Tehran University Medical Journal

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Background: Sepsis is the leading cause of death in critically ill patients throughout the world. The incidence is increasing despite the major advances in the development of antimicrobial agents and other supportive treatments. Based on multiple studies, it has been shown that patient outcome depends on Th1 and Th2 cytokine response. Moreover, whenever the Th2 response is predominant, the sepsis is more severe. The aim of this study was to evaluate the correlation between cytokine levels and the severity of sepsis in patients.
Methods: A cross-sectional study on the cellular levels of several pro-inflammatory cytokines was carried out in patients with sepsis and severe sepsis. The study included 37 patients (24 men and 13 women), 26 of them had sepsis and 11 had the severe form of sepsis Thirty-seven healthy volunteers served as controls. The average age of the patients was 57 years (±23.3 years), with a range of 21 to 92 years. From the whole blood of the subjects, we separated the monocytes and leukocytes, which were then cultured. Using an ELISA method, we measured levels of IFN- and IL-12 (associated with Th1), and IL-4 and IL-10 (associated with Th2) in the cultured cells with and without cell stimulation.
Results: No correlation was found for IFN- production in the cells of patients with sepsis and severe sepsis, regardless of whether the patients had died or survived. However, IL-12 levels were significantly decreased in severe sepsis compared with those of sepsis patients (P=0.048). Furthermore, the cells of expired patients also had significantly decreased IL-12 levels compared with those of surviving patients (P=0.028). We also found that the levels of IFN-, IL-4, and IL-10 were decreased in patients compared with those of controls, which correlated to their production. However, there was no correlation for IL-12 production between the cells of the patients compared with those of the controls. There was also no correlation for cytokine production between men and women with sepsis and in adults compared with that of elderly patients (>55 years old).
Conclusion: We have shown that the predominating T helper cell subset in patients with severe sepsis, as well as expired patients, is Th2. In conclusion, the correlation of Th1 cytokine production and progression of sepsis was demonstrated. Most probably IL-12 levels would be significantly lower in patients with severe sepsis and those who expired.

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Background: Rationalize of drug use in societies is one of the main responsibilities of health policy makers. In our country irrational use of dugs has increased in the recent years, for example one study in 1998 has shown that average number of medicines per prescription was 3.6, percentage of prescriptions containing antibiotics was 43% and percentage of prescriptions containing Injections was 39%. One of the best tools for evaluation of drug use is the WHO guideline for calculating prescribing indicators. In this study, we had an assessment about prescribing patterns in South of Tehran, Islamshahr and Rey Health Centers.
Methods: In order to evaluating prescribing indicators in Tehran University of Medical Sciences region 35 facilities which had pharmacy were selected according to WHO gridline and 4190 prescription from these facilities were studied. Indicators were calculated according to formulas has explained in article. Results: The average number of drug per prescription was 2.58, percentage of drug prescribed by generic name: 99.8%, percentage of encounters prescribed Antibiotics: 62.39% percentage of encounters prescribed Injection: 28.96% & the percentage of drugs prescribed from PHC formulary 99.46%. These findings were almost similar in the three Health Centers.
Conclusions: Health facilities are one of the most important bases to improve rational use of Drugs and general practitioners are the major chain in RUD cycle. Results show that we need to design intervention especially educational interventions to improve two WHO prescribing indicators, percentage of encounters prescribed Antibiotics & Injections in this region. For reaching this goals we need to design educational programs for physicians, pharmacists and people too. These educations can be as workshops, seminars, conferences or printed materials such as books, leaflets and etc

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Background: Type I diabetes is an autoimmune disease characterized by T-cell Mediated destruction of pancreatic β-cells. A variety of environmental, genetic and Immunologic factors are involved in the development of the disease. IL₁₈ is a cytokine secreted by macrophage and monocytes and play an important role in the pathogenesis of diabetes Type I through inducing IFN-γ production. It is shown to be strongly associated with the development of diabetes in NOD mice. It is also shown to have increased level in the subclinical stage of diabetes mellitus (type 1). Genetic polymorphisms in the IL-18 gene influence production and secretion of cytokine and are considered as a risk factor in auto-Immune diseases.

Methods: In this case control study, 75 type I diabetic patients and 88 healthy controls studied for polymorphism at positions -137 and -607. DNA extraction from the whole blood was performed according to the standardized method and polymorphism was determines by SSP-PCR. Data were analyzed by SPSS-12 using Chi-Square Test with 95% Confidence interval.

Results: A statistical significant difference in GG genotype (53%) and CC genotype (16%) at the -137 position of IL₁₈ gene was found, as compared to the control subjects (p=0.000) whereas we have not shown any statistical significance at the position -607.

Conclusion: IL₁₈ is a key cytokine secreted by macrophages and monocytes and stimulate the Th₁ lymphocyte. This cytokine can activate cytotoxic T lymphocytes (CTL) and destroy the pancreatic β cell. Our results show that the frequency of GG and CC genotypes at the position -137 may be associated with susceptibility to diabetes.

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Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 Background: The effect of ischemia/reperfusion (I/R) injury on kidney has been under investigation for many years. But the changes in liver function and oxidative stress status in renal I/R injury is not well known. Recent studies suggest a crosstalk between liver and kidneys. The aim of the present study was to assess liver changes after induction of various degrees of renal I/R injury.
Methods: This is an experimental study conducted on 20 male rats that were obtained from animal house of Physiology Department. Twenty male rats were subjected to either sham operation or ischemia (30, 45 and 60 min) followed by 60 min reperfusion periods. Blood samples were drawn post-operatively and plasma creatinine, BUN, ALT and AST were measured. Hepatic glutathione (GSH) and FRAP (ferric reducing antioxidant power) levels and the concentration of IL-10 and tumor necrosis factor (TNF) -alpha were evaluated.
Results: Both 45 and 60 min ischemia followed by 1h reperfusion periods resulted in significant increases in plasma creatinine (11.1±1.7mg/dl and 1.24±0.07mg/dl vs 0.55±0.15mg/dl, p<0.05) and BUN (34±3.85mg/dl and 35.0±2.81mg/dl vs 23.75±1.1mg/dl, p<0.05). These rats showed a significant decrease in liver GSH as well as significant increase in TNF-a & IL-10 concentrations.
Conclusion: Renal ischemia causes changes in liver function and oxidative stress status. A minimum of 45 min ischemia is needed to study the effects of renal injury on liver as a remote affected organ.

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Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 Background: Allergic rhinitis is a common disorder with great morbidity. Its prevalence has increased during recent years, therefore attracting attentions to its mechanisms. Type 2 cytokines play a major role in allergies. It has been proposed that Natural killer (NK) cells may be able to produce type 2 cytokines. This study was done to evaluate NK cells number and subtypes in patients with allergic rhinitis, comparing healthy subjects.
Methods: In a case control study, patients with allergic rhinitis were compared to healthy non-atopic subjects. Allergic rhinitis was diagnosed according to ARIA guidelines. NK cells quantity was studied by staining of peripheral blood mono nuclear cells with anti-CD16-FITC and anti-CD56-PE and evaluated by two color flowcytometry. Intracellular cytokines were evaluated by tri-color flowcytometry. NK cells were separated by magnetic beads, and cultured for 72 hours. Secretion of IL-4, IL-5, IL-10, IL-13, and IFN-γ was measured by ELISA, in stimulated and unstimulated conditions.
Results: Patients had more CD16+ CD56+ NK cells than control group. IL-4+ NK cells were significantly higher in patients (p<0.001), but the number of IFN-γ+ NK cells was not different. Cytokine secretion of NK cells was similar in case and control groups. Although IL-13 level after stimulation seemed higher in patients, the difference was not significant.
Conclusion: NK cells number is increased in patients with allergic rhinitis and a considerable number of them produce IL-4.

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Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 Background: Too many studies are in the process of determining the probable role of immune system in the etiopathogenesis of nasal polyposis. This study was designed to identify the probable participation of Th1, Th2 lymphocytes in the induction and progression of nasal polyposis.
Methods:  Seventy-five patients, 42 male and 33 female, with nasal polyposis were examined for total serum IgE, specific serum IgE and reaction to skin test for differentiating allergic from non-allergic participants in Rasoul Akram Hospital during 2010. To determine the possible correlation of allergic reactions in the upper respiratory tract and nasal polyposis, cytokine gene expression was evaluated on the extracted RNA by RT-PCR. The data were analyzed by using c², independent t-test, correlation and Receiver operating characteristic (ROC) curve.
Results:  The mean age of participants was 38 years (18-81 years). IFN-γ and IL-4 gene expressions were more prevalent in allergic than non-allergic individuals (IFN-γ: 39.5% vs. 14.2%, P=0.3 and IL-4: 44.7% vs. 18.9%, P=0.02, respectively). IL-10 and IL-12 (P35 and P40 fractions) genes were not significantly different between the two groups. IL-10 and IL-12 (P35, P40) genes did not differ significantly either.
Conclusion: This research suggests that overproduction of cytokines and an imbalance of Th1 and Th2 cell production may play an important role in the pathophysiology of allergic or non-allergic nasal polyp formation. Thus, although nasal polyposis is a multifactorial disease with several different etiological factors, chronic persistent inflammation is undoubtedly a major factor irrespective of the etiology.

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Background: Diabetes mellitus (DM) is a group of metabolic disorders such as DM I, DM II, secondary causes of DM and gestational diabetes mellitus characterized by hyperglycemic phonotype. The etiology of gestational diabetes mellitus is unknown. Recent studies address the chronic activity of immune system against infections (not autoimmunity) as an important cause of gestational diabetes mellitus. This study aimed to compare T-helper cells 1 and 2 cytokines and associated antibodies in patients with gestational diabetes mellitus and normal pregnant women.

Methods: This cross-sectional study was performed on 45 female patients with GDM and 45 healthy pregnant women in Bandar Abbas, Iran, from 2008- 2009. The exclusion criteria were presence of any infectious diseases or autoimmune disorders such as SLE or RA. Present and past medical histories were taken from the participants thorough physical examination. Blood samples (10 mL) were drawn and sent to laboratory for measuring serum IgE, IgG1, IgG2, IgG3, IgG4, interleukin-10 (IL-10), interleukin-12 (IL-12), transforming growth factor-beta (TGF1), and interferon-gamma (IFN) measurements. T-test and Kolmogorov-Smirnov test were used for data analysis.

Results: The mean age of the patients with GDM and healthy pregnant women was 32.5 and 27.9 yrs, respectively. T-helper 1 and 2 associated antibodies and cytokines had no significant differences between the case and control groups.

Conclusion: The changes in T-helper 1 and 2 associated antibodies and cytokines are not associated with gestational diabetes mellitus and could not be considered as a predictor for gestational diabetes mellitus.

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Background: Atopic dermatitis (AD) is one of the most common chronic, highly pruritic and inflammatory skin diseases. The exclusive influence of breastfeeding in the prevention of inflammatory diseases is a matter of debate. In this study, we aimed to determine the concentration of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-13 (IL-13) and interleukin-4 (IL-4) cytokines as anti Th2 or anti Th1 cytokines in breast milk and their relationship with atopic dermatitis in breastfed infants.
Methods: This study carried out in Afzalipour Hospital of kerman during one year from 2010 to 2011, we selected 50 breastfed infants with AD as cases and 50 healthy infants without AD or any other allergic disease as the controls. The concentrations of pro- and anti-inflammatory cytokines were measured by ELISA in the mothers' milk. The demographic characteristics were recorded in a data collection form. Moreover, severity of the disease was determined by SCORAD index. T-test and logistic regression were used for assessment of the correlation among study variables.
Results: The concentrations of IFN-γ and IL-13 were significantly higher (respectively, P=0.04, and P=0.02) in the case group. However, logistic regression revealed that only IFN-γ significantly increased the risk for atopic dermatitis (P=0.02). Concentration of TNF-α was similar in the milk from mothers belonging to the two groups.
Conclusion: The results indicate that the concentrations of IFN-γ, IL-13 and IL-4 cytokines are higher in the milk of mothers whose infants have AD. However, the risk for atopic dermatitis increases by 49% by every ten-unit (in pg/mL) increase in the level of IFN-γ.

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Asthma is a chronic inflammatory disorder of the airways, associated with airway re-modeling and hyperresponsiveness. It is expressed that asthma influences about 300 million people around the world, which is estimated to increase to about 400 million by 2025. The prevalence rate is 15 to 20 percent in children and 5 to 10 percent in adults, while its trend is still increasing. Inflammation plays an important role in the patho-physiology of asthma, which involves an interaction of different types of the immune cells and mediators. It leads to a number of pathophysiology changes, including bron-chial inflammation, airway obstruction, and clinical episodes such as cough, wheeze and shortness of breath. Asthma is now greatly being introduced as a heterogeneous disorder and it is pointed out to the role of T cells, including Th1, Th2, Th17, and regu-latory T cells. Other immune cells, especially neutrophils, macrophages and dendritic cells, as well structural cells such as epithelial and airway smooth muscle cells also pro-duce disease-associated cytokines in asthma. Increased levels of these immune cells and cytokines have been recognized in clinical samples and mouse models of asthma. Different cytokines, including pro-inflammatory cytokines (such as TNFα, IL-1, and IL-6), T helper 2 cytokines (such as IL-4, IL-5, IL-9, IL-13), and growth factors (such as GM-CSF, PDGF) play a role in the pathogenesis of asthma. Indeed chemokines (such as MPC-1, RANTES , MIP-1) and the chemokine receptors (such as CCR3, CCR4, CCL11, CCL24, and CCL26) play an important role in the recruitment of circu-lating inflammatory cells into the airways in asthmatic patients and also is related with increased T helper 2 cytokines after inhaled allergens. Among new approaches, treat-ment of asthma with anti-cytokine drugs such as antibodies blocking IL-4, IL-5, IL-9 could reduce recruitment inflammatory cells into the airways and remodeling. The final perspective of asthma treatments would be to alter from the symptomatic treatments to disease modifying.

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Background: Allergic Asthma is an inflammatory disease of the respiratory system that is well known by increased inflammatory cells in the airways and causes difficulty in respiration. The prevalence of allergic asthma is increasing worldwide, and it has become a significant cause of health challenge especially in developed countries. Inhaled β2-agonists and Inhaled or oral corticosteroids are common medications for treating the disease, but they cannot be used for long periods of time because of frequently occurring side effects and they can’t change the main pathogenesis of the problem. Deficiency in regulatory system against inflammation could be an important factor in allergic asthma. Mesenchymal stem cells (MSCs) have potential of cellular immunosuppressive therapy of inflammatory disorders. The aim of present study was to evaluate the effects of MSC therapy on mechanisms of allergic asthma in mice model. Methods: This experimental study was conducted from August 2014 to March 2015. The animals were housed and maintained in Biotechnology Center of Urmia University, Iran. Mice were sensitized by intra-peritoneal injection of ovalbumin (OVA) and aluminum hydroxide emulsion and then were challenged intra-nasally with OVA. Before allergen challenge on day 14, experimental mice received tail vein injection of MSCs in PBS. Regulatory T cells of spleen, cytokines and IgE analysis were carried out using lungs wash as well as serum samples. Results: Our results showed that MSCs significantly reduced total cells and eosinophilia, serum OVA-specific IgE concentration in OVA-sensitized and challenged mice. Also results showed that MSCs markedly inhibited expressions of Th2 cytokines and elevated levels of Treg cells and Treg cytokines. Conclusion: In the present study, we demonstrated the inhibitory effect of MSCs on airway inflammation using mice model of allergic asthma. The mice were sensitized with OVA and compared to the results of dexamethasone administration. Our results demonstrated that administration of MSCs could be used as a potential therapeutic approach for the allergic asthma.

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, involves almost all organs such as skin, heart, kidneys and central nervous system. The disease is characterized by vascular and connective tissue inflammation in a recurring pattern of remission and flare. Although the exact pathophysiology of disease has not been fully understood yet, the fundamental defect in SLE is attributed to dysfunction of T lymphocytes in controlling of B-cell that leads to polyclonal activation of B lymphocytes and production a large quantity of autoantibodies against nuclear and cytoplasmic components. These autoantibodies can damage tissues either directly or as a result of immune complex deposits. Several factors are involved in pathogenesis of SLE which can be divided into three major groups, environmental factors, genetic components, and immunological disturbances. They could breakdown body tolerance towards endogenous antigens and cause abnormal immunologic response to the healthy tissue, resulting in tissue damage. SLE occurs more frequently in female than male. It seems that immunological factors have important role in SLE. Inflammation and vascular endothelium irregularities are a number of main pathologies seen in SLE. Cytokines are protein mediators that play an essential role as regulator of innate and adaptive immune response against microbial agents or self-antigens. Influences of cytokines in autoimmune diseases such as SLE are poorly understood. Studies in both experimental animal models of lupus and patients with SLE have revealed a number of cytokine pathways that are important in the disease process. These studies showed that overexpression of inflammatory cytokines increases the proliferation of auto reactive B-cells and results in higher production of autoantibodies. Among them, the role of B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), TNF-α, IFN-α, IL-6, IFN-γ, IL-23/IL-17, IL-10, IL-21 are prominent, which is associated with the generation of pathogenic autoantibodies and formation of immune complexes. In this paper, the role of cytokines and their encoding genes are described, while therapeutic applications are also briefly presented.

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