Turner syndrome: results of the first Tunisian study group on Turner syndrome (TuSGOT).

OBJECTIVES: Early diagnosis in Turner syndrome is desirable to optimize growth and puberty and yet, it is often made late. Here, we aim to identify age at diagnosis, clinical features at presentation and potential strategies to improve the care of TS girls. METHODS: Retrospective study, including patients from 14 care centers across Tunisia including neonatal and pediatric care units, adult endocrinology and genetics departments. RESULTS: We identified 175 patients with TS, karyotype showing 45, xmonosomy in 83(47.4 %) with mosaicism in 37(20 %). Mean ± SD, median (range) age at diagnosis available in 173 patients was 13 ± 9.2,12 (birth-48) years. The diagnosis was antenatal in 4(2.3 %), from birth-2 years in 14 (8 %)with lymphoedema (8)and dysmorphic features (9),2-12 years in 53 (35.5 %) including 35 with short stature, 13-18 years in 43(28.8 %) with short stature(28) and delayed puberty(14) and 35(23.5 %) after 18 years, related to ovarian insufficiency (20) and short stature (11). The associated malformations were cardiac in 14 (12.8 %), renal in 22 (19.6 %). A total of 56 girls (32 %) had proven gonadal dysgenesis and 13 (7 %) had otological problems. Parental height was available in 71 girls (40 %) of whom 59 were below the lower end of parental target range (LTR) (83 %). CONCLUSIONS: This first Tunisian multicenter study, the first African of its kind, reveals that more than half of Turner syndrome cases are diagnosed after the age of 12 years. Subsequently, national strategies for an earlier TS diagnosis are needed such as measuring and plotting parental heights as well as introducing a systematic height screening at 5 years in Tunisia with a view to carrying out a re-audit in five years' time.

A cost-effectiveness analysis of PHiD-CV compared to PCV13 in a national immunization program setting in Tunisia.

BACKGROUND: In response to the substantial clinical and economic burden of diseases caused by Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) in Tunisia, the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) was recently introduced into the national immunization program. However, there has yet to be a full-scale health economic analysis comparing currently available pneumococcal conjugate vaccines (PCVs) in Tunisia. METHODS: A Markov model that simulated the disease processes of invasive pneumococcal disease (IPD), pneumonia, and acute otitis media (AOM) over a newborn cohort lifetime was used to evaluate the cost-effectiveness/utility of PHiD-CV and the 13-valent pneumococcal conjugate vaccine (PCV13) from payer's perspective, using 3% discounting. Vaccine effects were considered for up to 9 years of age. RESULTS: Vaccination with PHiD-CV or PCV13 was estimated to avert approximately 700 cases of IPD (200 meningitis, 500 bacteremia), and around 5,000 cases of all-cause pneumonia. However, PHiD-CV vaccination was estimated to avert around 4,000 additional AOM cases (18,000) versus PCV13 (14,000). Both PCVs were demonstrated to be cost-effective interventions, but PHiD-CV was estimated to generate additional cost savings of almost $1 million US dollars (USD) with similar levels of clinical benefits. An additional scenario which incorporated serotype-specific vaccine efficacy found no significant change in overall results. CONCLUSION: PCVs are a cost-effective strategy to relieve the burden associated with diseases caused by S. pneumoniae and NTHi in Tunisia. PHiD-CV is more cost-effective than PCV13, generating similar health benefits, at a reduced net cost of almost $1 million USD per vaccinated cohort.

Enterovirus meningitis in Tunisia (Monastir, Mahdia, 2011-2013): identification of virus variants cocirculating in France.

Acute enterovirus (EV) meningitis is a frequent cause of hospitalisation, and over 100 EV serotypes may be involved. A total of 215 patients of all ages with meningitis signs were investigated in 2 Tunisian hospitals. Their cerebrospinal fluid (CSF) was analysed retrospectively for EVs with a TaqMan real-time RT-qPCR. The virus strains were typed, and their evolutionary relationships were determined by Bayesian phylogenetic methods. An EV genome was detected in 21/215 patients (9.8%). The CSF viral loads ranged from 3.27 to 5.63 log10 genome copies/mL. The strains were identified in 13/21 patients and assigned to EV-B types. Viruses identified in Tunisian patients were genetically related to variants detected in France. The viral loads were similar in Tunisian and French patients for most EV types. The phylogenetic data and viral loads determined in Tunisian and French patients suggest that close EV variants were involved in aseptic meningitis in the 2 countries over a same period.

History of settlement of villages from Central Tunisia by studying families sharing a common founder Glycogenosis type III mutation.

Glycogen storage disease type III (GSD III; Cori disease; Forbes disease) is an autosomal recessive inherited metabolic disorder resulting from deficient glycogen debrancher enzyme activity in liver and muscle. In this study, we focused on a single AGL gene mutation p.W1327X in 16 Tunisian patients from rural area surrounding the region of Mahdia in Central Tunisia. This constitutes the largest pool of patients with this mutation ever described. This study was performed to trace the history of the patients' ancestries in a single region. After extraction of genomic DNA, exon 31 of AGL gene was sequenced. The patients were investigated for the hypervariable segment 1 of mitochondrial DNA and 17 Y-STR markers. We found that the p.W1327X mutation was a founder mutation in Tunisia Analysis of maternal lineages shows an admixture of autochthonous North African, sub-Saharan and a predominance of Eurasian haplogroups. Heterogeneity of maternal haplogroups indicates an ancient settlement. However, paternal gene flow was highly homogeneous and originates from the Near East. We hypothesize that the p.W1327X mutation was introduced into the Tunisian population probably by a recent migration event; then the mutation was fixed in a small region due to the high rate of consanguineous marriages and genetic drift. The screening for this mutation should be performed in priority for GSD III molecular diagnosis, for patients from the region of Mahdia and those from regions sharing the same settlement history.

Brain magnetic resonance imaging findings in adult patients with congenital adrenal hyperplasia: Increased frequency of white matter impairment and temporal lobe structures dysgenesis.

BACKGROUND: Congenital adrenal hyperplasia (CAH) is an inherited recessive disorder of adrenal steroidogenesis. The enzymes most commonly affected are 21-hydroxylase. Past reports suggested brain magnetic resonance imaging (MRI) abnormalities in CAH patients, affecting white matter signal, temporal lobe and amygdala structure and function. AIMS: In the present study, we aimed to investigate the frequency of white matter changes and temporal lobes structures dysgenesis in a population of patients having CAH due to 21-hydroxylase deficiency. MATERIALS AND METHODS: Neurological examination and brain MRI were performed in 26 patients. RESULTS: Neurological examination revealed mental retardation in three patients, tremor in two patients, tendon reflexes asymmetry in one patient, and cerebellar syndrome in one patient. Eleven patients (42.3%) showed MRI abnormalities: Eight of them had white matter hyperintensities, one patient had moderate atrophy in the right temporal, and hippocampal dysgenesis was found in the remaining two patients. CONCLUSIONS: Brain MRI abnormalities in CAH patients include white matter hyperintensities and temporal lobe structures dysgenesis. The mechanisms involved seem related to hormonal imbalances during brain development and exposure to excess exogenous glucocorticoids. Clinical implications of such lesions remain unclear. More extensive studies are required to define better the relationships between brain involvement and different CAH phenotypes and treatment regimens.

Antioxidant enzymes activities in obese Tunisian children.

BACKGROUND: The oxidant stress, expected to increase in obese adults, has an important role in the pathogenesis of many diseases. It results when free radical formation is greatly increased or protective antioxidant mechanisms are compromised. The main objective of this study is to evaluate the antioxidant response to obesity-related stress in healthy children. METHODS: A hundred and six healthy children (54 obese and 52 controls), aged 6-12 years old, participated in this study. The collected data included anthropometric measures, blood pressure, fasting glucose, total cholesterol, triglycerides and enzymatic antioxidants (Superoxide dismutase: SOD, Catalase: CAT and Glutathione peroxidase: GPx). RESULTS: The first step antioxidant response, estimated by the SOD activity, was significantly higher in obese children compared with normal-weight controls (p < 0.05). Mean activities of anti-radical GPx and CAT enzymes were not affected by the BMI increase. Although, total cholesterol levels were statistically higher in the obese group, there was no significant association with the SOD activity. CONCLUSIONS: The obesity-related increase of the oxidant stress can be observed even in the childhood period. In addition to the complications of an increased BMI, obesity itself can be considered as an independent risk factor of free radical production resulting in an increased antioxidant response.

Metabolic profile and cardiovascular risk factors in adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND: In congenital adrenal hyperplasia (CAH), long-term glucocorticoid treatment coupled with increased androgens may lead to undesirable metabolic effects. The aim of our report was to determine the prevalence of metabolic abnormalities and cardiovascular risk factors in a population of adult patients with CAH due to 21 hydroxylase deficiency. MATERIALS AND METHODS: Twenty-six patients (11 males and 15 females, mean age ± SD=27.4±8.2 years) were recruited. Anthropometry, body composition, metabolic parameters and cardiovascular risk factors were studied. RESULTS: Obesity (overweight included) was noted in 16 patients (61.5%), with android distribution in all cases. Bioelectrical impedance showed increased body fat mass in 12 patients (46.1%). Lipid profile alterations and carbohydrate metabolism disorders were detected in seven (26.9%) and five (19.2%) patients respectively. Moderate hepatic cytolysis, associated with hepatic steatosis, was found in one patient. Seven patients (27%) had insulin resistance. Ambulatory blood pressure monitoring showed abnormalities in six patients (23%). Increased carotid intima media thickness was found in 14 patients (53.8%). CONCLUSION: Adult CAH patients tend to have altered metabolic parameters and a higher prevalence of cardiovascular risk factors. Lifelong follow-up, lifestyle modifications, and attempts to adjust and reduce the glucocorticoid doses seem important.

High frequency of W1327X mutation in glycogen storage disease type III patients from central Tunisia.

Glycogen storage disease type III (GSD III) is an autosomal recessive disorder caused by the deficiency of glycogen debranching enzyme (AGL). It is characterized by hepatomegaly, progressive myopathy, cardiomyopathy and fasting hypoglycemia. Several mutations in AGL gene have been described in different populations. The W1327X mutation was reported in one Tunisian patient resident in Italy. We looked in this report to determine the frequency of W1327X mutation among Tunisian patients. The W1327X mutation was screening in 26 GSD III patients originated from various geographic locations in Tunisia. The sequence analysis revealed that among nine patients carried the W1327X mutation. Eight of them were from six unrelated families and they were originated from Mahdia (centre of Tunisia) suggesting the existence of a founder effect in this region. Taking into account historical migratory waves, screening for this mutation should be performed in priority for molecular diagnosis confirmation of GSD III in North African populations.

Steroid 21-hydroxylase gene mutational spectrum in 50 Tunisian patients: characterization of three novel polymorphisms.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease of steroid biosynthesis in humans. More than 90% of all CAH cases are caused by mutations of the 21-hydroxylase gene (CYP21A2), and approximately 75% of the defective CYP21A2 genes are generated through an intergenic recombination with the neighboring CYP21A1P pseudogene. In this study, the CYP21A2 gene was genotyped in 50 patients in Tunisia with the clinical diagnosis of 21-hydroxylase deficiency. CYP21A2 mutations were identified in 87% of the alleles. The most common point mutation in our population was the pseudogene specific variant p.Q318X (26%). Three novel single nucleotide polymorphism (SNP) loci were identified in the CYP21A2 gene which seems to be specific for the Tunisian population. The overall concordance between genotype and phenotype was 98%. With this study the molecular basis of CAH has been characterized, providing useful results for clinicians in terms of prediction of disease severity, genetic and prenatal counseling.

Trace element status and fatty acids metabolism during healthy ageing: an example of a population from the Tunisian eastern coast.

Micronutrients as well as essential fatty acids are indispensable for the correct functioning of the organism. The risk of disturbance in the associated nutrition and metabolism is expected to increase during ageing. In addition, it seems that trace elements are involved in the fatty acids metabolism. The aim of the present study was then to assess age-related changes in trace elements status and in plasma essential fatty acids composition with an emphasis on the desaturase activity estimation. Two hundred healthy Tunisian subjects (30-85 years old) were recruited and separated into two subgroups: elderly (65-85 years old) and middle-aged (30-60 years old). The findings revealed that plasma zinc and calcium concentrations significantly decreased according to age. The prevalence of zinc deficiency was therefore shown to increase in old age (over 60% of elderly subjects were deficient or at risk of deficiency). No age-related changes were obtained for copper or magnesium status. The Δ6 desaturase, involved in the EFAs conversion, was shown to decrease according to age and to be associated with the plasma zinc level. Since elderly subjects were at risk of nutritional imbalance, it would be interesting to set optimal dietary proportion. This will help to prevent age-associated alterations and diseases for a better and healthy ageing.

Long-term outcome of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

INTRODUCTION: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder affecting adrenal steroid synthesis. In this study, the authors aim to evaluate the impact of CAH due to 21-hydroxylase deficiency on final height (FH), bone health, cardiometabolic risk, fertility, neurocognition and quality of life in a hospital-based sample from Tunisia. METHODS: Twenty-six patients (11 males and 15 females; mean age: 27.4 ± 8.2 years) were recruited. RESULTS: Mean FH was 159.5 ± 9.7 cm. Twenty-one patients (80.7%) had a FH below the target height. Ten patients (38.4%) exhibited bone demineralization. Eight patients (30.7%) had obesity. Lipid profile alterations and carbohydrate metabolism disorders were detected in 10 (38.4%) and 5 (19.2%) patients, respectively. Seven patients (27%) had insulin resistance. Ambulatory blood pressure monitoring showed abnormalities in 6 patients (23%). Increased carotid intima-media thickness was found in 14 patients (53.8%). Inhibin B level was decreased in 4 male patients. Semen analysis showed abnormalities in 4 of 10 patients. Testicular tumors were detected in 6 of 11 patients. Anti-Müllerian hormone level was reduced in 4 female patients. Six patients showed poly-cystic ovary syndrome. Brain magnetic resonance imaging showed abnormalities in 11 patients (42.3%). Quality of life was reduced in 14 of 22 patients (63.6%). Many of the suboptimal outcomes appeared to be related to poor adherence to medication schedules, some to overtreatment. CONCLUSION: CAH patients have a number of issues due to the disease or its treatment. Regular follow-up, early lifestyle interventions, bone health assessment, testicular ultrasound and psychological management are needed.

[Idiopathic steroid-resistant nephrotic syndrome in child : study of 20 cases]. / Syndrome néphrotique idiopathique corticorésistant de l'enfant : Etude de 20 cas.

BACKGROUND: Idiopathic steroid-resistant nephrotic syndrome (ISRNS) is rare and represents a significant therapeutic dilemma for paediatricians and paediatric nephrologists. AIM: To analyze characteristics of the ISRNS in the child. METHODS: Retrospective study of 20 cases of ISRNS enrolled in paediatric department of nephrology in Sahloul hospital (Tunisia) between June 1993 and December 2007 (14 years period). RESULTS: There were eight girls and 12 boys (mean age: 5.8± 3.7 years) originating from the center or the south of Tunisia. Eight of them had a minimal-change disease (MCD), 11 a focal and segmental glomerulosclerosis (FSGS) and one a mesangioproliferative glomerulonephritis (MePGN). In this group, no family form could be identified. All patients were treated by cyclosporine associated with low dose of steroid. We noted a complete remission (CR) in nine cases, partial remission (PR) in three cases and no response to cyclosporine in eight cases. Among patients with CR, six presented MCD and three a FSGS. In this group, we observed relapse of nephrotic syndrome in six cases. End stage renal disease (ESRD) was noted in 10 patients of which five not responded to cyclosporine, two initially having presented a RC and three having since the beginning a PR. Among them, two only could be grafted; one relapses on transplant was observed with a single patient initially presenting a secondarily transformed MePGN in FSGS. CONCLUSION: Our study confirms the clinical, histological and evolutive heterogeneity of idiopathic steroid-resistant nephrotic syndrome. Although there is any therapeutic consensus in this domain, cyclosporine remains indicated in first intention in sporadic forms of ISRNS. On the other hand, renal transplantation constitutes the only therapeutic alternate in genetic forms that constantly evolve at ESRD.

Primary resistance to clarithromycin, metronidazole and amoxicillin of Helicobacter pylori isolated from Tunisian patients with peptic ulcers and gastritis: a prospective multicentre study.

BACKGROUND: The frequency of primary resistance to antibiotics in H. pylori isolates is increasing worldwide. In Tunisia, there are limited data regarding the pattern of H. pylori antibiotic primary resistance. AIM: To evaluate the primary resistance of H. pylori to clarithromycin, metronidazole and amoxicillin and to detect the mutations involved in clarithromycin resistance. MATERIALS AND METHODS: 273 strains isolated from adults and children were enrolled. The primary resistance to clarithromycin, metronidazole and amoxicillin was evaluated by means of E-test minimal inhibitory concentration (MIC). The real-time PCR using Scorpion primers was performed in all cases to assess clarithromycin primary resistance and point mutations involved. RESULTS: No resistance to amoxicillin was detected. For adults, resistance to clarithromycin and metronidazole was found respectively in 14.6% and 56.8%, and respectively in 18.8% and 25% in children. Overall, the rates of global primary resistance to clarithromycin and metronidazole in Tunisia were respectively determined in 15.4% and 51.3%.By the use of Scorpion PCR, the A2143G was the most frequent point mutation observed (88.1%), followed by the A2142G (11.9%); the A2142C was not found and 18 of 42 patients (42.8%) were infected by both the resistant and the susceptible genotype.The association of clarithromycin resistance with gender was not statistically significant, but metronidazole resistant strains were isolated more frequently in females (67.8%) than in males (32.2%) and the difference was significant. As for gastroduodenal diseases, the difference between strains isolated from patients with peptic ulceration and those with non peptic ulceration was not statistically significant. When about the distribution of resistant strains to clarithromycin and metronidazole between the three Tunisian cities (Tunis, Menzel Bourguiba and Mahdia), the difference was not statistically significant. CONCLUSION: Local data regarding the primary resistance of H. pylori to clarithromycin, metronidazole and amoxicillin and the main genetic mutation involved in clarithromycin resistance in vivo (A2143G) are necessary to prove a clear need for a periodic evaluation of antibiotic consumption and new therapeutic strategies in Tunisia in order to avoid the emergence of resistant strains.

Contribution of laparoscopy in the abdominal tuberculosis diagnosis: retrospective study of about 11 cases.

OBJECTIVE: Abdominal tuberculosis is one of the most frequent extra-pulmonary localizations. Its diagnosis is difficult and may lead to a delayed prescription of specific treatment. This study is aimed at stressing the role of laparoscopy associated with a biopsy in the diagnostic confirmation of abdominal tuberculosis particularly in doubtful cases. METHODS: The diagnostic features of 11 cases hospitalized for abdominal tuberculosis in the Paediatric Surgery Department of Fattouma Bourguiba Hospital in Monastir for a 6-year period (2001-2006), were evaluated retrospectively. The diagnosis of abdominal tuberculosis was substantiated histopathologically by laparoscopy in all cases. The epidemiological and clinical characteristics along with the laboratory, radiological and histological data were studied. RESULTS: Eleven cases of abdominal tuberculosis with a mean age of 5.6 years were diagnosed. It was peritoneal tuberculosis in all cases and associated with intestinal localization in one case. A conversion to laparotomy was practiced in three patients: appendicular plastron in one case, pseudo-tumor aspect of an intestinal loop in another case and because of their pathological aspect appendicectomy and caecum biopsy in the third. The diagnosis was confirmed histologically by biopsies in nine cases and on excision pieces in the other two cases. All patients had an uneventful course with an antituberculosis treatment. CONCLUSION: Abdominal tuberculosis is still frequent in Tunisia. Because of its non-specific clinical presentation and the limited means of investigation, a laparoscopy with biopsy should be practiced as first line diagnostic tool in case of doubtful abdominal tuberculosis. The earlier the diagnosis is established and an adapted antituberculosis treatment is started, the better the prognosis is.

Maternally inherited Leigh syndrome: T8993G mutation in a Tunisian family.

Leigh syndrome is a genetically heterogeneous, neurodegenerative disorder that predominantly affects children and leads to death within months or years. Mutations causing this disease have been found in both mitochondrial and nuclear DNA. The present report describes a Tunisian family with a maternally inherited Leigh syndrome harboring the mitochondrial T8993G mutation in the ATPase 6 gene. Polymerase chain reaction-restriction fragment length polymorphism analysis with the MspI restriction endonuclease, quantified with a digital image analyzer and gel documentation system, showed that the T8993G mutation was present with a high percentage in the blood of the three patients tested. This mutation was also detected in the asymptomatic mothers of these three patients (90, 96, and 60%). Two novel mitochondrial mutations were identified in the mitochondrial ATP6 gene -- T8741G (L72R) and A8795G (H90R) -- and three novel polymorphisms. Altogether, Leigh syndrome presenting the T8993G mutation in the ATPase 6 gene with variable heteroplasmic loads (44-98%) in a single Tunisian family is a novel finding.

[Primary hyperoxaluria in children in central Tunisia]. / Hyperoxalurie primitive chez l'enfant au centre Tunisien.

AIM: The goal of this work is to analyze clinical and therapeutics particularities of primary hyperoxaluria in children in Tunisian centre. METHODS: We studied retrospectively 15 cases of primary hyperoxaluria enrolled during 9 years period (1994-2002). RESULTS: It is about 2 boys and 13 girls (sex - ratio = 4.5) aged 2 month to 13 years (mean age: 4 years). Six patients presented the infantile form and nine the juvenile form of HP. At the moment of diagnosis, renal function was normal in one patient, moderately altered in another and severely altered in the other patients. All patients had nephrocalcinosis and 6 among them radio-opaque renal calculi associated. Diagnosis of HP was established in 11 cases by hyperoxaluria and/or important hyperoxalemia or on the data of the renal biopsy and biochemical analysis of renal calculi in 4 cases. The so-called "maghrebin" mutation (Ile244Thr) sought-after in 9 children, has cannot be identified that in 2 among them. Eight patients died of the continuations of their illness. The seven other patients again in life present a terminal renal insufficiency treated by haemodialysis. No patient could benefit from organ transplantation. CONCLUSION: Primary hyperoxaluria is a very heterogeneous disease on the plan clinic that genetic. In Tunisia where it constitutes a frequent cause of end stage renal failure, prenatal diagnosis of this disease is of a big interest.

Localization of tissue transglutaminase and N (epsilon)-(gamma) -glutamyl lysine in duodenal cucosa during the development of mucosal atrophy in coeliac disease.

Expression and transamidation activity of tissue transglutaminase (tTG) may be involved in the morphological modifications leading to the mucosal atrophy observed in coeliac disease (CD). We aimed to investigate the localization of tTG within the duodenal mucosa during the development of villous atrophy. The localization and level of expression of N epsilon-(gamma-glutamyl) lysine isopeptides which could reflect the transamidation activity of tTG were also analyzed. tTG and N epsilon-(gamma-glutamyl) lysine were localized using an immunohistochemical technique on duodenal biopsies obtained from 75 patients with CD and 51 subjects with normal mucosa (control group). The number of cases displaying tTG-expressing cells in the basement membrane and lamina propria was significantly higher in CD patients than in the control group. Moreover, the intensity of tTG staining in these areas was higher in CD. In contrast, the number of biopsies with tTG-expressing enterocytes was significantly lower in CD than in the control group. There was no difference in N epsilon-(gamma-glutamyl) lysine between the two populations. Tissue transglutaminase was differently expressed in the various areas of the mucosa according to the stage of atrophy, whereas the localization and the intensity of the labelling of N epsilon-(gamma-glutamyl) lysine isopeptides did not show any modification. The preferential localization in the basement membrane and lamina propria may reflect the involvement of tTG in the development of mucosal atrophy in CD.

[Involved factors in stability of children's asthma. A study of 150 children in Mahdia]. / Les facteurs intervenant dans la stabilite de l'asthme de l'enfant. Etude de 150 enfants de la région de Mahdia.

In order to reduce the mortality and morbidity by asthma in perpetual increasing, taking in charge of asthmatic child must be general (therapeutic and educative) with the intention to stabilize il cause of the lack of curing ait. The aim of our work was to determinate the factors in stability of asthma. Our study was retrospective, inducing 150 asthmatic children regularly observed since at least 6 months and more than 4 years old: 77 of them was judged stable and 73 unstable. Stable asthma concerned insignificatively children who are more than 8 year old, from urban areas, unexposed to tobacco living is sunny homes and when there is no associated factors like effort asthma and gastro-oesophagien reflux. Instability of asthma has been in significantly correlated with the initial severity and non adaption to treatment.