First successful heart-lung transplantation for cystic fibrosis in Israel.
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Adolescent↗
Biomedical subjects
H Blau
Publications and source records attributed to H Blau.
Clinical and genetic risk factors for cystic fibrosis-related liver disease.
OBJECTIVE: The aim of this study was to define the role of possible risk factors for the development of cystic fibrosis (CF)-related liver disease and to analyze the association between liver disease and the different genotypes present in the Israeli CF patient population. PATIENTS AND METHODS: All patients followed at the seven CF centers in Israel were included in this study. Liver disease was determined by persistently elevated serum liver enzymes and/or bilirubin, and/or significant ultrasonographic changes suggestive of chronic liver disease. The following clinical parameters were evaluated: ethnic origin, age at assessment of liver function, sex, history of meconium ileus, pancreatic function, history of distal intestinal obstruction syndrome, pulmonary function, and cystic fibrosis transmembrane conductance regulator mutation analysis. RESULTS: Of the 288 patients screened, 80 (28%) had liver disease. Of the 256 patients with pancreatic insufficiency, 80 (31%) had liver disease compared with none of the 32 patients with pancreatic sufficiency. Genotype-phenotype correlation was performed on 207 patients carrying identified mutations that were previously classified according to phenotype severity. Liver disease was found in 56 (32%) of 173 patients carrying mutations associated with a severe phenotype and in 6 (38%) of 16 patients carrying at least one mutation associated with a variable genotype (G85E and/or 5T allele). None of the 18 patients carrying the 3849+10kb C->T mutation had liver disease. Prevalence of liver disease increased with age. No correlation was found between liver disease and severity of lung disease, nutritional status, history of meconium ileus, or distal intestinal obstruction syndrome. CONCLUSION: CF patients who have pancreatic insufficiency and carry mutations associated with a severe or a variable genotype are at increased risk to develop liver disease.
Adolescent↗
Rapid induction of clinical response with a short-term high-dose starting schedule of budesonide nebulizing suspension in young children with recurrent wheezing episodes.
BACKGROUND: There are no data currently available on the correct schedule for the initiation of treatment with nebulized suspension of budesonide in children with recurrent wheezing episodes. We compared the efficacy and safety of starting with a high dose followed by a stepwise decrease to a continuous low dose. METHODS: In a double-blind design, 42 children aged 6 months to 3 years were randomly allocated to receive either a high starting dose of 1 mg budesonide twice daily followed by a stepwise decrease of 25% every second day for 1 week (group A) or a low dose of 0.25 mg twice daily for 1 week (group B). Efficacy was assessed with daily symptom scores and the systemic effect of the corticosteroids with the adrenocorticotropic hormone test. RESULTS: The two groups were comparable for all parameters evaluated. During the first week of treatment, there was a significant decrease in asthmatic symptomatology only in group A: a 59% decrease for wheezing (p = 0.0001), 39% for diurnal cough (p = 0.036), and 39% for nocturnal cough (p = 0.04). Mean time to clinical response was 3.0 days in group A and 5.7 days in group B (p = 0.02). This early improvement was sustained for the rest of the follow-up period. The high dose starting schedule was not associated with any change in serum cortisol level. CONCLUSIONS: The administration of nebulized suspension of budesonide at a high starting dose schedule followed by a rapid (1 week) stepwise decrease yields a significant early improvement in asthma symptoms and causes no change in serum cortisol levels.
Administration, Inhalation↗
Gene therapy: progress, problems, prospects.
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Acquired Immunodeficiency Syndrome↗
Nitric oxide production by rat alveolar macrophages can be modulated in vitro by surfactant protein A.
Alveolar macrophage and type II cells are known to generate nitric oxide, which is a highly reactive molecule that plays a role in host defense against pathogens, as well as tissue damage associated with inflammation in the lung. Both types of cells are known to generate the nitric oxide by inducible nitric oxide synthase (iNOS). Surfactant-associated protein A (SP-A) from various sources (human alveolar proteinosis, rat and recombinant rat) was found to upregulate nitric oxide production by alveolar macrophages in a concentration- and time-dependent manner, whereas type II cells were unresponsive to SP-A. The increase in nitric oxide production was associated with elevation in the expression of iNOS. However, only 30-50% of the cells responded by expressing iNOS, as was observed by immunofluorescence staining. The stimulatory effect of SP-A was found to be 30-50% lower than the known nitric oxide agonists interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). However, addition of the cytokines interleukin-1 or granulocyte macrophage colony-stimulating factor elevated the levels of nitric oxide production to that of LPS and IFN-gamma. Special attention was given to exclude the possibility that contaminating LPS in the various SP-A species stimulated nitric oxide production by the macrophages. Our results indicate that SP-A is the agonist and not a contaminating LPS. The data presented in this report extend our knowledge regarding the nonsurfactant-related functions of SP-A.
Animals↗
The significance of sweat Cl/Na ratio in patients with borderline sweat test.
Recently a few cystic fibrosis (CF) patients with borderline or normal sweat tests have been reported. These patients present a diagnostic challenge. We aimed to study the sweat Cl/Na ratio in cystic fibrosis patients and to assess whether this ratio could be used as a diagnostic criteria. The mean sweat Cl/Na ratio of 3 groups was compared: Group A: 71 CF patients carrying 2 mutations known to be associated with severe disease presentation (delta F508, W1282X, G542X, N1303K, 1717-1G --> A). Group B: 10 compound heterozygous patients who carry one mutation associated with mild clinical disease (3849 + 10 kb --> T). Group C: 142 normal subjects. Sweat chloride levels higher than those of sodium were found in 96% of patients in Group A as compared to 3% of patients in Group C. In Group B 40% of the patients had sweat chloride levels higher than or equal to sodium levels. The mean Cl/Na ratio of Group A (1.2 +/- 0.1) differed significantly from that of Group B (0.94 +/- 0.1) and both groups had significant higher mean Cl/Na ratio compared to Group C (0.7 +/- 0.4) (P < 0.001). Thus in individuals with a borderline sweat test and a Cl/Na ratio > or = 1 the diagnosis of CF should be considered. However, a Cl/Na ratio < 1 does not exclude CF, since patients carrying mild mutations may have sweat sodium levels higher than those of chloride. Our findings suggest that the sweat Cl/Na ratio in CF is genetically determined and it may be of help in establishing the diagnosis of CF in patients with a borderline sweat test.
Child↗
Highly variable incidence of cystic fibrosis and different mutation distribution among different Jewish ethnic groups in Israel.
The incidence of cystic fibrosis (CF) and the frequency of disease-causing mutations varies among different ethnic and geographic populations. The Jewish population around the world is comprised of two major ethnic groups; Ashkenazi and non-Ashkenazi. The latter is further classified according to country of origin. In this study, we analyzed the incidence of CF and the distribution of CF mutations in the general Jewish population in Israel and in most of the Jewish ethnic subgroups. The disease frequency varies considerably among the latter. Among Ashkenazi Jews, the frequency of CF is 1:3300, which is similar to the frequency in most Caucasian populations. Among non-Ashkenazi Jews, the disease occurs at a similar frequency among Jews from Libya (1:2700), Georgia (1:2700), Greece and Bulgaria (1:2400), but is rare in Jews from Yemen (1:8800), Morocco (1:15000), Iraq (1:32000), and Iran (1:39000). So far, only 12 mutations have been identified in Israeli Jews, and this enables the identification of 91% of the CF chromosomes in the entire Jewish CF population. However, in each Jewish ethnic group, the disease is caused by a different repertoire of mutations. The frequency of identified mutations is high in Ashkenazi Jews (95%), and in Jews originating from Tunisia (100%), Libya (91%), Turkey (90%), and Georgia (88%). However, a lower frequency of mutations can be identified in Moroccan (85%), Egyptian (50%), and Yemenite (0%) Jews. For genetic counseling of a Jewish individual, it is necessary to calculate the residual risk according to ethnic origin. Carrier screening of healthy Jewish individuals is currently feasible for Ashkenazi Tunisian, Libyan, Turkish, and Georgian Jews. These results provide the required information for genetic counseling of Jewish CF families and screening programs of Jewish populations worldwide.
Africa, Northern↗
Interaction of surfactant protein A with bacterial lipopolysaccharide may affect some biological functions.
Cultured alveolar type II cells and alveolar macrophages were found to secrete colony-stimulating factors (CSF) into the medium. Surfactant protein A (SP-A; 0.1-5 micrograms/ml) and bacterial lipopolysaccharide (LPS; 10-20 micrograms/ml) were found to upregulate the secretion of CSF (seven-fold) from these cells. However, a reversal of the stimulatory effect was observed when the two agents were added simultaneously to the cells. SP-A-enhanced phagocytosis of bacteria by alveolar macrophages was also inhibited by simultaneous addition of SP-A and LPS. Thus some biological activities attributed to either SP-A or LPS are inhibited in the simultaneous presence of the two agents. We therefore investigated the possibility of interaction and binding between SP-A and LPS molecules. Our biochemical data that include immunoblots and enzyme-linked immunosorbent assay support the notion that SP-A is capable of binding LPS, and this interaction is time and concentration dependent. The binding was partially inhibited (60%) by antibody to SP-A. The binding was calcium independent and was not affected by excess carbohydrates such as methyl alpha-D-mannopyranoside or heparin. Lipid A, the hydrophobic component of LPS, however, inhibited the SP-A-LPS interaction and also caused a partial reversal of the binding. Thus these results indicate that lipid A is associated with this binding. The biological implication of SP-A-LPS interaction, especially during inflammatory responses, is discussed.
Animals↗
Secretion of cytokines by rat alveolar epithelial cells: possible regulatory role for SP-A.
Cultured alveolar type II cells and pulmonary epithelial (PE) cells in long-term culture were found to secrete colony-stimulating factors (CSF) into the medium in similar fashion to alveolar macrophages. CSF activity was determined by using the in vitro assay for myeloid progenitor cells [colony-forming units in culture (CFU-C)]. Both lipopolisaccharide (LPS) and interleukin-1 alpha (IL-1 alpha) were found to upregulate the secretion 6.5- to 8-fold from alveolar type II cells and macrophages. However, no stimulatory effect of these factors was observed in PE cells that release CSF into the medium constitutively, possibly due to the conditions of long-term culture. The CSF activity was partially neutralized (70% inhibition) by antibodies against murine granulocyte/macrophage (GM)-CSF and IL-3, thus indicating the presence of both GM-CSF and IL-3-like factors in the CSF. However, the presence of other cytokines in the CSF is highly probable. Surfactant-associated protein A (SP-A), which is known to play a central role in surfactant homeostasis and function, was also found to upregulate secretion of CSF (at concentrations of 0.1-5 micrograms/ml) from alveolar type II cells and macrophages. Control cells such as rat peritoneal macrophages, alveolar fibroblasts, and 3T3/NIH cell line could not be elicited by SP-A to release CSF. The results are discussed in relation to the possible participation of the alveolar epithelial cells in various intercellular signaling networks. Our studies suggest that alveolar type II cells and SP-A may play an important regulatory role in the modulation of immune and inflammatory effector cells within the alveolar space.
Animals↗
Sweat electrolytes in patients with advanced renal failure.
The sweat gland has some similarity with the convoluted tubules of the kidney. Little is known about sweat secretion and electrolyte content of sweat in the uremic gland. A pilocarpine ionotophoresis sweat test was performed in 40 patients with advanced renal failure (RF). Sweat secretion was measured and analyzed for Na, K, and Cl and correlated to blood parameters, type, and duration of dialysis. The sweat weight was significantly lower in all RF patients when compared with this parameter in healthy controls (p < 0.0001). No difference was noted between patients undergoing hemodialysis, those undergoing continuous ambulatory peritoneal dialysis, and those not undergoing dialysis. Men sweated more than women among RF patients and among controls (p < 0.0001). An inverse correlation was found between sweat weight and blood calcium levels (p < 0.001). Sweat K concentration was significantly higher (p < 0.0001) in patients with RF than in healthy controls, while the concentrations of Na and Cl were similar. Several mechanisms are suggested as possible explanations for these changes.
Aged↗
Mild cystic fibrosis and normal or borderline sweat test in patients with the 3849 + 10 kb C-->T mutation.
Different mutations in the cystic fibrosis (CF) gene appear to contribute to heterogeneity of the CF phenotype. We investigated 15 patients with CF who have the 3849 + 10 kb C-->T mutation. All were Ashkenazi Jews. Their clinical features were compared with those of CF patients with the delta F508/delta F508, W1282X/W1282X, W1282X/delta F508 mutations, which are known to be associated with a severe disease. Patients with the 3849 + 10 kb mutation were older, had been diagnosed as having CF at a more advanced age, and were in a better nutritional state. Sweat chloride values were normal (below 60 mmol/L) in 5 3849 + 10 kb patients (33%). 4 of these patients and 6 others (total 66%) had normal pancreatic function. However, age-adjusted pulmonary function did not differ between the two groups. None of the patients with 3849 + 10 kb C-->T had had meconium ileus or had liver disease or diabetes mellitus. We conclude that this mutation is associated with a mild type of CF.
Age Factors↗
Assessment of exercise capacity in asthmatic children with various degrees of activity.
Physical fitness in a group of 49 stable asthmatic children was determined by an incremental exercise test. Thirty-one normal children served as a control group. The asthmatic children were divided into three groups. Group 1 was comprised of 16 children who actively participated in organized sports, Group 2 of 16 children who did not participate in organized sports but who engaged in free-play, and Group 3 of 17 children with a sedentary life-style who avoided even free-play. The results of cardiopulmonary evaluation before and after maximal incremental exercise testing have shown that Groups 1 and 2 behaved like the control group and their physical fitness was similar. Group 3 whose life-style was sedentary had poor physical fitness as compared to the other asthmatics and to the control group. This was the result of poor cardiovascular conditioning and was unrelated to the respiratory limitation. We conclude that poor physical fitness in asthmatic children is the result of a sedentary life-style and can be potentially normalized.
Adolescent↗
[Pneumothorax in cystic fibrosis: intrapleural instillation of Atabrine].
Intrapleural instillation of quinacrine HC1 (Atabrine) was used to treat spontaneous pneumothorax in 2 young men, aged 26 and 36 years, respectively, with advanced pulmonary disease due to cystic fibrosis. Pneumothorax did not recur until 1 year later in 1 case and 2 years later in the other. This mode of therapy for pneumothorax provides a valuable alternative to surgery for the patient with cystic fibrosis, severe lung disease and marginal pulmonary reserve. Quinacrine sclerosis should be considered for management of pneumothorax in cystic fibrosis because of the high rate of recurrence. However, caution should be exercised since heart-lung transplantation cannot be performed after pleural sclerosis.
Adult↗
Expression and DNA sequence analysis of a human embryonic skeletal muscle myosin heavy chain gene.
Vertebrate myosin heavy chains (MHC) are represented by multiple genes that are expressed in a spatially and temporally distinct pattern during development. In order to obtain molecular probes for developmentally regulated human MHC isoforms, we used monoclonal antibodies to screen an expression cDNA library constructed from primary human myotube cultures. A 3.4 kb cDNA was isolated that encodes one of the first MHCs to be transcribed in human skeletal muscle development. A portion of the corresponding gene encoding this isoform has also been isolated. Expression of this embryonic MHC is a hallmark of muscle regeneration after birth and is a characteristic marker of human muscular dystrophies. During normal human development, expression is restricted to the embryonic period of development prior to birth. In primary human muscle cell cultures, devoid of other cell types, mRNA accumulation begins as myotubes form, reaches a peak 2 days later and declines to undetectable levels within 10 days. The expression of the protein encoded by the embryonic skeletal MHC gene follows a similar time course, lagging behind the mRNA by approximately two days. Thus, expression of the human embryonic gene is efficiently induced and then repressed in cultured muscle cells, as it is in muscle tissue. The study of the regulation of a human MHC isoform with a central role in muscle development and in muscle regeneration in disease states is therefore amendable to analysis at a molecular level.
Amino Acid Sequence↗
Fetal type 2 pneumocytes form alveolar-like structures and maintain long-term differentiation on extracellular matrix.
We investigated the effects of reconstituted basement membrane (a crude extract of the Engelbreth-Holm-Swarm tumor) on type 2 pneumocyte differentiation during long-term culture. Cells were derived from mature 29 d fetal rabbits. Morphology was studied by light and electron microscopy. On thin gel, the cells initially segregated into clumps; they were cuboidal with apical microvilli and contained lamellar bodies, but dedifferentiated by 8 d. On thick gel, epithelial cells associated into spherical clusters surrounding a central lumen. These alveolarlike structures persisted at least 22 d. The cells were cuboidal and had lamellar bodies and intercellular tight junctions; they exhibited polarity, with apical microvilli facing the lumen, basally located nuclei, and gel matrix abutting the basal surface. In contrast, cells cultured on plastic formed colonies, then a monolayer, but dedifferentiated 5-7 d after plating. [14C]Acetate was used to label newly synthesized phospholipids. The amount of disaturated phosphatidylcholine (DSPC), expressed as a percentage of total phosphatidylcholine (PC), was used as an indicator of surfactant lipid production; percentage DSPC synthesized by cells cultured on thick gel did not change significantly, from 55 +/- 3 at 3 d, to 63 +/- 2 at 22 d in culture. DSPC synthesized by cells cultured on plastic decreased from 57 +/- 1% at 3 d to 45 +/- 2% at 22 d (p less than 0.001), which is consistent with the morphologic evidence of dedifferentiation. Synthesis of total PC compared with total phospholipid did not vary with either time in culture or substrate. This study emphasizes the importance of a complex extracellular matrix for maintenance of type 2 pneumocyte differentiation. The system should prove useful for studying the interaction of these cells with basement membrane, including the role of events occurring at the cell surface in modulating expression of a differentiated phenotype.
Animals↗
Two-level regulation of cardiac actin gene transcription: muscle-specific modulating factors can accumulate before gene activation.
We have previously proposed that the upstream regions of the human cardiac actin gene contain sequences that interact with muscle-specific factors with direct high-level transcription of this gene in differentiated muscle cells. In this study we showed that these factors already accumulate in the dividing myoblasts of the mouse C2C12 cell line before differentiation of the cells. The endogenous cardiac actin gene in the C2C12 line is expressed only at a low level in myoblasts but at a high level when these cells differentiate into multinucleate myotubes. In contrast, human cardiac actin genes stably introduced into C2C12 cells show high-level expression in both myoblasts and myotubes, indicating that the endogenous cardiac actin gene is repressed in myoblasts by a mechanism which does not affect transfected genes. In a second muscle cell line (the rat L8 cell line), the level of expression of transfected cardiac actin genes increases when these cells differentiate into myotubes, paralleling the expression of the endogenous sarcomeric actin genes. We suggest that the level of transcriptional modulating factors is low in L8 myoblasts and increases when these cells differentiate into myotubes. Our results demonstrate that at least two steps are necessary for high-level cardiac actin gene expression: activation of the gene and subsequent modulation of its transcriptional activity. Furthermore, the results indicate that the two regulatory steps can be dissociated and that the factors involved in modulation are distinct from those involved in gene activation.
Actins↗
Cardiac actin is the major actin gene product in skeletal muscle cell differentiation in vitro.
We examined the expression of alpha-skeletal, alpha-cardiac, and beta- and gamma-cytoskeletal actin genes in a mouse skeletal muscle cell line (C2C12) during differentiation in vitro. Using isotype-specific cDNA probes, we showed that the alpha-skeletal actin mRNA pool reached only 15% of the level reached in adult skeletal muscle and required several days to attain this peak, which was then stably maintained. However, these cells accumulated a pool of alpha-cardiac actin six times higher than the alpha-skeletal actin mRNA peak within 24 h of the initiation of differentiation. After cells had been cultured for an additional 3 days, this pool declined to 10% of its peak level. In contrast, over 95% of the actin mRNA in adult skeletal muscle coded for alpha-actin. This suggests that C2C12 cells express a pattern of sarcomeric actin genes typical of either muscle development or regeneration and distinct from that seen in mature, adult tissue. Concurrently in the course of differentiation the beta- and gamma-cytoskeletal actin mRNA pools decreased to less than 10% of their levels in proliferating cells. The decreases in beta- and gamma-cytoskeletal actin mRNAs are apparently not coordinately regulated.
Actins↗
Detection of cystic-fibrosis genotypes.
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Cystic Fibrosis↗