LIMS1 risk genotype and T cell-mediated rejection in kidney transplant recipients.

BACKGROUND: This study aims to examine the association of LIM zinc finger domain containing 1 (LIMS1) genotype with allograft rejection in an independent kidney transplant cohort. METHODS: We genotyped 841 kidney transplant recipients for the LIMS1 rs893403 variant by Sanger sequencing followed by polymerase chain reaction confirmation of the deletion. Recipients who were homozygous for the LIMS1 rs893403 genotype GG were compared with the AA/AG genotypes. The primary outcome was T cell-mediated or antibody-mediated rejection (TCMR or ABMR, respectively) and secondary outcome was allograft loss. RESULTS: After a median follow-up of 11.4 years, the rate of TCMR was higher in recipients with the GG genotype (n = 200) compared with the AA/AG genotypes (n = 641) [25 (12.5%) versus 35 (5.5%); P = 0.001] while ABMR did not differ by genotype [18 (9.0%) versus 62 (9.7%)]. Recipients with the GG genotype had 2.4 times higher risk of TCMR than those who did not have this genotype [adjusted hazard ratio2.43 (95% confidence interval 1.44-4.12); P = 0.001]. A total of 189 (22.5%) recipients lost their allografts during follow-up. Kaplan-Meier estimates of 5-year (94.3% versus 94.4%; P = 0.99) and 10-year graft survival rates (86.9% versus 83.4%; P = 0.31) did not differ significantly in the GG versus AA/AG groups. CONCLUSIONS: Our study demonstrates that recipient LIMS1 risk genotype is associated with an increased risk of TCMR after kidney transplantation, confirming the role of the LIMS1 locus in allograft rejection. These findings may have clinical implications for the prediction and clinical management of kidney transplant rejection by pretransplant genetic testing of recipients and donors for LIMS1 risk genotype.

A shared motif of hla-dpb1 affecting the susceptibility to pr3-anca positive granulomatosis with polyangiitis: comparative analysis of a Turkish cohort with matched healthy controls.

We aimed to analyse the distribution of HLA Class 2 genotypes which were reported among the genetic risk factors for ANCA-associated vasculitis (AAV) among Turkish patients in comparison with healthy subjects and previously reported data of AAV cohorts. Ninety-eight patients (F/M: 47/51 and mean age: 49 ± 1.14) were enrolled in the study and records of gender and birthplace-matched 196 healthy kidney donors were used as the control group. Patients were classified according to the clinical subgroups and ANCA serotypes (MPO-AAV, PR3-AAV). DNA was isolated from venous blood from all patients, and high-resolution HLA Class 2 genotyping was carried out by using NGS-Omixon Holotype HLA Kit. The frequencies of HLA-DQB1*03:03, - *06:04, and -DPB1*13:01, -*16:01 and -*66:01:00 alleles were significantly higher, and the frequencies of HLA-DQB1*02:02, -DPB1*02:01 and -*04:01 alleles were lower in the PR3-AAV subgroup (n = 53) compared to the controls. Comparison of amino acid sequences of the associated HLA-DPB1 alleles revealed the sequence of D-E-A-V in risk alleles replaced with the G-G-P-M sequence in protective alleles between 84 and 87th positions. Structural analysis of the HLA-DPB1*02:01 showed that this shared position is in the contact area between HLA-DP α and ß chains and within pocket 1 of the antigen-binding groove. First HLA genotyping analysis in Turkish AAV patients revealed a negative correlation between PR3-ANCA positivity and certain HLA-DPB1 alleles contradictory to the results reported from European cohorts. Known functional effects of D-E-A-V sequence on HLA-DPB1 support the importance of our finding, but further studies are needed to reveal its pathogenic mechanisms.

Nigella sativa (black seed) oil does not affect the T-helper 1 and T-helper 2 type cytokine production from splenic mononuclear cells in allergen sensitized mice.

Nigella sativa Linn. (Ranunculaceae) is known to have beneficial effects on a wide range of diseases including asthma. However, the mechanism of action in asthma and other allergic diseases is not entirely clear. The present study was planned to evaluate the effects of Nigella sativa on cytokine production of splenic mononuclear cells in ova-sensitized mice. Nineteen two-month-old BALB/c mice were given 0.3 mL of Nigella sativa oil by oro-eosophageal cannula once a day for a month. The control group consisting of 10 mice took 0.3 mL of 0.9% saline solution by the same route for the same period. In the third week of the study, all mice were sensitized by means of intraperitoneal injections of 20 microg of ovalbumin (OVA-Grade VI, Sigma). Ova injections were repeated three times with 7-day intervals. After another week, all mice were sacrificed by means of cervical dislocation. Then the splenic mononuclear cells (MNCs) of mice were cultured with OVA or Concavalin A (Con-A). From the culture supernatants, IL-4, IL-10 and IFN-gamma were assessed by means of ELISA. The cytokine production of splenic MNCs of mice that were given Nigella sativa for 30 days was not significantly different than those who took saline solution instead. In conclusion, Nigella sativa oil seems not to have an immunomodulatory effect on Th1 and Th2 cell responsiveness to allergen stimulation.

Clastogenicity of selective serotonin-reuptake inhibitors.

OBJECTIVE: Selective serotonin-reuptake inhibitors (SSRIs) are used in the treatment of various forms of psychiatric disorders. Preclinical studies in laboratory animals have indicated that SSRIs were not genotoxic, but clear results from in vitro testing of SSRIs in a human cell system are currently scarce. The purpose of this study was to investigate whether SSRIs might be genotoxic. Sertraline was chosen as model SSRI, since it appears to be at least as well-tolerated as other SSRIs and may even have a more favourable side-effect profile. Unlike fluoxetine, fluvoxamine and paroxetine, sertraline has low potential for pharmacokinetic drug interactions. So, sertraline would be considered first in the treatment of psychiatric disorders requiring SSRI therapy in the future. We therefore examined peripheral lymphocytes from sertraline-treated patients for both sister chromatid exchanges (SCEs), cells with a high frequency of SCEs (HFC) and chromosome aberrations (CA) to evaluate the clastogenicity of SSRIs. METHOD: Ten sertraline-treated patients meeting 'Structured Clinical Interview for DSM-IV' criteria for both generalized anxiety disorder and major depression were compared with 18 healthy volunteers and 18 non-treated patients with similar psychopathology. Sertraline hydrochloride was administered orally at 50 mg daily for 10 months to 1 year. The participants were selected on the basis of similar responses to a questionnaire assessing risk of genotoxicity related to other aspects of life. All participants had very similar lifestyles, medical histories, biological and dietary factors. All subjects were non-smokers. RESULT: A statistically significant difference between patients with both generalized anxiety disorder and major depression (sertraline-treated or non-treated) and healthy volunteer groups was found by both SCE frequencies and HFC percentages. Both patient groups showed higher frequencies of SCEs than the healthy controls. No statistically significant difference was found between SCE frequencies or HFC percentages observed in sertraline-treated and non-treated patient groups. No statistical difference was found between groups with respect to the frequency of CA. CONCLUSION: There are no adequate studies analysing the clastogenicity of SSRIs, in particular of sertraline. The SCE frequency, the percentage HFC and the frequency of CA in patients with both generalized anxiety disorder and major depression exposed to daily doses of sertraline do not indicate a possible clastogenic hazard. The increased SCE frequencies in patients with both generalized anxiety disorder and major depression in our study-irrespective of sertraline treatment-indicate a possible genotoxic effect. However, our observations were based on a limited number of patients; the results may be explained by psychogenic stress.

Sister chromatid exchanges in lymphocytes of nuclear medicine physicians.

OBJECTIVE: The aim of this study was to assess whether occupational exposure to chronic, low doses of Iodine 131 (I-131) and Technetium 99m (Tc-99m) may lead to genotoxicity. Medical personnel occupied in nuclear medicine departments are occupationally exposed to low doses of I-131 and Tc-99m. The determination of the frequency of sister chromatid exchanges (SCEs) and of cells with a high frequency of SCEs (HFC) is considered to be a sensitive indicator for detecting genotoxic potential of mutagenic and carcinogenic agents. Therefore, we examined peripheral lymphocytes from nuclear medicine physicians for the presence of both SCE and HFC. METHODS: Sixteen exposed nuclear medicine physicians (non-smokers) were compared to 16 physicians (non-smokers) who had not been exposed to chemical or physical mutagens in their usual working environment at the same hospital. RESULTS: A statistically significant difference was found between SCE frequencies and HFC percentages measured in lymphocytes from the exposed and control groups. CONCLUSIONS: The present observation on the effect of chronic low doses of I-131 and Tc-99m indicates the possibility of genotoxic implications of this type of occupational exposure. Hence, the personnel who work in nuclear medicine departments should carefully apply the radiation protection procedures and should minimize, as low as possible, radiation exposure to avoid possible genotoxic effects.