Balint Farkas

Peripheral Blood TIM-3 Positive NK and CD8+ T Cells throughout Pregnancy: TIM-3/Galectin-9 Interaction and Its Possible Role during Pregnancy

Problem The T-cell immunoglobulin and mucin domain (TIM) family is a relatively newly described group of molecules with a conserved structure and important immunological functions. Identification of Galectin-9 as a ligand for TIM-3 has established the Galectin-9/TIM-3 pathway as an important negative regulator of Th1 immunity and tolerance induction. Data about the TIM-3/Gal-9 pathway in the pathogenesis of human diseases is emerging, but their possible role during human pregnancy is not precisely known. The aim of our study was to investigate the number, phenotype and functional activity of TIM-3+ peripheral blood mononuclear cells during healthy human pregnancy. Methods of Study 57 healthy pregnant women [first trimester (n = 16); second trimester (n = 19); third trimester (n = 22)] and 30 non-pregnant controls were enrolled in the study. We measured the surface expression of TIM-3 by cytotoxic T cells, NK cells and NK cell subsets as well as Galectin-9 expression by regulatory T cells by flow cytometry. We analyzed the cytokine production and cytotoxicity of TIM3+ and TIM3- CD8 T and NK cells obtained from non-pregnant and healthy pregnant women at different stages of pregnancy by flow cytometry. Serum Galectin-9 levels were measured by ELISA. Results Our results show that the numbers of peripheral NK and cytotoxic T cells and their TIM-3 expression do not change between the first, second and third trimesters of pregnancy. Compared to non-pregnant individuals, regulatory T cells show higher level of Galectin-9 expression as pregnancy proceeds, which is in line with the level of Galectin-9 in the patients sera. Cytotoxic T cells, NK cells and NK cell subsets expressing TIM-3 molecule show altered cytokine production and cytotoxicity during pregnancy compared to non-pregnant individuals. Conclusion Our results indicate that Galectin-9 expressing regulatory T cells, TIM-3+ cytotoxic T cells and NK cells could play an important role in the maintenance of healthy pregnancy.

Involvement of Galectin-9/TIM-3 Pathway in the Systemic Inflammatory Response in Early-Onset Preeclampsia

Background Preeclampsia is a common obstetrical disease affecting 3-5% of pregnancies and representing one of the leading causes of both maternal and fetal mortality. Maternal symptoms occur as an excessive systemic inflammatory reaction in response to the placental factors released by the oxidatively stressed and functional impaired placenta. The T-cell immunoglobulin domain and mucin domain (TIM) family is a relatively newly described group of molecules with a conserved structure and important immunological functions. Identification of Galectin-9 as a ligand for TIM-3 has established the Galectin-9/TIM-3 pathway as an important regulator of Th1 immunity and tolerance induction. Methods The aim of our study was to investigate the expression and function of Galectin-9 and TIM-3 molecules by peripheral blood mononuclear cells and the possible role of Galectin-9/TIM-3 pathway in the immunoregulation of healthy pregnancy and early-onset preeclampsia. We determined TIM-3 and Gal-9 expression and cytotoxicicty of peripheral lymphocytes of early-onset preeclamptic women and healthy pregnant woman using flow cytometry. Results Investigating peripheral lymphocytes of women with early-onset preeclampsia, our results showed a decreased TIM-3 expression by T cells, cytotoxic T cells, NK cells and CD56dim NK cells compared to healthy pregnant women. Interestingly, we found a notably increased frequency of Galectin-9 positive cells in each investigated lymphocyte population in the case of early-onset preeclamptic patients. We further demonstrated increased cytotoxic activity by cytotoxic T and CD56dim NK cells in women with early-onset preeclampsia. Our findings showed that the strongest cellular cytotoxic response of lymphocytes occurred in the TIM-3 positive subpopulations of different lymphocytes subsets in early-onset preeclampsia. Conclusion These data suggest that Gal-9/TIM-3 pathway could play an important role in the immune regulation during pregnancy and the altered Galectin-9 and TIM-3 expression could result an enhanced systemic inflammatory response including the activation of Th1 lymphocytes in preeclampsia.

Sexual Function after Modified Laparoscopic Vecchietti’s Vaginoplasty

STUDY OBJECTIVE To report on minor modification of laparoscopic Vecchietti vaginoplasty and to examine the quality of sexual life after the operation. DESIGN A retrospective study to examine the role of minor modification during laparoscopic Vecchietti operation to prevent injuries and to evaluate the sexual function of patients with neovagina. SETTING Department of Obstetrics and Gynecology, University of Pécs, Faculty of Medicine, a tertiary supply center in Hungary. PATICIPANTS: Twenty-three adolescents or young adults, ages 16 to 26 with vaginal agenesis (Mayer-Rokitansky-Küster-Hauser syndrome) were operated. Twenty-five sexually active patients with matched age served as controls. INTERVENTIONS Laparoscopic Vecchietti operation was modified with the use of endovaginal ultrasound transducer to visualize the narrow vesico-rectal space. The quality of sexual life 2-11 years after the operation was measured by the Female Sexual Function Index (FSFI). MAIN OUTCOME MEASURES Complications occurring during operations; desire, arousal, orgasm, satisfaction, lubrication, and pain during sexual intercourse. RESULTS The technical modification of the operation, with endovaginal transducer, improved the method. Serious injuries of the bladder or rectum could be avoided. Anatomic and functional results shown by the total FSFI scores did not differ from that of the control group. Desire, arousal, orgasm, and satisfaction of the operated patients were similar to controls; however, patients with neovagina tended to have less lubrication and more pain during sexual intercourse. CONCLUSIONS Laparoscopic Vecchietti operation modified by the use of endovaginal transducer is a safe procedure to create a neovagina, which guarantees good quality of sexual life with high satisfaction for patients.

Investigating the clinical potential for 14-3-3 zeta protein to serve as a biomarker for epithelial ovarian cancer

ObjectiveRecently, 14-3-3 zeta protein was identified as a potential serum biomarker of epithelial ovarian cancer (EOC). The goal of this study was to investigate the clinical potential of 14-3-3 zeta protein for monitoring EOC progression compared with CA-125 and HE4.DesignProspective follow-up study.SettingUniversity of Pecs Medical Center Department of Obstetrics and Gynecology/Oncology (Pecs, Hungary).PopulationThirteen EOC patients with advanced stage (FIGO IIb-IIIc) epithelial ovarian cancer that underwent radical surgery and received six consecutive cycles of first line chemotherapy (paclitaxel, carboplatin) in 21-day intervals.MethodsPre- and post-chemotherapy computed tomography (CT) scans were performed. Serum levels of CA-125, HE4, and 14-3-3 zeta protein were detected by enzyme-linked immunosorbent assay (ELISA) and quantitative electrochemiluminescence assay (ECLIA).Main outcome measuresSerum levels of CA-125, HE4, and 14-3-3 zeta protein, as well as lesion size according to pre- and post-chemotherapy CT scans.ResultsSerum levels of CA-125 and HE4 were found to significantly decrease following chemotherapy, and this was consistent with the decrease in lesion size detected post-chemotherapy. In contrast, 14-3-3 zeta protein levels did not significantly differ in healthy postmenopausal patients versus EOC patients.ConclusionsDetermination of CA-125 and HE4 serum levels for the determination of the risk of ovarian malignancy algorithm (ROMA) represents a useful tool for the prediction of chemotherapy efficacy for EOC patients. However, levels of 14-3-3 zeta protein were not found to vary significantly as a consequence of treatment. Therefore we question if 14-3-3 zeta protein is a reliable biomarker, which correlates with the clinical behavior of EOC.

Commitment of Decidual Haematopoietic Progenitor Cells in First Trimester Pregnancy

Citation Szereday L, Miko E, Meggyes M, Barakonyi A, Farkas B, Varnagy A, Bodis J, Lynch L, O’Farrelly C, Szekeres‐Bartho J. Commitment of decidual haematopoietic progenitor cells in first trimester pregnancy. Am J Reprod Immunol 2012; 67: 9–16

Assessment of cells in the ascitic fluid of women with ovarian hyperstimulation syndrome: The clinical implications for subsequent ovarian malignancy

BackgroundAlthough some studies have reported a potential connection between ovulation induction therapy (OIT) and malignant ovarian diseases, the results have been inconclusive. In the present study, we sought to determine whether women undergoing OIT at our in vitro fertilization (IVF) clinic, especially those with severe ovarian hyperstimulation syndrome (OHSS) and suspicious cytologic findings, were at risk for developing malignant ovarian tumours after treatment.MethodsPatients who underwent OIT at our IVF clinic were enrolled in this study and assessed for any evidence of malignant ovarian tumours. Patients who developed severe OHSS as a result of OIT were treated with a culdocentesis. Cells from the ascitic fluid were cytologically scored for abnormality and malignancy. Peripheral blood samples were obtained from patients with severe OHSS to determine serum levels of the tumour markers (CA-125 and HE4) that were used to calculate the Risk for Ovarian Malignancy Algorithm (ROMA) index.ResultsFollow-up data were available for 1,353 of the 1,587 patients (85%) who underwent OIT at our IVF clinic between January 2006 and December 2012. Twenty-three patients (1.4%) were hospitalized with OHSS. Culdocentesis was performed 16 times in nine patients with severe OHSS (age range, 23–34 years; mean, 27.1 years). Although cytological examination of the ascitic cells of these patients suggested malignant ovarian neoplasia, over the course of the observation period, the ovarian volume gradually decreased and became normal. Subsequent cytological and histological examinations failed to find evidence of any malignant tumours in these nine patients. None of the 1,353 participants who underwent OIT developed any malignant ovarian tumours during the study period. Moreover, none of the 462 patients who were in our ovarian tumour registry were also participants in the IVF program.ConclusionsThe presence of atypical cells in the ascitic fluid of women with severe OHSS does not likely indicate malignancy; therefore, radical surgical intervention is not justified. The risk of malignancy is minimal shortly after OIT. At our centre, OIT has not been associated with any cases of ovarian tumour.

Hungarian language validation of the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR).

Introduction and HypothesisUntil now, no valid Hungarian questionnaire has existed to evaluate the sexual quality of life of women with pelvic floor disorders. The aim of this study was to translate the Prolapse/Urinary Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR), into Hungarian and to validate the translated PISQ-IR.MethodsPISQ-IR was translated and validated using three steps, as guided by the IUGA international protocol: forward translation by two urogynecologists, a community review process consisting of one-on-one cognitive interviews with 20 patients, and backward translation by a native English speaker. The final version was approved by the IUGA Working Group comprising the original authors.ResultsAmong sexually active women, good internal consistency was observed for all scales of the adapted instrument: global quality (Cronbach’s α = 0.75), condition impact (α = 0.87), desire (α = 0.82), arousal/orgasm (α = 0.67), partner-related (α = 0.61) and condition-specific (α = 0.67). Among women who were not sexually active, internal consistency was valid for three scales: condition-specific (α = 0.70), global quality (α = 0.81) and condition impact (α = 0.86). Cronbach’s α could not be determined in the partner-related domain because only two items were included. Criterion validity and reliability showed strong significant correlations with the UI at the Clinical-Q values and the FSFI and PFDI-20 tests.ConclusionsThe PISQ-IR Hungarian version is a valid and reliable tool that is equivalent to the original English questionnaire and assesses sexual function in Hungarian women with pelvic organ prolapse, urinary incontinence and/or fecal incontinence.

Platelet-associated regulatory system (PARS) with particular reference to female reproduction.

BackgroundBlood platelets play an essential role in hemostasis, thrombosis and coagulation of blood. Beyond these classic functions their involvement in inflammatory, neoplastic and immune processes was also investigated. It is well known, that platelets have an armament of soluble molecules, factors, mediators, chemokines, cytokines and neurotransmitters in their granules, and have multiple adhesion molecules and receptors on their surface.MethodsSelected relevant literature and own views and experiences as clinical observations have been used.ResultsConsidering that platelets are indispensable in numerous homeostatic endocrine functions, it is reasonable to suppose that a platelet-associated regulatory system (PARS) may exist; internal or external triggers and/or stimuli may complement and connect regulatory pathways aimed towards target tissues and/or cells. The signal (PAF, or other tissue/cell specific factors) comes from the stimulated (by the e.g., hypophyseal hormones, bacteria, external factors, etc.) organs or cells, and activates platelets. Platelet activation means their aggregation, sludge formation, furthermore the release of the for-mentioned biologically very powerful factors, which can locally amplify and deepen the tissue specific cell reactions. If this process is impaired or inhibited for any reason, the specifically stimulated organ shows hypofunction. When PARS is upregulated, organ hyperfunction may occur that culminate in severe diseases.ConclusionBased on clinical and experimental evidences we propose that platelets modulate the function of hypothalamo-hypophyseal-ovarian system. Specifically, hypothalamic GnRH releases FSH from the anterior pituitary, which induces and stimulates follicular and oocyte maturation and steroid hormone secretion in the ovary. At the same time follicular cells enhance PAF production. Through these pathways activated platelets are accumulated in the follicular vessels surrounding the follicle and due to its released soluble molecules (factors, mediators, chemokines, cytokines, neurotransmitters) locally increase oocyte maturation and hormone secretion. Therefore we suggest that platelets are not only a small participant but may be the conductor or active mediator of this complex regulatory system which has several unrevealed mechanisms. In other words platelets are corpuscular messengers, or are more than a member of the family providing hemostasis.

Oral Contraceptive Pills as Primary Prevention for Ovarian Cancer: A Systematic Review and Meta-analysis.

To the Editor: We congratulate Havrilesky et al on their comprehensive systematic review and meta-analysis. After reading the article thoroughly, there are some questions that we feel should be addressed, primarily because ovarian cancer is a very serious disease with a high mortality rate. The authors state, “Unfortunately, screening studies to date have not demonstrated reductions in mortality and false-positive rates have been high.” The studies cited for this statement relied on serum CA 125 measurement and pelvic ultrasonography. We know that high levels of serum CA 125 also are associated with benign gynecologic diseases (eg, cysts, endometriosis). Furthermore, in 2008, Moore and colleagues identified human epididymis protein 4 as a biomarker for ovarian cancer. Based on these findings, a risk-of-ovarian-malignancy algorithm was developed and currently is used to predict the presence of malignant ovarian cancer using a combination of CA 125 levels, human epididymis protein 4 expression, and menopausal status. In particular, the combination of human epididymis protein 4 and CA 125 in the risk-of-ovarian-malignancy algorithm has been associated with a higher sensitivity than any single biomarker. We would like to ask why the authors did not include any data or mention this novel biomarker in their article. Do they believe that including this novel biomarker in future studies, instead of just CA 125, could increase sensitivity and lead to better overall results in screening? Finally, we agree with the authors that oral contraceptive pill use can decrease the risk of developing ovarian cancer, but we believe that further studies still are required.

Impact of maternal obesity on the fetal electrocardiogram during labor.

Abstract Objective: Maternal obesity affects one in every five women giving birth worldwide. This condition is associated with adverse perinatal outcomes, as well as increased morbidity and mortality for mother and offspring. Methods: We carried out a prospective study at the University of Pecs Medical Center, Pecs, Hungary, between 1 January 2013 and 1 January 2014. We enrolled 60 obese (body mass index >30 kg/m2) low-risk pregnant women and 108 age-, ethnicity-, and parity-matched nonobese pregnant control subjects. The ST segment of the fetal electrocardiogram was assessed by STAN® monitoring. Neonatal outcomes and cord gas analysis of the umbilical vessels were evaluated after birth. Results: No infant with definitive metabolic acidosis was delivered in either group. We observed 32 and 106 ST events in the obese and control group, respectively, but this difference was not statistically significant. To date, none of the infants delivered as part of this study have demonstrated developmental insufficiency. Conclusions: Obesity might not influence the fetal electrocardiogram during labor as an independent risk factor for adverse pregnancy outcomes. Studies with larger cohort sizes are needed to confirm our findings.