Enhanced oxidative stress in Hashimoto's thyroiditis: Inter-relationships to biomarkers of thyroid function

ObjectivesOxidative stress has been implicated in the pathogenesis of several inflammatory and immune-mediated disorders including Hashimoto's thyroiditis (HT). The objectives of the present cross-sectional investigation were to estimate serum glutathione (GSH) status and the activities of its recycling enzymes in HT and to explore their interrelationships with biomarkers of autoimmunity and thyroid function.Design and methodsNewly diagnosed females with HT (n = 44) and 58 matched control subjects were recruited. Thyroid hormone profile, anti-thyroperoxidase anti-body (TPO-AB), anti-thyroglublin antibody (Tg-AB), thyroid volume (Tvol), urinary iodine excretion (UIE), GSH and the activities of glutathione peroxidase (GPx), glutathione reductase and gamma-glutamyltransferase were assessed.ResultsMedian UIE in HT was slightly but not significantly higher than that of controls. HT group exhibited higher levels of TSH, TPO-AB, Tg-AB and larger Tvol when compared with controls (P < 0.001). The means of GSH and GPx in HT patients were significantly different from those of controls (P < 0.001). In HT subjects, significant associations were seen between Tvol on TSH, GSH on TPO-AB, GSH on TSH and TPO-AB titers on TSH, respectively.ConclusionsThis is the first study to demonstrate a substantial reduction in GSH status in HT subjects. Secondly, the interrelationship between the GSH contents and TPO-AB titers in HT provides a preliminary data to support the notion that GSH diminution is a hallmark of in the events leading to oxidative stress activation and the development of immunological intolerance in HT. Further studies are required to elucidate the role of GSH in the etiology of down-regulation of thyroid function.     

Inducible IL-23p19 expression in human microglia via p38 MAPK and NF-kappaB signal pathways

Activated microglia can release a variety of proinflammatory cytokines that play a crucial role in the pathogenesis of multiple sclerosis (MS). IL-23, a novel proinflammatory cytokine, is required for the induction of experimental autoimmune encephalomyelitis. Previously we demonstrated that IL-23 is expressed in MS lesions and that microglia are one cellular source of IL-23 in MS patients. In the present study we investigated the inducible expression and regulation of p19, a key subunit of IL-23, in human microglia. We demonstrated the inducible expression of IL-23p19 by lipopolysaccharide-stimulated microglial cells. Using signaling pathway-specific inhibitors, we showed that blocking p38 MAP kinase or NF-kappaB signaling pathway significantly reduced p19 expression in microglia. The regulatory role of p38 MAP kinase in p19 expression was further confirmed by decreased expression in microglia transduced with dominant-negative p38. We concluded that the p38 MAP kinase and NF-kappaB signaling pathways play an important role in regulation of IL-23p19 expression on human microglia, and are thus potential therapeutic targets in the treatment of MS.     

Transitions between the stages of smoking in Iranian adolescents

Objective

This study examined the prevalence of smoking, the rates of transitions, and predictors of transition through the three stages of smoking.

Methods

A total of 1785 high school students in Tabriz (northwest of Iran) were assessed at 2 time points with a 12-month interval in 2005 and 2006, regarding changes in smoking stages. The predictor variables were measured when the students were in the 10th grade. Logistic regression was employed to predict the different smoking stages at grade 11.

Results

The results showed that 14.3% (95% confidence interval, 12.3%-16.4%) and 2.8% (2.0%-4.0%) of the never smokers became experimenters and regular smokers, respectively, whereas 16.5% (12.4%-21.7%) of the experimenters became regular smokers. Among never smokers, participation in groups with at least one smoker (odds ratio, 1.24 (95% confidence interval, 1.05-1.47)), having smoker friends (1.85 (1.21-2.83)), and a positive attitude toward smoking (1.22 (1.02-1.46)) predicted smoking experience. Among the experimenters, those who had general risk behaviors (2.56 (1.12-5.87)) and participated in groups with at least one smoker (2.58 (1.26-5.31)) significantly progressed to becoming a regular smoker at the follow-up.

Conclusion

Prevention of smoking in adolescence should begin by focusing on the predictors of transition through smoking stages, especially participating in smoker groups.     

Immune responses to Helicobacter pylori infection in children with intellectual disabilities

Infection with Helicobacter pylori was assessed through serum H. pylori IgG antibody in children with intellectual disabilities (ID). The sero-status of cytotoxin-associated gene A (CagA) was determined as a risk determinant for severe H. pylori-associated diseases. In total, 210 children with ID were included who were permanent resident of three institutes in Tehran. Medical history and demographic data were collected by reviewing the medical file records. The anti H. pylori IgG antibody was detected in serum of 74.8% of children using ELISA. Significant correlations were found between the rate of infection and age (P = 0.001) and duration of institutionalization (P = 0.018). The likelihood of H. pylori IgG positive response increased with age with the highest response in 15-18 years age group (OR = 6.66, 95% CI: 2.14-20.17; P = 0.001). Similarly, the average titers of H. pylori IgG antibody were increased with age. The institutionalization duration of more than 49 months affected the likelihood of H. pylori IgG positive response (OR = 2.437, 95% CI: 1.12-5.26; P = 0.023). Anti-CagA titers were higher than 5 arbU/ml in 92 (58.6%) children, indicating a positive response against CagA protein. The titer of H. pylori IgG was significantly higher in CagA-positive (mean ± SE = 51.04 ± 3.41) than in CagA-negative children (38.07 ± 4.18; P = 0.017). In contrast to total H. pylori IgG titers, anti-CagA antibody had non-regular trend of alterations with age. The seropositivity rate of H. pylori infection in ID children was higher than other reports in healthy children from various regions of the country. The risk of H. pylori infection is increased with age and duration of institutionalization. The serostatus of CagA in children with IDs has not been reported so far. The regular monitoring of the CagA-positive carriers is recommended; since CagA positive cases carry the risk of progression of infection toward severe H. pylori associated sequels such as gastric cancer and duodenal ulcers.     

Morphine Preconditioning Protects Against LPS-Induced Neuroinflammation and Memory Deficit

Recent studies show that morphine possesses protective preconditioning effects in different ischemia/reperfusion models. However, there is very little information about the antineuroinflammatory role of morphine and its protective effect against memory deficit. In the present study, we evaluated the role of morphine preconditioning in a model of mild neuroinflammation induced by intraperitoneal lipopolysaccharide (LPS) injection (1 mg/kg). Rats were trained on passive avoidance apparatus and challenged with LPS 20 h later. Four hours after LPS, rats were subjected to passive avoidance testing and then for the assessments of inflammatory and apoptotic cell death mediators in the hippocampus. LPS significantly increased the nuclear NF-κB and expression of COX-2, IL-1β, and TNF-α, augmented the activity of caspase-3 and PARP cleavage, and in parallel shortened the latencies to enter the dark compartment. Although morphine injection in a noninflammatory context was able to induce a neuroinflammatory response and memory loss, morphine preconditioning at the dose of 4 mg/kg significantly prevented the LPS-induced neuroinflammation and memory deficit. Morphine preconditioning was abolished by naloxone and, therefore, is dependent on opioid receptors. These results suggest that acute morphine injection, in spite of the induction of a neuroinflammatory response and amnesia per se, exerts an antineuroinflammatory role and protects from cell death and memory deficit in an inflammatory context.     

Study of disabling T-cell activation and inhibiting T-cell-mediated immunopathology reveals a possible inverse agonist activity of CD4 peptidomimetics

We designed a new class of aromatically modified exocyclic peptides based on the structure of CD4 by engineering one of the cysteine residues in a peptidomimetic derived from the CDR3 region of the CD4 molecule. All three species mediate inhibition of T-cell proliferation at concentrations ranging from 10 to 100 microM. The mimetics CD4-Cys and CD4-Met bind to sCD4 with affinities ranging from 1 to 2 microM, while CD4-Ser shows poor binding in radioisotope assay. Though these mimetics have similar structures, they exhibit different biochemical and biological functions. Activation of T-cells as measured by thymidine incorporation or IL-2 production revealed that CD4-Cys and CD4-Ser mimetics behave as classical antagonists. On the other hand, the CD4-Met species inhibited T-cell proliferation with an IC(50) of 30 microM but unexpectedly increased IL-2 secretion modestly at a less than 3 microM concentration. In experimental autoimmune encephalitis (EAE), CD4-Ser and CD4-Cys mimetics reduced the severity of EAE symptoms while the CD4-Met mimetic exacerbated the conditions. We propose that CD4-Cys and CD4-Ser are classical antagonists, but CD4-Met may possess properties of an inverse agonist. The structure-activity relationship of mimetics reveals that a minor change in the net hydropathic value is enough to alter the dynamic nature of the receptor-ligand complex.     

Effects of neurofeedback on the short-term memory and continuous attention ofpatients with moderate traumatic brain injury: A preliminary randomized controlled clinical trial

Purpose: There are some studies which showed neurofeedback therapy (NFT) can be effective in clients with traumatic brain injury (TBI) history. However, randomized controlled clinical trials are still needed for evaluation of this treatment as a standard option. This preliminary study was aimed to evaluate the effect of NFT on continuous attention (CA) and short-term memory (STM) of clients with moderate TBI using a randomized controlled clinical trial (RCT). Methods: In this preliminary RCT, seventeen eligible patients with moderate TBI were randomly allocated in two intervention and control groups. All the patients were evaluated for CA and STM using the visual continuous attention test and Wechsler memory scale-4th edition (WMS-IV) test, respectively, both at the time of inclusion to the project and four weeks later. The intervention group participated in 20 sessions of NFT through the first four weeks. Conversely, the control group participated in the same NF sessions from the fifth week to eighth week of the project. Results: Eight subjects in the intervention group and five subjects in the control group completed the study. The mean and standard deviation of participants'' age were (26.75 ± 15.16) years and (27.60 ± 8.17) years in experiment and control groups, respectively. All of the subjects were male. No significant improvement was observed in any variables of the visual continuous attention test and WMS-IV test between two groups (p≥0.05). Conclusion: Based on our literature review, it seems that our study is the only study performed on the effect of NFT on TBI patients with control group. NFT has no effect on CA and STM in patients with moderate TBI. More RCTs with large sample sizes, more sessions of treatment, longer time of follow-up and different protocols are recommended.     

Role of the innate immune system in autoimmune inflammatory demyelination

Considerable research has been devoted to the role of the adaptive immune system in the pathogenesis of autoimmune inflammatory demyelination (AID). AID is thought to occur spontaneously in patients with multiple sclerosis (MS), a common cause of neurological disability. AID is also observed in the best characterized animal model of MS, experimental autoimmune encephalomyelitis (EAE). The adaptive immune system recognizes and responds to antigens via highly specific T-cell receptors. Myelin-reactive T-cells may initiate pathological immune responses that lead to central nervous system damage in MS and EAE. By contrast, the innate immune system recognizes evolutionarily conserved structures that are common to invading pathogens with high efficiency for rapid recognition and elimination of viruses, bacteria, and fungi. This recognition is mediated by pattern-recognition receptors such as Toll-like receptors (TLRs) expressed on cells of the innate immune system (dendritic cells and CNS-resident cells, such as microglia) that have the potential to activate autoimmune responses by inducing the production of inflammatory cytokines and chemokines. Conversely, the innate immune system can also regulate autoimmune inflammation by inducing the production of immunoregulatory molecules such as type I interferons, which are currently used in the treatment of MS. We review the evidence that TLRs can exacerbate or regulate AID and discuss the therapeutic potential of targeting either process.     

Comparable Outcomes of Allogeneic Peripheral Blood versus Bone Marrow Hematopoietic Stem Cell Transplantation in Major Thalassemia: A Multivariate Long-Term Cohort Analysis

Allogeneic hematopoietic stem cell transplantation (HSCT) currently is the only available curative option for transfusion-dependent thalassemia. Peripheral blood is a more convenient source for HSCT in comparison with bone marrow. Information about the relative success of transplantation with these 2 graft sources would help physicians and patients choose between them. The aim of this study was to evaluate the pros and cons of using peripheral blood instead of bone marrow as the graft source in thalassemia transplantation. We analyzed the transplant results of 567 transfusion-dependent thalassemia patients who received a transplant between 1998 and 2015 considering their stem cell source as a comparative variable. In multivariate Cox analysis the survival advantage for bone marrow compared with peripheral blood was not significant after adjusting for sex, age, and hepatic fibrosis presence. Rejection incidence was significantly lower in patients who used peripheral blood as their graft source. Acute and chronic graft-versus-host disease were more frequent in peripheral blood transplants, but the difference was not statistically significant. This study shows that peripheral blood could be an alternative stem cell source in patients undergoing allogeneic HSCT for thalassemia.