radiological abnormalities followed by improvement of laboratory abnormalities. This case report should raise the awareness of the potential benefits of steroids in the treatment of severe pneumonia in children. Prospective randomized trials are needed to confirm the efficacy of steroids in this setting and to determine which patients would benefit most from this.
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Papers by David Shoseyov