ILC3 deficiency and generalized ILC abnormalities in DOCK8-deficient patients.

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency is the main cause of the autosomal recessive hyper-IgE syndrome (HIES). We previously reported the selective loss of group 3 innate lymphoid cell (ILC) number and function in a Dock8-deficient mouse model. In this study, we sought to test whether DOCK8 is required for the function and maintenance of ILC subsets in humans. METHODS: Peripheral blood ILC1-3 subsets of 16 DOCK8-deficient patients recruited at the pretransplant stage, and seven patients with autosomal dominant (AD) HIES due to STAT3 mutations, were compared with those of healthy controls or post-transplant DOCK8-deficient patients (n = 12) by flow cytometry and real-time qPCR. Sorted total ILCs from DOCK8- or STAT3-mutant patients and healthy controls were assayed for survival, apoptosis, proliferation, and activation by IL-7, IL-23, and IL-12 by cell culture, flow cytometry, and phospho-flow assays. RESULTS: DOCK8-deficient but not STAT3-mutant patients exhibited a profound depletion of ILC3s, and to a lesser extent ILC2s, in their peripheral blood. DOCK8-deficient ILC1-3 subsets had defective proliferation, expressed lower levels of IL-7R, responded less to IL-7, IL-12, or IL-23 cytokines, and were more prone to apoptosis compared with those of healthy controls. CONCLUSION: DOCK8 regulates human ILC3 expansion and survival, and more globally ILC cytokine signaling and proliferation. DOCK8 deficiency leads to loss of ILC3 from peripheral blood. ILC3 deficiency may contribute to the susceptibility of DOCK8-deficient patients to infections.

Pediatricians' approach to children with acute urticaria.

BACKGROUND: Acute urticaria is a common condition in childhood that concerns both patients and pediatricians. The aim of this study was to evaluate the general approach of pediatricians to children with acute urticaria. METHODS: A data collection form consisting of 17 questions was created to evaluate pediatricians' general knowledge and practical approaches about urticaria. This form was distributed at the hospitals where pediatricians and pediatric residents work. The data was recorded in SPSS for Windows v.15 (SPSS, Inc., Chicago, IL, USA). The frequency (%) was used for descriptive data, while Pearson χ2 and Fisher's Exact tests were used for comparisons between groups. P<0.05 was considered significant. The study was approved by the local ethics committee. RESULTS: Pediatricians suggest that foods and food additives are the most common etiological factors in the development of urticaria and, therefore, often advise dietary changes. Second-generation antihistamines are preferred for treatment and are administered for about 5-7 days. Pediatric residents were found to prefer parenteral drug administration for the treatment of urticaria. A different generation antihistamine therapy was applied for treatment of patients who did not respond to the initial treatment. It was also determined that patients were referred to allergists when urticaria was accompanied by angioedema or when patients were resistant to conventional treatment. CONCLUSIONS: Pediatricians' knowledge regarding the diagnosis and treatment of urticaria was less extensive than expected. According to the results, there was some confusion among physicians regarding the etiological role of some foods in acute urticaria and the strategies for removal of these foods from the diet during the treatment. Participants' treatment approaches were partially correct and sufficient. In general, there were no differences observed between pediatric residents and pediatricians in terms of the management of patients with urticaria, except the route of administration.

Cyclosporin treatment improves skin findings in omenn syndrome.

Omenn syndrome is a combined immunodeficiency characterized by a generalized erythematous skin rash, enlarged lymph nodes, hepatosplenomegaly, severe susceptibility to infections, eosinophilia, and hyperimmunoglobulinemia E. A 3-month-old girl was admitted to our hospital with a history of recurrent sepsis. Physical examination revealed severe erythroderma, hepatosplenomegaly, lymphadenopathy, and failure to thrive. Laboratory findings revealed leukocytosis, lymphocytosis with high CD3 T-cells, a high CD4:CD8 ratio, absence of CD19 B-cells, high eosinophil count, and low immunoglobulin levels. A heterozygote RAG1 gene mutation was found. She had itchy, scaling, ichthyosiform erythroderma and protracted diarrhea. Cyclosporin treatment up to 10 mg/kg effectively resolved erythroderma and lowered total eosinophil counts, and she gained weight during treatment. Since extensive erythroderma with generalized itching causes patient discomfort in Omenn syndrome, cyclosporin treatment can be considered while waiting for treatment with hematopoietic stem cell transplantation.

Cold, cholinergic and aquagenic urticaria in children: presentation of three cases and review of the literature.

Urticaria can be induced with a wide variety of environmental stimuli, such as cold, pressure, vibration, sunlight, exercise, temperature changes, heat, and water. Urticaria caused by physical factors has been reported as the cause of 6-17% of the chronic urticaria in children. We present three cases here - cholinergic, cold and aquagenic urticaria - in which the diagnosis was proven with exercise, ice-cube and water provocation tests, respectively.

[Effects of Imipenem, Tobramycin and Curcumin on Biofilm Formation of Pseudomonas aeruginosa Strains]. / Pseudomonas aeruginosa Suslarinda Imipenem, Tobramisin ve Curcuminin Biyofilm Olusumu Üzerine Etkisi.

Aminoglycoside antibiotics and imipenem are reported to stimulate exopolysaccharide alginate production and cause an increased biofilm volume in Pseudomonas aeruginosa. Recently, some remarkable studies have been conducted on the effects of curcumin (Turmeric), which is the fenolic form of Curcuma longa plant, on virulence factors of P.aeruginosa. In this study, we aimed to investigate the effects of MIC and sub-MIC concentrations of imipenem, tobramycin, and curcumin on biofilm formation of P.aeruginosa strains. P.aeruginosa strains (n= 2) used in this study were isolated from deep oropharyngeal swab samples of two cystic fibrosis patients. Antimicrobial susceptibilities of the two strains to imipenem, tobramycin, and curcumin were investigated by broth microdilution method, and biofilm production was assessed by using crystal violet staining method. In our study, MIC values of imipenem, tobramycin and curcumin for strain-1 were 8 µg/ml, 8 µg/ml and 16 µg/ml, respectively, while those values were 4 µg/ml, 8 µg/ml and 16 µg/ml for strain-2. Biofilm optical density values of the strain-1 and strain-2 before being treated with the test substances were 0.937 and 0.313 (control: 0.090), respectively, Biofilm optical densities of the both strains showed an increase following treatment with MIC concentrations of imipenem and tobramycin. The treatment of the strains with MIC and sub-MIC concentrations of curcumin led to no significant increase in biofilm optical density. The data obtained in this study supported the promising inhibitory effect of curcumin on P.aeruginosa biofilms. However, further more comprehensive studies are required to provide satisfactory data about the use of curcumin to treat P.aeruginosa infections characterized by biofilm formation.

Immunoglobulin abnormalities and effects of enzyme replacement therapy in children with Gaucher disease.

Hyperimmunoglobulinemia is documented in patients with Gaucher disease of all ages. We investigated the frequency of hyperimmunoglobulinemia in 12 pediatric patients with type I and III Gaucher disease and the effects of enzyme replacement therapy on these abnormalities. The incidence of hyperimmunoglobulinemia was 77%, 66%, and 60% at the diagnosis, before and after ERT, respectively. Immunoglobulin G abnormalities were the most commonly seen isotype abnormality. After enzyme replacement therapy normalization of IgA and IgM levels were recorded but decline in IgG levels was less likely to occur. This study indicated the higher frequency of hyperimmunoglobulinemia in pediatric Gaucher patients.

Outcome of enzyme replacement therapy in Turkish patients with Gaucher disease: does late intervention affect the response?

We aimed to evaluate the outcome of enzyme replacement therapy (ERT) in Turkish Gaucher patients since it first became available in our country. Eleven patients with type I and one patient with type III Gaucher disease (GD) received therapy as 30-60 U/kg and 120 U/kg every two weeks, respectively, for at least six months, starting a mean period of 4.2 years after the diagnosis. Assessment of response included serial measurements of hematological and biochemical parameters and liver and spleen volumes. Symptoms and signs of bone disease, growth and severity scores were also evaluated. ERT in Turkish patients led to marked improvement in hematological parameters and organomegaly in the majority of them. Patients with growth failure demonstrated catch-up growth. Progression of bone disease was not observed except in two patients who experienced a delay of 15 and 8.6 years, respectively, between the diagnosis and the start of ERT.

Pulmonary tuberculosis in infants under one year of age.

This study describes the clinical and radiological features of tuberculosis in infants under one year of age. Medical records were reviewed for infants aged 12 months or less with proven tuberculosis. Six patients' data were evaluated. Cough and tachypnea were the major symptom and sign, respectively. Contact with an adult case of tuberculosis was present in five of the cases. Tuberculin skin test was positive in only one case. Mycobacterium tuberculosis was cultured from gastric aspirates of four of five infants and from cerebrospinal fluid in one case. Consolidation was the most common parenchymal lung lesion occurring in four of the patients. Mediastinal or hilar lymphadenopathies were also detected in four of the patients and calcifications were seen within the enlarged nodes in two of them. Antituberculous treatment appeared to be well tolerated without significant adverse effects. Significant radiological improvement was noted after a mean period of 4.6 months.

Effects of Intraperitoneal Injection of Allogeneic Bone Marrow-derived Mesenchymal Stem Cells on Bronchiolitis Obliterans in Mice Model.

Bone marrow-derived mesenchymal stem cells (BMSCs) can ameliorate a variety of lung diseases such as asthma, lung fibrosis, and acute lung injury by its anti-inflammatory and immunmodulatory effects. In this study, we developed a mouse model of bronchiolitis obliterans (BO) and evaluated the effects of the intraperitoneal administration of BMSCs on lung histopathology and cytokine levels. 25 BALB/c mice were divided into four groups; control group (Group I), BO developed and 1x106 BMSCs-injected group (Group II), non-BO, 1x106 BMSCs-injected group (Group III), and BO developed and saline-injected group (Group IV). Histological and immunohistochemical findings of the lung tissue and the migration of BMSCs to the lung were evaluated using light and confocal microscopy techniques. Confocal microscopy evaluations showed that there was no noteworthy amount of BMSCs in the lung tissue of group III while significant amount of BMSCs was detected in group II. Wall thicknesses of terminal bronchiole and periterminal bronchiolar collagen deposition were significantly lower in group II compared to the group IV (p<0.05). Furthermore, according to the immunohistochemical staining results, CD3, CD4, CD8, CD20, CD68 and neutrophil elastase positive immune cells of group II were stained more positive than group IV cells (p<0.05). IFN-γ IL-2 and TNF-α levels in bronchoalveolar lavage fluid (BALF) were significantly lower in group II compared to group IV (p<0.05). The findings of this study indicate that intraperitoneally administered BMSCs have potent effects on histopatological changes of the lung tissue and cytokine levels in the murine model of BO.

Efficacy of asthma education program on asthma control in children with uncontrolled asthma.

We aimed to evaluate the efficacy of a group education program on asthma control for children with uncontrolled asthma. Patients were randomized to receive 1-hour group education program with their parents or usual care. Our primary outcome was the change in asthma control test (ACT) between baseline and month 3 and secondary outcomes were health care utilizations and self report of exacerbations of asthma symptoms and missed school days. Change of ACT between baseline and 1st month and 3rd month was not significant in education and usual care groups. Health care utilizations and self reported exacerbations in the study groups were similar while missed school days were significantly higher in usual care group. The results of the study suggest that group education may play a useful role in the management of children with uncontrolled asthma but it is not significantly effective when compared with usual care.

Effects of Quercetin Treatment on Epithelium-derived Cytokines and Epithelial Cell Apoptosis in Allergic Airway Inflammation Mice Model.

Quercetin is a dietary flavonoid which has anti-inflammatory effects. This study aimed to evaluate the influence of quercetin on histopathological aspects and airway epithelium in  allergic airway  inflammation mice model. Twenty-eight BALB/c mice were randomly divided into four groups: Group I (control), Group II (untreated mice with allergic airway inflammation), Group III (allergic airway inflammation quercetin-treated [16mg/kg/day]), Group IV (allergic airway inflammation dexamethasone-treated [1mg/kg/day]). Ovalbumin was administered intraperitoneally and via inhalation to achieve allergic airway inflammation mice model and treatments were also given intraperitoneally. Epithelium thickness, subepithelial smooth muscle thickness, number of mast and goblet cells, and basement membrane thickness were examined on samples isolated from lung. Immunohistochemical evaluationof lung tissues was performed using  IL-25, IL-33, thymic stromal lymphopoietin (TSLP), terminal deoxynucleotidyl transferase-mediated dUTP nick endlabeling (TUNEL) and cysteine-dependent aspartate-specific proteases(caspase)-3 antibodies. IL-4, IL-25, IL-33, TSLP were quantified in bronchoalveolar lavage (BAL) and OVAspecific IgE levels was measured in serum by standard ELISA protocols. IL-25, IL-33, thymic stromal lymphopoietin (TSLP) and cysteine-dependent aspartate-specific proteases (caspase)-3. Quercetin treatment led to lower epithelial thickness, subepithelial smooth muscle thickness, goblet and mast cell numbers compared to untreated  mice with allergic airway inflammation (p<0.05). However, quercetin treatment was not effective on improving basal membane thickness. Immunohistochemical scores of IL-25, IL-33, TSLP, caspase-3 and TUNEL were lower in quercetin-treated mice  t compared to untreated mice with allergic airway inflammation (p<0.05). IL-4, IL-25, IL-33, TSLP levels in BAL and OVA-specific IgE in serum were lower in quercetin treated mice compared to untreated mice (p<0.05). These findings suggest that quercetin improves chronic histopathological changes except basal membrane thickness in lung tissue and its beneficial effects on inflammation might be related to modulating epithelium derived cytokines and epithelial apoptosis.

Resveratrol ameliorates 2,4-dinitrofluorobenzene-induced atopic dermatitis-like lesions through effects on the epithelium.

Background. Resveratrol is a natural polyphenol that exhibits anti-inflammatory effects. The aim of this study was to investigate the effects of resveratrol treatment on epithelium-derived cytokines and epithelial apoptosis in a murine model of atopic dermatitis-like lesions. Material and Methods. Atopic dermatitis-like lesions were induced in BALB/c mice by repeated application of 2,4-dinitrofluorobenzene to shaved dorsal skin. Twenty-one BALB/c mice were divided into three groups: group I (control), group II (vehicle control), and group III (resveratrol). Systemic resveratrol (30 mg/kg/day) was administered repeatedly during the 6th week of the experiment. After the mice had been sacrificed, skin tissues were examined histologically for epithelial thickness. Epithelial apoptosis (caspase-3) and epithelium-derived cytokines [interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP)] were evaluated immunohistochemically. Results. Epithelial thickness and the numbers of IL-25, IL-33, TSLP and caspase-3-positive cells were significantly higher in group II compared to group I mice. There was significant improvement in epithelial thickness in group III compared with group II mice (p < 0.05). The numbers of IL-25, IL-33, and TSLP-positive cells in the epithelium were lower in group III than in group II mice (p < 0.05). The number of caspase-3-positive cells, as an indicator of apoptosis, in the epithelium was significantly lower in group III than in group II mice (p < 0.05). Conclusion. Treatment with resveratrol was effective at ameliorating histological changes and inflammation by acting on epithelium-derived cytokines and epithelial apoptosis.

Cross-reactivity syndromes: presentation of two cases and review of the literature.

Cross-reactivity has important consequences in some immune disorders, including allergic and autoimmune diseases, which can affect both diagnostic and therapeutic approaches. One of the most common cross-reactivity syndromes is pollen-food syndrome (PFS). The patient is sensitized with pollen by the airways and exhibits an allergic reaction to food antigen with a structural similarity to the pollen. PFS usually presents with pruritus and swelling of the mouth and throat during or just after ingestion of fresh, uncooked fruits and vegetables. Latex fruit syndrome is another cross-reactivity syndrome. It is the association of latex allergy and allergy to plant foods, which affects up to 50% of latex-allergic patients. Here, we present two cases with crossreactivity syndrome.

Survival of an infant with homozygous surfactant protein C (SFTPC) mutation.

Lung diseases caused by surfactant protein C (SFTPC) mutations are inherited as autosomal traits with variable penetrance and severity or as sporadic disease caused by a de novo mutation on one allele. Here, we report the case of a child surviving with a homozygous surfactant protein C mutation after aggressive clinical management unlike his six siblings who died in infancy. This presentation raises the suspicion of an autosomal recessive inheritance that is discussed in this report.

Effects of inhaled L-arginine administration in a murine model of acute asthma.

Increased arginase activity in the airways decreases L-arginine and causes deficiency of bronchodilating and anti-inflammatory nitric oxide (NO) in asthma. As, it is suggested that L-arginine may have therapeutic potential in asthma treatment, we aimed to investigate the effects of inhaled L-arginine on oxygen saturation (SaO2) and airway histology in a murine model of acute asthma. Twenty eight BALB/c mice were divided into four groups; I, II, III and IV (control). All groups except the control were sensitized and challenged with ovalbumin. After establishement of acute asthma attack by metacholine administration, the mice were treated with inhaled L-arginine (Group I), saline (Group II) and budesonide (Group III), respectively. SaO2was measured by pulse oximeter just before and 5 min after methacholine. A third measurement of SaO2was also obtained 15 min after drug administration in these study groups. Inflammation in the lung tissues of the sacrificed animals were scored to determine the effects of the study drugs. The number of eosinophils in bronchoalveolar lavage (BAL) was determined. The results indicated that inflammatory scores significantly improved in groups receiving study drugs when compared with placebo and L-arginine was similar in decreasing scores when compared with budesonide. SaO2had a tendency to increase after L-arginine administration after acute asthma attack and this increase was statistically significant (p=0.043). Eosinophilia in BAL significantly reduced in group receiving L-arginine when compared with placebo (p<0.05). Thus in this study we demonstrated that L-arginine improved SaO2and inflammatory scores in an acute model of asthma.

Effects of curcumin on lung histopathology and fungal burden in a mouse model of chronic asthma and oropharyngeal candidiasis.

BACKGROUND AND AIMS: Oropharyngeal candidiasis (OPC) is one of the most common local side effects of current therapy in chronic asthma. New therapeutic options with fewer side effects and reverse chronic changes are needed. Curcumin, as a promising antiinflammatory and antifungal agent, could be a candidate of alternative therapy in asthma. This study aimed to determine the efficacy of orally administrated curcumin on lung histopathology, serum nitric oxide levels and fungal burden in a murine model of asthma and OPC. METHODS: Thirty five BALB/c mice were divided into five groups: I, II, III, IV (placebo) and V (control). All groups except the control were sensitized and challenged with ovalbumin. OPC model was established after the model of chronic asthma. Lung histology, serum nitric oxide levels and fungal burden were evaluated after 5 days of treatment with curcumin, dexamethasone, curcumin-dexamethasone combination and placebo. Evaluation of lung histology included subepithelial smooth muscle and epithelial thickness and number of goblet and mast cells by using light microscopy. RESULTS: All histological parameters improved in curcumin group similar to dexamethasone group. Curcumin and dexamethasone-curcumin combination were also as effective as dexamethasone on decreasing nitric oxide levels. Oral fungal burden was significantly lower in curcumin-treated group than dexamethasone. CONCLUSIONS: In our study we demonstrated that curcumin administration alleviates the pathological changes in asthma and decreases the fungal burden. Curcumin may have a potential effect on treating chronic asthma and decreasing the frequency of the OPC.