Genotype and allele frequency of CYP2C19*17 in a healthy Iranian population

Background: Cytochrome P450 2C19 (CYP2C19) is important in metabolism of wide range of drugs. CYP2C19*17 is a novel variant allele which increases gene transcription and therefore results in ultra-rapid metabolizer phenotype (URM). Distribution of this variant allele has not been well studied worldwide. The aim of present study was to investigate allele and genotype frequencies of CYP2C19*17 in a healthy Iranian population and compare them with other ethnic groups. Methods: One hundred eighty healthy unrelated Iranian volunteer took part in this study and were genotyped for CYP2C19 *2, *3, *17 (-3402) by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and CYP2C19*17 (-806) by a nested-PCR assays. The distribution of CYP2C19*17 polymorphism in Iranian population was then compared with other ethnic groups. Results: The CYP2C19*17 allele frequency was 21.6 in Iranian population. Among studied subjects 5.5 were homozygous for CYP2C19*17 and phenotyped as ultra-rapid metabolizers; 28.8 were genotyped as CYP2C19*1*17 (extensive metabolizers) and 3.3 as CYP2C19*2*17 (intermediate metabolizers). Conclusion: The CYP2C19*17 genetic distribution in Iranian population is similar to Middle East or European countries. The high frequency of CYP2C19*17 in Iranian population highlights the importance of this new variant allele in metabolism of CYP2C19 substrates. Thus, future association studies are required to reveal clinical consequence of this genetic polymorphism in carrier individuals

Elevation of CD56brightCD16- lymphocytes in MDR pulmonary tuberculosis

Background: Protective immune responses induced in the majority of people infected with Mycobacterium tuberculosis enable them to control TB infection. Objective: The aim of this study was to investigate CD56 and CD16 positive peripheral blood mononuclear cells (PBMCs) and leukocyte subsets from multi-drug resistant pulmonary tuberculosis (MDR-TB), and compare them with nonresistant (NR) TB patients and healthy controls. Methods: 13 MDR-tuberculosis patients, 20 NR-TB individuals and 40 healthy subjects were included. Peripheral blood mononuclear cells were double stained with fluorochrome conjugated antibodies against CD56 and CD16 cell surface markers. The phenotype of positive cells was then analyzed by flow cytometry and the percent- ages of CD56+ CD16+, CD56- CD16+, CD56dimCD16+/-, and CD56brightCD16+/- subsets were calculated. Results: There was a significant decline in the percentage of CD56+CD16+ lymphocytes in both MDR and NR-TB patients compared with healthy controls. We also observed lower proportions of CD56dim/brightCD16+ in addition to higher percentages of CD56dim/brightCD16- subsets in all TB patients (p�0.05). In MDR- TB, our findings demonstrated a distinct phenotypic feature with increased levels of CD56brightCD16- in comparison with both NR-TB and healthy subjects. Conclusion: Considering the function of CD56/CD16 expressing cells in TB, we suggest that pheno- typic characteristics of PBMCs in MDR-TB may correlate with their status of drug re- sistance and probably with their high mortality rates

Nonlinear actuation of micromechanical Casimir oscillators with topological insulator materials toward chaotic motion:Sensitivity on magnetization and dielectric properties

We have investigated the dynamical actuation of micro-electromechanical systems under the influence of attractive and repulsive Casimir forces between topological insulator plates as a function of their dielectric function and coating magnetization. The analysis of the Casimir force in the limit of strong and weak magnetization shows that the attractive force, which is produced for plate magnetizations in the same direction, is greater than the repulsive force that is produced for opposite magnetizations. However, both forces remain comparable for intermediate magnetizations. Moreover, for weak magnetization, the attractive force becomes stronger for an increasing dielectric function, while the opposite occurs for the repulsive force. On the other hand, increasing magnetization decreases the influence of the dielectric function on both the repulsive and attractive forces. Furthermore, for conservative systems, bifurcation and phase portrait analysis revealed that increasing magnetization decreases the regime of stable operation for devices with attractive forces, while their operation remains always stable under the presence of repulsive forces. Finally, for non-conservative periodically driven systems, the Melnikov function and Poincaré portrait analysis show that for magnetizations in the same direction leading to strong attractive Casimir forces, chaotic motion toward stiction is highly likely to occur preventing the long-term prediction of actuating dynamics. A remedy for this situation is obtained by the application of any magnetization in opposite directions between the interacting surfaces since the repulsive force makes it possible to prevent stiction

Adipose tissue-derived mesenchymal stem cells exert in vitro immunomodulatory and beta cell protective functions in streptozotocin-induced diabetic mice model

Regenerative and immunomodulatory properties of mesenchymal stem cells (MSCs) might be applied for type 1 diabetes mellitus (T1DM) treatment. Thus, we proposed in vitro assessment of adipose tissue-derived MSCs (AT-MSCs) immunomodulation on autoimmune response along with beta cell protection in streptozotocin- (STZ-) induced diabetic C57BL/6 mice model. MSCs were extracted from abdominal adipose tissue of normal mice and cultured to proliferate. Diabetic mice were prepared by administration of multiple low-doses of streptozotocin. Pancreatic islets were isolated from normal mice and splenocytes prepared from normal and diabetic mice. Proliferation, cytokine production, and insulin secretion assays were performed in coculture experiments. AT-MSCs inhibited splenocytes proliferative response to specific (islet lysate) and nonspecific (PHA) triggers in a dose-dependent manner (P < 0.05). Decreased production of proinflammatory cytokines, such as IFN-γ, IL-2, and IL-17, and increased secretion of regulatory cytokines such as TGF-β, IL-4, IL-10, and IL-13 by stimulated splenocytes were also shown in response to islet lysate or PHA stimulants (P < 0.05). Finally, we demonstrated that AT-MSCs could effectively sustain viability as well as insulin secretion potential of pancreatic islets in the presence of reactive splenocytes (P < 0.05). In conclusion, it seems that MSCs may provide a new horizon for T1DM cell therapy and islet transplantation in the future. © 2015 Hossein Rahavi et al

The predictive value of HLA-DR matching and cytokine gene polymorphisms in renal allograft acute rejection: A living-unrelated donor (LURD) study

Background: In addition to Human Leukocyte Antigens (HLA) compatibility, gene polymorphisms in cytokines might also be important in the quality of allogeneic immune response. Objective: To evaluate the influence of HLA-DR matching and a number of cytokine gene polymorphisms on acute rejection after living-unrelated donor (LURD) kidney transplantation. Methods: A total of 42 renal transplants performed at Hashemi Nejad Kidney Hospital (Tehran/Iran) and followed up for 3 months post-transplantation were included. Using PCR-SSP, HLA-DR alleles (DR1-18) of recipients and donors and gene polymorphisms in TNF-a, TGF-b1, IL-10, IL-6, and IFN-γ of recipients were determined. Results: Acute rejection was observed in 11(26.2) of renal recipients. The frequency of one and two HLA-DR mismatches in rejector group was 2(18.2) and 9(81.8) and in non-rejector group was 13(41.9) and 17(54.8), respectively. HLA-DR incompatibility was not significantly higher in rejector (1.82±0.40) compared with non-rejector (1.52±0.57) recipients (P=0.069) and more than half of non-rejectors had completely mismatched HLA-DR antigens with donors. Polymorphisms associated with the mentioned cytokines had no correlation with acute rejection. Conclusion: The predictive value of HLA-DR mismatching for acute rejection is not as prominent in LURD kidney transplantation as in the cadaveric one. In addition, we failed to demonstrate an association between combined cytokine genotypes and HLA-DR matching with acute rejection. Further and more detailed immunogenetic investigations are required in order to have a better prediction of the transplant outcome

Study of NGEP expression in androgen sensitive prostate cancer cells: A potential target for immunotherapy

Background: Prostate cancer is one of the leading causes of cancer deaths among men. New gene expressed in prostate (NGEP), is a prostate-specific gene expressed only in normal prostate and prostate cancer tissue. Because of its selective expression in prostate cancer cell surface, NGEP is a potential immunotherapeutic target. To target the NGEP in prostate cancer, it is essential to investigate its expression in prostate cancer cells. Methods: In the present study, we investigated NGEP expression in LNCaP and DU145 cells by real time and RT-PCR, flow cytometric and immunocytochemical analyses. Results: Real time and RT-PCR analyses of NGEP expression showed that NGEP was expressed in the LNCaP cells but not in DU145 cells. The detection of NGEP protein by flow cytometric and immunocytochemistry analyses indicated that NGEP protein was weakly expressed only in LNCaP cell membrane. Conclusion: Our results demonstrate that LNCaP cell line is more suitable than DU145 for NGEP expression studies; however, its low-level expression is a limiting issue. NGEP expression may be increased by androgen supplementation of LNCaP cell culture medium

Immunomodulatory effects of human amniotic epithelial cells on naive CD4+ T cells from women with unexplained recurrent spontaneous abortion

Abstract Introduction Immune imbalance at the maternal-fetal interface plays a fundamental role in the pathogenesis of unexplained recurrent spontaneous abortion (URSA). Human amniotic epithelial cells (hAECs) possess pregnancy-friendly immunomodulatory effects. Here, we investigated how function of naive CD4+ T cells from URSA patients is affected by hAECs. Methods Phenotypic characteristics of hAECs were determined by flow cytometry and their effect on proliferation of allogeneic peripheral blood mononuclear cells (PBMCs) was evaluated by a BrdU cell proliferation assay. Naive CD4+ T cells were isolated from 25 URSA patients and 5 healthy women and co-cultured with hAECs. Immunomodulatory effects of hAECs on cytokines profile, proliferation of stimulated CD4+ T cells and induction of regulatory T cells (Tregs) were assessed by ELISA and flow cytometry, respectively. Functional competency of Tregs was evaluated in an allogeneic mixed lymphocyte reaction (MLR) system. Results hAECs did not elicit allogeneic proliferative responses of PBMCs, inhibited proliferation of naive CD4+ T cells, induced production of Th2 and suppressed production of Th1 and Th17 cytokines. hAECs showed the ability to induce differentiation of Tregs and production of transforming growth factor-beta1 (TGF-β1) and interleukin-10 (IL-10). This ability was found to be superior in control subjects compared to URSA patients. Indeed, Tregs generated in the presence of hAECs expressed higher levels of CTLA-4 compared to Tregs generated in their absence and restrained the proliferation of autologus PBMCs in MLR system. Conclusion Based on these findings, hAECs can be considered as one potential candidate in immunotherapy of patients with URSA. Keywords Immunomodulatory effects Amniotic epithelial cells Naive T cells Unexplained recurrent spontaneous abortio

BMJ open effect of FTY720 (fingolimod) on graft survival in renal transplant recipients: A systematic review protocol

Introduction: Studies have shown that FTY720 has inconsistent effects in kidney transplant recipients. Several review articles on FTY720 have been published, but most have focused on the mechanism of action of FTY720. Therefore, this review aims to evaluate and determine the beneficial and harmful effects of FTY720 therapy in kidney transplant recipients. Methods and analysis: We electronically searched the following databases: PubMed, Scopus, the Web of Sciences, EMBASE, Cochrane databases and the Cochrane Central Registry of Controlled Trials. Any clinical, randomised controlled trials relating to FTY720 for treating kidney transplant recipients were included without publication status or language restriction. Study selection, data extraction and assessment of study quality were performed independently by two researchers. Data were synthesised by either the fixed effects or the random effects model according to a heterogeneity test. If the extracted data were suitable for meta-analysis, STATA software was used to combine the relative risks for dichotomous outcomes, and the mean differences for continuous outcomes with 95 CIs were measured. Death, loss of function and incidence of acute kidney rejection were assessed as the primary outcomes. Renal graft function, malignancy, delayed graft function and infection were evaluated as secondary outcomes. Ethics/dissemination: This review does not require formal ethics approval because the data are not individualised. The resulting review article will be submitted for publication in a peer-reviewed journal

Fas and fas-ligand promoter polymorphisms in hepatitis b virus infection

Background: The FAS and FAS-Ligand (FASL) system is an important apoptosis pathway in the liver. The FAS-mediated pathway functions by binding the FASL on the activated cytotoxic T lymphocytes and Natural Killer (NK) cells to the FAS receptor on infected hepatocytes. FAS and FASL polymorphisms, which are related to apoptosis, might influence the outcome of Hepatitis B Virus (HBV) infection. Objectives: Thus, the present study aimed to determine if FAS and FASL promoter polymorphisms are associated with the clinical outcome of HBV infection. Patients and Methods: DNA samples were obtained from the infected individuals including chronic carrier (n = 50), chronic hepatitis (n = 50), cirrhosis (n = 25), naturally recovered (n = 26) and compared with those of their matched healthy controls (n = 100). Genotyping for polymorphisms of FAS-670 A/G and -1377 G/A, and FASL -844 C/T was performed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assays. Results: Multiple analyses for genetic association of FAS and FASL polymorphisms were not statistically different between HBV patients (n = 125) and healthy controls (n = 100). However, genotype and allele frequencies of FASL-844 C/T were significantly different between recovered individuals and patients with cirrhosis (P = 0.02 and P=0.01, respectively). Whereas, FAS-670A/G and -1377G/A polymorphisms were similarly distributed in these two groups (P = 0.8 and P = 0.47, respectively). Conclusions: The current study results showed that bearing -844T allele in FASL promoter region has a protective effect on cirrhosis and is involved in recovery from infection. In conclusion, it is proposed that HBV infection outcome might be influenced by FASL-844C/T polymorphism through alteration in apoptosis of hepatocytes. © 2015, Kowsar Corp

Evaluating the Perception and Awareness of Patients Regarding Ovarian Cysts in Peshawar, Pakistan

Purpose: To evaluate patients’ perception regarding ovarian cyst as well as their awareness of the symptoms and health management of the disease.Methods: A quantitative research approach was used to conduct this study. Patients were selected from the Gynecology wards, Hayatabad Medical Complex, Peshawar and a questionnaire was designed to evaluate the patients’ knowledge and awareness.Results: When women were asked if they had prior knowledge about the ovarian cyst, 37 (58.7 %) responded that they were first told by the  physician during their visit to the clinic or hospital while the patients  responded, “Still don’t know” are 22 (34.9 %). With respect to educational level of the patients, they seemed to be less aware of the disease. Their perception regarding the disease is that they had a “water filled” balloon or tumor.Conclusion: Prior to discharge of an ovarian cyst patient from the hospital, she should be counseled on the disease and successful treatment outcomes. Counseling of the patients may result in compliance with therapy, good quality of life and lower economic burden.Keywords: Ovarian cyst, Menstrual cycle, Awareness, Perception, Treatment outcome