Assessment of IgE- and cell-mediated immunity in pediatric patients with eosinophilic esophagitis.

Summary: Eosinophilic esophagitis (EoE) is a chronic allergen/immune-mediated disease leading to esophageal dysfunction. Food allergens play critical roles in the pathogenesis and treatment of EoE via different mechanisms. This study aimed to present the characteristics and evaluate the ability of skin prick test (SPT), skin prick to prick test (SPP) (IgE-mediated), and atopic patch test (APT) (cell-mediated) individually or simultaneously to diagnose food allergy in patients suffering from EoE. This prospective study was conducted on 58 patients with EoE. Seven patients (12.1%) were positive to only one, 3 (5.2%) were simultaneously positive to two, and 32 (55.2%) were simultaneously positive to three tests. Single and double sensitizations were totally 10.4% in IgE-mediated reactions, while 36.5% in cell-mediated reactions. In contrast, poly sensitization (> 2 allergens) was 51.7% in IgE-mediated tests and 20.7% in the cell-mediated test. Multiple sensitization findings showed egg white, milk, yolk, and soy were the most frequent allergens. Our findings indicate that EoE is early onset and associated with multiple food sensitizations, particularly via IgE-mediated mechanisms. These immune-mediated responses encompass both IgE-mediated (SPT and SPP) and cell-mediated (APT) reactions simultaneously not individually. Therefore, employing multiple assays may strengthen the diagnosis of food sensitization.

Household transmission of 2009 H1N1 influenza virus in Yazd, Iran.

OBJECTIVES: The 2009 pandemic influenza A (H1N1) virus is a public health challenge. Notably, laboratory-confirmed cases do not represent the age group most susceptible to infection. To characterize the age distribution of all cases of H1N1 influenza, we studied the personal contacts of confirmed cases to identify the age group at the highest risk. METHODS: We investigated the family members of 162 laboratory-confirmed cases of 2009 H1N1 in Yazd, Iran. Family members were retrospectively asked whether they had ≥2 respiratory symptoms within 7days of the last contact with the associated index cases. The ages and symptoms of the patients as well as the interval between diagnosis and the onset of symptoms among household contacts were determined using a questionnaire. RESULTS: We identified 596 family members of index cases, 83 (13.9%) of whom developed acute respiratory illness. No acute respiratory illness was found in 104 families (64%); however, there were 2 cases in 15 families (9.3%) and ≥3 cases in 4 families (24%). Household contacts from 5 to 18years old were more susceptible to acute respiratory illness than those who were ≥51years old (RR=3.174, 95% CI 1.313-7.675 P-value=0.01). CONCLUSION: Individuals ≤18years old were most susceptible to infection by the H1N1 virus. Therefore, in low-income populations, prevention of the spread of H1N1 to this age group should be emphasized.

Full and partial peroxisome proliferation-activated receptor-γ agonists, but not δ agonist, rescue of dopaminergic neurons in the 6-OHDA parkinsonian model is associated with inhibition of microglial activation and MMP expression.

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor that has been shown to have anti-inflammatory and matrix metalloproteinase (MMP) inhibitor properties. PPARγ agonists have been shown to have neuroprotective effects in various neurodegeneration models where inflammation is implicated, including models of Parkinson's disease. However, no studies have looked at the effects of partial PPARγ agonists. EXPERIMENTAL APPROACH: The neuroprotective effects of the PPARγ full agonist, pioglitazone (20 mg/kg), partial PPARγ agonist GW855266X (15 mg/kg) and PPAR-δ full agonist GW610742X (10 mg/kg) were investigated in the 6-hydroxydopamine (6-OHDA) model of Parkinson's disease when administered prior to or post 6-OHDA lesioning. The integrity of the nigrostriatal system was assessed by assessing the numbers dopaminergic neurons in the substantia nigra (SN) and by assessing striatal dopamine content. The degree of microglia activation in the SN was also immunohistochemistry assessed utilizing the marker OX-6 for activated microglia and CD-68 a marker for phagocytic microglia. Additionally we performed immunocytochemistry for MMP3 in the SN. Finally, we investigated whether a period of drug withdrawal for a further 7 days affected the neuroprotection produced by the PPARγ agonists. KEY RESULTS: Both pioglitazone and GW855266X protected against 6-OHDA induced loss of dopaminergic neurons in the substantia nigra and depletion of striatal dopamine when administered orally twice daily for either 1) 7 day prior to and 7 days post lesioning or 2) for 7 days starting 2 days post lesioning when neurons will be severely traumatized. 6-OHDA lesioning was associated with an increase in microglia activation and in numbers of MMP-3 immunoreactive cells which was attenuated by pioglitazone and GW855266X. Neuroprotective effects were not replicated using the PPARδ agonist GW610742X. Subsequent withdrawal of both pioglitazone and GW855266X, for a further 7 days negated any neuroprotective effect suggesting that long-term administration may be required to attenuate the inflammatory response. CONCLUSIONS AND IMPLICATIONS: For the first time a partial PPAR-γ agonist has been shown to be neuroprotectory when administered post lesioning in a parkinsonian model. Effects may be via the inhibition of microglial and MMP activation and support further research.

Cyproheptadine for the treatment of functional abdominal pain in childhood: a double-blinded randomized placebo-controlled trial.

AIM: The management of functional abdominal pain (FAP) in children and adolescents is challenging for health care professionals, and there are only limited or inconclusive studies of pharmacologic or behavioral therapy in childhood FAP. The objective of this randomized placebo-controlled clinical trial was to determine the potential efficacy and safety of cyproheptadine in the treatment of pediatric FAP. METHODS: Between January 2006 and March 2007, 29 clinically referred children and adolescents with FAP (aged 4.5 to 12 years) completed a 2-week, double-blinded randomized placebo-controlled trial of cyprohetadine. Primary outcome measure was the self-reported change of frequency and duration of abdominal pain by using a 6-point scale, and the parents' impression or assessment of the children's improvement. RESULTS: By week 1 and 2 of the intervention, the intensity and frequency of abdominal pain among the patients treated with cyproheptadine, were rated as complete resolved and very much improved or improved for 3 (20%), 10 (66.6%), respectively. However, in the placebo-receiver children, these scales had no change in 7 (50%), rated as improved or very much improved in 5 (35.7%), and become worse in 2 (14.3%). The patients' self-reported and the parents' impression in the cyproheptadine group were significantly better than it in the placebo group (P=0.003). CONCLUSION: Among children with functional abdominal pain, cyproheptadine is enough effective to improve the intensity and frequency of abdominal pain in a short-term period.

Association between ABO and Rhesus blood group systems among confirmed human T lymphotropic virus type 1-infected patients in Northeast Iran.

The distribution of ABO and Rhesus blood group types was investigated in 984 randomly selected human T lymphotropic virus-1(HTLV-1)-infected blood donors from April 2004 to March 2007. A total of 1081 healthy controls admitted for blood donation in this period were enrolled in this study. Infected and control individuals were from the same region and their ABO/Rhesus blood group types were determined by the standard tube test technique. All blood samples were screened for HTLV-1 using an enzyme-linked immunosorbent assay (ELISA) and positive samples were confirmed by Western blot (WB). The unmatched analyses showed significant differences in frequency of the A+ blood group between healthy controls and HTLV-1-infected individuals (OR = 0.8, 95% CI = 0.66-0.97) and also a significant association was observed between these two groups(OR = 1.42, 95% CI = 1.1-1.99, p = 0.021). No significant difference in blood group (A-, B+, B-, O+, O-, and AB-) was observed between cases and controls. It is the first report of an association between HTLV-1-infected patients and ABO/Rh blood groups in our literature review. Our results might suggest that the A+ blood group decrease the risk of HTLV-1 infection in healthy controls, while the AB+ blood group is more frequent in HTLV-1 carriers and increases the risk of HTLV-1 infection.

A novel ligand in lymphocyte-mediated cytotoxicity: expression of the beta subunit of H+ transporting ATP synthase on the surface of tumor cell lines.

Extracellular adenosine triphosphate (eATP) has been suggested to play a role in lymphocyte-induced tumor destruction. We now provide evidence that a protein responsible for ATP synthesis in mitochondria may also play a physiologic role in major histocompatibility complex-independent, lymphocyte-mediated cytotoxicity. A 51.5-kD protein (p51.5) bearing structural and immunologic characteristics of the beta subunit of H+ transporting ATP synthase (E.C. 3.6.1.34, beta-H+ATPase, published molecular mass of 51.6 kD) was detected on the plasma membrane of three different human tumor cell lines studied. NH2-terminal amino acid sequence analysis of purified p51.5 from K562 tumor cells revealed 100% homology of 16 residues identified in the first 21 positions to the known sequence of human mitochondrial beta-H+ ATPase. Antibody directed against a 21-mer peptide in the ATP binding region of beta-H+ ATPase (anti-beta) reacted with only one band on Western blots of whole tumor extracts and tumor membrane extracts suggesting that the antiserum reacts with a single species of protein. Anti-beta reacted with the cell membranes of tumor cells as determined by fluorescence-activated flow cytometry and immunoprecipitated a 51.5-kD protein from surface-labeled neoplastic cells (but not human erythrocytes and lymphocytes). Purified p51.5 bound to human lymphocytes and inhibited natural killer (NK) cell-mediated cytotoxicity. Furthermore, anti-beta treatment of the K562 and A549 tumor cell lines inhibited NK (by > 95%) and interleukin 2-activated killer (LAK) cell (by 75%) cytotoxicity, respectively. Soluble p51.5 upon binding to lymphocytes retained its reactivity to anti-beta suggesting that the ATP binding domain and the lymphocyte-receptor binding domain reside in distinct regions of the ligand. These results suggest that beta-H+ ATPase or a nearly identical molecule is an important ligand in the effector phase (rather than the recognition phase) of a cytolytic pathway used by naive NK and LAK cells.

Suppression of C3H/HeJ cell activation by lipopolysaccharide endotoxin.

Earlier studies in our laboratory showed that the lipopolysaccharide (LPS) of Salmonella typhi, which fails to activate B lymphocytes of C3H/HeJ mice, can suppress proliferation and polyclonal antibody synthesis by these cells when they are stimulated by polyclonal activators. In order to determine what stage of the cell cycle was blocked, resting B cells from C3H/HeJ spleens were activated by using different mitogens in the presence of inhibitory concentrations of LPS and analyzed by flow cytometry, using acridine orange to stain DNA and RNA. LPS was found to inhibit the progression of cells into the G1 stage of the cell cycle. Furthermore, [3H]uridine uptake studies showed that RNA synthesis is inhibited during the early phase of activation. These results indicate that inhibition by LPS of the signalling process occurs during a critical period of the cell cycle when the cells become susceptible to the inhibitory effects of LPS. To examine whether LPS acts only on B cells or whether it can suppress other immunocompetent cells from C3H/HeJ mice, studies were carried out on activated thymocytes and macrophages. LPS was found to inhibit thymocyte proliferation stimulated by concanavalin A or the combination of phorbol myristate acetate and ionomycin. Prostaglandin E2 synthesis by macrophages was also blocked by LPS. Thus, LPS is a potent inhibitor of the functioning of the major immunocompetent cells of C3H/HeJ mice.

Synovial fat necrosis associated with ischemic pancreatic disease.

A 59-year-old man with ischemic pancreatic disease, polyarthritis, and cutaneous nodules has shown histopathologic findings indicative of disseminated fat necrosis in a percutaneous biopsy specimen from the right knee. The histopathologic findings in the synovium included necrotic fat cells, distorted fat cells and adjacent lymphocytes, lipid laden histiocytes, and giant cells. In prior histopathologic studies of the joint involvement associated with this disorder, fat cell necrosis has been found only in the periarticular tissues, and the synovium has appeared normal or showed nonspecific inflammation. However, the present study shows that the synovial membrane may also be the site of fat necrosis and an associated inflammatory reaction; thus patients with this disorder may manifest arthritis in addition to periarthritis.