Therapeutic Effect of Anti-CD52 Monoclonal Antibody in Multiple Sclerosis and Its Animal Models Is Mediated via T Regulatory Cells.

The objective of this study is to determine the mechanism of action of anti-CD52 mAb treatment in patients with relapsing-remitting multiple sclerosis (RRMS). Experimental autoimmune encephalomyelitis (EAE), an animal model of the disease, was used to address the role of T regulatory cells (Tregs) in the anti-CD52 mAb-induced suppression of the disease. In vitro studies on PBMCs from RRMS patients and matched healthy controls determined the effect of IL-7 on the expansion of CD4+CD25+CD127- Tregs and induction of their suppressive phenotype. This study using EAE animal models of MS has shown that mouse anti-CD52 mAb suppression of clinical disease was augmented by coadministration of IL-7 and partially reversed by anti-IL-7 mAb. In vitro human studies showed that IL-7 induced expansion of CD4+CD25+CD127- Tregs and increased their FOXP3, GITIR, CD46, CTLA-4, granzyme B, and perforin expression. Anti-CD52 mAb treatment of mice with relapsing-remitting EAE induced expansion of Foxp3+CD4+ Tregs and the suppression of IL-17A+CD4+ and IFN-γ+CD4+ cells in peripheral immune organs and CNS infiltrates. The effect was detected immediately after the treatment and maintained over long-term follow-up. Foxp3+CD4+ Treg-mediated suppression of IL-17A+CD4+ and IFN-γ+CD4+ cells in the spinal cord infiltrates was reversed after inducible Foxp3 depletion. Our results demonstrated that the therapeutic effect of U.S. Food and Drug Administration-approved anti-CD52 mAb is dependent on the presence of Tregs.

Constitutive High Expression of NOXA Sensitizes Human Embryonic Stem Cells for Rapid Cell Death.

Human embryonic stem (hES) cells are highly sensitive to apoptotic stimuli such as DNA damage, which allows for the rapid elimination of mutated cells during development. However, the mechanisms that maintain hES cells in the primed apoptotic state are not completely known. Key activators of apoptosis, the BH3-only proteins, are present at low levels in most cell types. In contrast, hES cells have constitutive high levels of the BH3-only protein, NOXA. We examined the importance of NOXA for enabling apoptosis in hES cells. hES cells deleted for NOXA showed remarkable protection against multiple apoptotic stimuli. NOXA was constitutively localized to the mitochondria, where it interacted with MCL1. Strikingly, inhibition of MCL1 in NOXA knockout cells was sufficient to sensitize these cells to DNA damage-induced cell death. Our study demonstrates that an essential function of constitutive high levels of NOXA in hES cells is to effectively antagonize MCL1 to permit rapid apoptosis.

IL-11 Induces Encephalitogenic Th17 Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.

IL-11+CD4+ cells accumulate in the cerebrospinal fluid of patients with early relapsing-remitting multiple sclerosis (MS) and in active brain MS lesions. Mouse studies have confirmed a causal role of IL-11 in the exacerbation of relapsing-remitting experimental autoimmune encephalomyelitis (RREAE). Administration of IL-11 at the time of clinical onset of RREAE induced an acute exacerbation and increased clinical scores, which persisted during the entire course of the disease. IL-11 increased the numbers of spinal cord inflammatory foci, as well as the numbers of peripheral and CNS-infiltrating IL-17+CD4+ cells and IL-17A serum levels. Ag recall assays revealed that IL-11 induces IL-17A+, GM-CSF+, and IL-21+CD4+ myelin Ag-reactive cells. Passive transfer of these encephalitogenic CD4+ T cells induced severe RREAE with IL-17A+CCR6+ CD4+ and B cell accumulation within the CNS. Furthermore, passive transfer of nonmanipulated CNS-derived mononuclear cells from mice with RREAE after a single dose of IL-11 induced severe RREAE with increased accumulation of IL-17A+ and CCR6+ CD4+ cells within the CNS. These results suggest that IL-11 might serve as a biomarker of early autoimmune response and a selective therapeutic target for patients with early relapsing-remitting MS.

IL-11 antagonist suppresses Th17 cell-mediated neuroinflammation and demyelination in a mouse model of relapsing-remitting multiple sclerosis.

IL-11 induced differentiation and expansion of Th17 cells in patients with early relapsing-remitting multiple sclerosis (RRMS). In mice with relapsing-remitting experimental autoimmune encephalomyelitis (RREAE), IL-11 exacerbated disease, induced demyelination in the central nervous system (CNS), increased the percentage of IL-17A+CD4+ Th17 cells in the CNS in the early acute phase, and up-regulated serum IL-17A levels and the percentage of IL-17A+CD4+ Th17 cells in lymph nodes, and IFN-γ+CD4+ T cells in spinal cord in the RR phase. IL-11 antagonist suppressed RREAE disease activities, inhibited IL-17A+CD4+ cell infiltration and demyelination in the CNS, and decreased the percentage of IL-17A+CD4+ T cells in peripheral blood mononuclear cells and ICAM1+CD4+ T cells in brain and SC. Diffusion Tensor Imaging indicated that IL-11 antagonist inhibited demyelination in several brain regions. We conclude that by suppressing Th17 cell-mediated neuroinflammation and demyelination, IL-11 antagonist can be further studied as a potential selective and early therapy for RRMS.

Sleep-disordered breathing as presenting manifestation of Chiari type I malformation: a case report.

Chiari Type I malformation (CM-I) is a rare disorder with displaced cerebellar tonsils through foramen magnum. Here we present a 30-year-old man with severe central and obstructive sleep apneas as presenting manifestations of CM-I. The patient underwent neurosurgery and the follow-up polysomnography revealed the resolution of central apnea while obstructive apnea remained unchanged. Central sleep apnea (CSA) could be associated with an underlying pathology; thus, further investigation is recommended in affected subjects.

Addressing the changing sources of health information in iran.

BACKGROUND: Following the entrance of new technologies in health information era, this study aimed to assess changes in health information sources of Iranian people during past decade. METHODS: Totally 3000 people were asked about their main sources of health information. They were selected as two community-based samples of 1500 people of more than 18-years-old in two different periods of time in August 2002 and August 2010 from the same locations in Tehran, the capital of Iran. Data analyzed based on age group, sex, educational level and household income in two different periods of time using Chi-square. Odds ratios associated with each basic characteristic were calculated using logistic regression. RESULTS: Most common sources of health information in 2002 were radio and television (17.7%), caregivers (14.9%) and internet (14.2%) and in 2010 were radio and television (19.3%), internet (19.3%) and caregivers (15.8%) (P < 0.001). In 2010, young adults female used television and radio and male used internet as the main source of health information (P = 0.003). In moderate educational level women got their health information from radio and television and caregivers; while men used radio and television and internet as main source of health information (P = 0.005). Highly educated women and men mainly got their health information from internet and radio and television (P > 0.05). CONCLUSION: Although during 8 years of study radio and television remained as main source of health information but there is an increasing tendency to use internet especially in men. Policymakers should revise their broadcasting strategies based on people demand.

Factors Associated with Delay in Thrombolytic Therapy in Patients with ST-Elevation Myocardial Infarction.

BACKGROUND: Treatment delay in the management of ST-elevation myocardial infarction conversely correlates with prognosis and survival of the patients. This study aimed to investigate factors associated with delay in the thrombolytic therapy of these patients in Tehran. METHODS: Between 2007 and 2010, the interval between the self-reported time of the onset of symptoms and initiation of the thrombolytic agent in 513 patients with a diagnosis of acute ST-elevation myocardial infarction was recorded. Medical history and socio-demographic characteristics of the patients treated within two hours after the onset of symptoms and patients treated after two hours from the onset of symptoms were compared, and the odds ratios were calculated using logistic regression. RESULTS: The mean age of the patients was 61.2 (SD = 11.1) years, and 76% of the patients were male. The median time between the onset of symptoms and treatment was 158 (SD = 30.4) minutes. Mean for decision time was 61 (SD = 19), which was responsible for 83% of the entire treatment delay. The mean transportation time was 34 (SD = 12) minutes, and the median door-to-needle time was 44 minutes. Odds ratio for history of diabetes mellitus was 1.90 (95% CI: 1.26-2.87), for hypertension was 1.55 (95% CI: 1.08-2.23), and for prior coronary heart disease was 1.47 (95% CI: 1.17-1.84). CONCLUSION: The most important factor associated with delay in treatment was decision time. Improving emergency medical services dispatch time, obtaining pre-hospital electrocardiograms for early diagnosis, and pre-hospital initiation of thrombolytic therapy may reduce the delay time.