Mohammad Amin Kashef

DNAH11 Localization in the Proximal Region of Respiratory Cilia Defines Distinct Outer Dynein Arm Complexes

Primary ciliary dyskinesia (PCD) is a recessively inherited disease that leads to chronic respiratory disorders owing to impaired mucociliary clearance. Conventional transmission electron microscopy (TEM) is a diagnostic standard to identify ultrastructural defects in respiratory cilia but is not useful in approximately 30% of PCD cases, which have normal ciliary ultrastructure. DNAH11 mutations are a common cause of PCD with normal ciliary ultrastructure and hyperkinetic ciliary beating, but its pathophysiology remains poorly understood. We therefore characterized DNAH11 in human respiratory cilia by immunofluorescence microscopy (IFM) in the context of PCD. We used whole-exome and targeted next-generation sequence analysis as well as Sanger sequencing to identify and confirm eight novel loss-of-function DNAH11 mutations. We designed and validated a monoclonal antibody specific to DNAH11 and performed high-resolution IFM of both control and PCD-affected human respiratory cells, as well as samples from green fluorescent protein (GFP)-left-right dynein mice, to determine the ciliary localization of DNAH11. IFM analysis demonstrated native DNAH11 localization in only the proximal region of wild-type human respiratory cilia and loss of DNAH11 in individuals with PCD with certain loss-of-function DNAH11 mutations. GFP-left-right dynein mice confirmed proximal DNAH11 localization in tracheal cilia. DNAH11 retained proximal localization in respiratory cilia of individuals with PCD with distinct ultrastructural defects, such as the absence of outer dynein arms (ODAs). TEM tomography detected a partial reduction of ODAs in DNAH11-deficient cilia. DNAH11 mutations result in a subtle ODA defect in only the proximal region of respiratory cilia, which is detectable by IFM and TEM tomography.

HODGKIN LYMPHOMA DEVELOPING IN A 4.5-YEAR-OLD GIRL WITH HYPER-IgE SYNDROME

The authors report a case of Hodgkin lymphoma developing in a 4.5-year-old female child with hyper-IgE syndrome. This is one of the few cases of malignancy reported in this syndrome. The patient had severe atopic dermatitis, asthma, recurrent pneumonia, recurrent skin infections, and growth retardation. Immunologic evaluation revealed a high level of immunoglobulin E (7000 IU/mL) and peripheral eosinophilia. She was found to have normal values for serum IgG, IgM, IgA, WBC chemotaxis, serum complement function and normal sweat chloride test. The development of fatal Hodgkin lymphoma in this patient with hyper-IgE syndrome may suggest an increased risk for developing premature malignancies in hyper-IgE syndrome, although the precise immunologic defect is still unknown.

Lack of association between interleukin-13 gene polymorphisms (−1055 C/T and +2044 G/A) in Iranian patients with lung cancer

Lung cancer is one of the leading causes of death from cancer. Both immune cells and tumor cells play a key role in lung cancer immunity by secretion of cytokines and developing type-2 cell-mediated immune response. IL-13 is an immunoregulatory cytokine affecting tumor immunosurveillance by deviation of immune response from Th1 to Th2. In the present study we sought to determine the association of single nucleotide polymorphisms (SNPs) of IL-13 gene at positions +2044 (G/A) and −1055 (C/T) and lung cancer. One hundred forty one patients and 113 controls were recruited; control group was subdivided into smoker and nonsmoker individuals for serum detection. Genotyping was carried out by PCR-RFLP assay and IL-13 detection by ELISA method. No statistically significant difference was found in the frequency of genotypes, alleles, and haplotypes at positions +2044 (G/A) and −1055 (C/T) of IL-13 gene between lung cancer patients and controls. Serum level of IL-13 was not detectable in both groups. The results of this study reveal that although +2044 (G/A) and −1055 (C/T) SNPs in IL-13 are implicated in some pulmonary processes, they do not confer susceptibility to lung cancer in Iranian population.

Antiphospholipid antibodies and hepatitis C virus infection in Iranian thalassemia major patients.

Although the precise nature of Antiphospholipid antibodies is still not clearly defined, they are known to have association with thromboembolic events and have been found in hepatitis C virus (HCV) infection. Moreover, high prevalence of HCV infection and thrombotic risk is described in thalassemia. We aimed at investigating the prevalence of anticardiolipin antibodies (aCLAbs), lupus anticoagulant (LA), and their relation with HCV infection in Iranian thalassemic patients. Presence of anti‐HCV antibody, serum HCV‐RNA, aCLAbs, and LA activity was determined in 131 patients with thalassemia major (male/female: 63/68 aged 3–29 years) registered at thalassemia unit, Dastgheib Hospital, Shiraz, Iran. Sixty‐one healthy controls were also included. Anti‐HCV antibody was positive in 24 (18.3%), IgG aCLAbs in 56 (42.7%), and LA activity in 9 (6.9%) patients. 87.5% of patients positive for aCLAbs had a low titer of aCLAbs. Although none of the participants had a previous history of thrombosis, higher prevalence of aCLAbs was detected in thalassemic patients compared with controls. No significant difference in the prevalence of aCLAbs was found between HCV‐infected and noninfected patients. A high prevalence of aCLAbs, the majority in low titers, was detected in Iranian thalassemic patients irrespective of previous history of thrombosis and presence of HCV infection.

Bone mineral density in children wth systemic lupus erythematosus and juvenile rheumatoid arthritis.

BACKGROUND Although there is increasing interest in bone metabolism in patients with rheumatic disorders, few data exist on bone mineral density (BMD) in children with rheumatic disorders or on the association of BMD with disease-related variables. We determined BMD in Iranian children with systemic lupus erythematosus (SLE) and juvenile rheumatoid arthritis (JRA) to evaluate the relationship between disease-related variables and BMD. PATIENTS AND METHODS Twenty patients (13 girls and 7 boys) with SLE (n=15) and JRA (n=5) with a mean age of 13.10±3.29 years (range, 6–17 years), attending a pediatric rheumatology clinic and 20 healthy controls (matched for age and sex with each patient) were enrolled in a cross-sectional study between 2001 and 2003. BMD (g/cm2) of the femoral neck (BMD-F) and lumbar vertebrae (BMD-L) were measured by dual energy X-ray absorptiometry (DEXA). The correlation between BMD and cumulative dose of steroids, daily dose of steroid, disease duration, disease activity, height, weight, and age was investigated. RESULTS BMD in the patients (BMD-F=0.72±0.15, BMD-L=0.70±0.19) was significantly lower than controls (BMD-F=0.95±0.17, BMD-L=0.98±0.20, P<0.001). The severity of decreased BMD was more prominent in lumbar vertebrae than the femoral neck (P= 0.04). None of the variables were consistently related to a decrease in BMD. CONCLUSION BMD was significantly lower in patients compared with controls. It was more prominent in lumbar vertebrae (trabecular bone). Although cumulative dose of steroids and disease duration appeared to have some influence on BMD, none were independently correlated with BMD.

Combined Use of Growth Hormone and Gonadotropin-Releasing Hormone Analogue in Short Normal Adolescent Girls: A Survey from Iran

Combined therapy with gonadotropin‐releasing hormone (GnRH) analogue and growth hormone (GH) has been used to increase the height of adolescents who are not GH deficient and who have normally timed puberty. Its use, however, is still controversial. For 2 years simultaneously, we treated eight healthy girls with very low predicted adult height (PAH < 145 cm) who were entering into normally timed puberty. The GnRH analogue triptorelin pamoate (Decapeptyl, 100 μg/kg intramuscularly every 4 weeks) and GH (0.1 IU/kg/day subcutaneously, 6 days/week) were administered. The mean chronologic age (CA) of our patients was 11.01 ± 0.95 years, and mean bone age (BA) was 12.25 ± 1.13 years. With a height of 131.50 ± 5.83 cm (−2.37 ± 0.35 SD below the mean) and PAH of 140.87 ± 3.53 cm, they were all in Tanner stage 2‐3 of puberty (except one patient in stage 4). In all cases, GH and thyroid hormone deficiency were ruled out before the study began. Height and BA were measured immediately after discontinuation of therapy. PAH was determined before and at the end of therapy. Combined treatment resulted in a 4.13 ± 1.19 cm increase in PAH (p < 0.01). Height increased significantly to 142.66 ± 3.54 cm at the end of treatment (p < 0.01). Height standard deviation score for CA increased from −2.37 ± 0.35 to −2.32 ± 0.67, showing no significant improvement (p = 0.5). Height age (HA)/BA ratio and BA/CA ratio both demonstrated significant growth during the treatment (p < 0.03 and p < 0.01, respectively), whereas HA/CA ratio did not improve significantly (p < 0.32). During treatment, puberty was completely suppressed in all cases. Combination therapy with GnRH analogue and GH resulted in significant improvement in height and PAH during therapy. Additional, and perhaps more long‐term, studies are required to show whether this kind of treatment is effective in improving final adult height. The cost‐benefit of such therapies should also be taken into account.

Influence of atopic history on cord blood IgE.

eosinophilia, interstitial lung disease, necrotic nodule), and serositis (pleural effusion, pericarditis, pleuropericarditis, myocarditis).2 Respiratory pathologies generally arise after diagnosis of IBD. However, they may arise simultaneously or previously.9 Abnormalities of PFT in IBD are not so common. Obstructive and restrictive disorders and bronchial hyperreactivity can be observed.2,4,10,11,12 These findings become obvious especially in the activation period of the disease. A restrictive disorder was present in only one (5%) of our patients. However, the majority (64%) of our patients were in a remission period. Bronchial hyperreactivity in the range of 17% to 45% was detected in different studies.13,14 We detected hyperreactivity in 29% of our cases. Abnormalities such as bronchiectasis, air-trapping, tree-in-bud appearance, and ground glass opacity may be observed in HRCT even when there is no respiratory symptoms in IBD.4,9,10 Songur et al found no relationship between HRCT pathologies and PFT.7 Our study also yielded no correlation between HRCT pathologies and PFT. Alveolitis may be lymphocytic, neutrophilic, or eosinophilic according to the presence of bronchiectasis, associated granulomatous disorders, drug usage and smoking.4,15,16 Our study demonstrated lymphocytic and neutrophilic alveolitis in 40% and 6.6%, respectively. Ground glass opacity, neutrophilic alveolitis, and restrictive-type PFT were observed all together in one patient. Tracheobronchial involvement has been defined in tracheal mucosa biopsies of patients with Crohn’s disease.6 Tracheobronchitis may be an extraintestinal manifestation of Crohn’s disease and it responds very well to inhaled budesonide therapy. Camus et al have shown an intense infiltration of lymphocyte and plasma cells in mucosa biopsies.9 Karadag et al have identified lymhocyte infiltration, fibrosis and thickening in alveolar septas.4 Submucosal inflammatory cell infiltation was identified in 2 of our cases. In conclusion, there was no relationship between the radiological and hystopathological findings of the respiratory system in IBD patients. In our study, this may be due to the small number of cases. However, even in the absence of respiratory symptoms, cases with IBD should be evaluated for pulmonary involvement because extraintestinal involvement is frequently observed in IBD.