Diverse Regulation of Vitamin D Receptor Gene Expression by 1,25-Dihydroxyvitamin D and ATRA in Murine and Human Blood Cells at Early Stages of Their Differentiation.

Vitamin D receptor (VDR) is present in multiple blood cells, and the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25D) is essential for the proper functioning of the immune system. The role of retinoic acid receptor α (RARα) in hematopoiesis is very important, as the fusion of RARα gene with PML gene initiates acute promyelocytic leukemia where differentiation of the myeloid lineage is blocked, followed by an uncontrolled proliferation of leukemic blasts. RARα takes part in regulation of VDR transcription, and unliganded RARα acts as a transcriptional repressor to VDR gene in acute myeloid leukemia (AML) cells. This is why we decided to examine the effects of the combination of 1,25D and all-trans-retinoic acid (ATRA) on VDR gene expression in normal human and murine blood cells at various steps of their development. We tested the expression of VDR and regulation of this gene in response to 1,25D or ATRA, as well as transcriptional activities of nuclear receptors VDR and RARs in human and murine blood cells. We discovered that regulation of VDR expression in humans is different from in mice. In human blood cells at early stages of their differentiation ATRA, but not 1,25D, upregulates the expression of VDR. In contrast, in murine blood cells 1,25D, but not ATRA, upregulates the expression of VDR. VDR and RAR receptors are present and transcriptionally active in blood cells of both species, especially at early steps of blood development.

Diagnostic accuracy of interleukin-6 levels in peritoneal fluid for detection of endometriosis.

PURPOSE: To determine, with extended receiver operating characteristic (ROC) curve analysis, the diagnostic value of cytokines showing significantly different peritoneal concentrations between women with and without endometriosis. METHODS: Multiplex cytokine concentration measurement of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ levels in peritoneal fluid of women with minimal to mild (n = 10) and moderate to severe (n = 26) endometriosis, and 42 controls. RESULTS: Only IL-6 and IL-10 concentrations were significantly higher in endometriosis patients than in controls. Specifically, significantly higher IL-6 and IL-10 levels were found in moderate to severe but not in minimal to mild endometriosis as compared to controls. For evaluation of diagnostic significance, ROC analysis determined discriminating parameters for IL-6, while those calculated for IL-10 were useless. Importantly, ROC analysis for IL-6 levels limited to women with moderate to severe endometriosis showed the highest area under the curve with the sample size sufficient to achieve 90 % power of the test. Finally, extended ROC including cost of analysis for this group of patients determined the optimal cut-off leading to high specificity and positive likelihood ratio resulting in 79 % effectiveness of the test. CONCLUSIONS: While our outcomes show moderate usefulness of peritoneal IL-6 levels in discrimination of moderate to severe endometriosis, further studies might be needed to determine the usefulness of peritoneal IL-6 levels in detection of early stages of endometriosis, as such a finding would be more relevant in clinical decision making.

[The crucial role of the proto-oncogene c-mos in regulation of oocyte maturation]. / Rola protoonkogenu c-mos w regulacji procesu dojrzewania komórki jajowej.

Meiosis arrest before fertilization is a common and unique feature of oogenesis in many animal species. On account of the unclear biological significance of meiosis arrest at various stages and for different durations in different animal species, this process and its regulation are the subject of many scientific studies. Studies on the development of ovarian teratomas proved to be helpful in defining the role of particular genes and biochemical cycles in control of the cell cycle in animals. These benign tumors are a valuable source of information on oocyte maturation. The c-mos proto-oncogene, which is specifically expressed in female and male germ cells, plays a crucial role in control of meiotic cell division in mammals. Its product--Mos protein kinase--acting through mitogen-activated protein kinases (MAPKs) regulates critical cellular functions required for homeostasis and decides about cell survival or apoptosis. The MAPK kinase kinase--MAPK kinase--MAPK (MKKK-MKK-MAPK) phosphorelay system, in view of its role in cells, seems to be the ideal target for therapeutic intervention in cancer and other diseases. The recent research on human oocytes suggests that the basic mechanisms regulating various stages of oocyte maturation are similar to those described in animals.

[The role of selected molecular pathways in the pathogenesis of ovarian teratomas]. / Wybrane szlaki molekularne komórki w patogenezie potworniaków jajnika.

From the research point of view--ovarian teratomas, especially mature ones, are an interesting group of germ-cell tumors of the ovary. The WHO classification, which is not simple but includes all tumors that arise from germ cells, emphasizes the complexity of this group. Their complex pathophysiology is also very interesting from the clinical point of view because of their frequent occurrence,especially among young women of reproductive age. Mature ovarian teratomas are benign germ-cell tumors, but in rare cases, especially when they contain solid elements, peritoneal implants may be present which can stimulate malignant processes. Dermoid cysts, a subtype of ovarian teratomas, arise from totipotential germ cells and may therefore contain elements of all three germ layers, although ectodermal structures usually predominate. Radical surgical treatment is not necessity for this type of tumor because conservative surgery usually brings full recovery.However, they make perfect material for gaining interesting information regarding oocyte maturation and such critical cellular functions as proliferation, migration, differentiation, and apoptosis.There are still no unequivocal conclusions related to the role of mutation in genes which influence the mechanisms involved in control of the cell cycle and which may play important roles in the development of ovarian teratomas. In this review the roles of the Patched/Hedgehog and PI3K/Akt pathways and cyclin D protein in the neoplastic transformations of the germ cells are described.

Flow cytometric evaluation of intracellular cytokine synthesis in peripheral mononuclear cells of women with endometriosis.

Systemic changes related to cytokine expression levels in women with endometriosis remain a subject of controversy. There are many studies concerning this topic showing differential serum cytokine levels; however, there are limited data presenting cytokine expression at the single-cell level. This study focused on this question by measuring intracellular cytokine staining of activated peripheral CD3+ and CD14+ cells from women with endometriosis (investigative group) compared with those with uterine leiomyoma (control group). Isolated peripheral blood mononuclear cells from women with endometriosis and uterine leiomyoma were stimulated with PMA and ionomycin or with LPS to induce intracellular synthesis of TNF-alpha, IFN-gamma, and IL-8 in subpopulations of CD3+ cells and TNF-alpha, IL-6, IL-10, MCP-1, and IL-8 in CD14+ cells. Comparison of the total groups of patients showed no significant differences in any of the intracellular cytokines investigated in the T cells and monocytes of women with endometriosis compared with controls. When the group of women with endometriosis was divided with regard to severity of disease, a significantly lower percentage of CD3+CD8- lymphocytes stained for IFN-gamma and a significantly higher percentage of CD14+ cells stained for MCP-1 in advanced endometriosis patients compared with the control group were observed. We conclude that peripheral mononuclear cells in women with advanced endometriosis may have differential cytokine synthesis in vitro. These results support the idea that differing immune cell activity measured by intracellular cytokine profiles in women with advanced endometriosis may be more a consequence of the disease than a cause.

Differential flow cytometric detection of intracellular cytokines in peripheral and peritoneal mononuclear cells of women with endometriosis.

OBJECTIVE: The pathogenesis of endometriosis is related to functional changes in CD3+ and CD14+ cells observed both at the local and systemic level. Here we investigated whether, and if so, how the body compartment influences cytokine expression in stimulated peritoneal and peripheral CD3+ and CD14+ cells of women with endometriosis. STUDY DESIGN: Isolated peripheral blood (PB) and peritoneal fluid (PF) mononuclear cells from women with endometriosis were cultured under non-adherent conditions and stimulated with PMA and ionomycin for 6h to induce intracellular cytokine synthesis of TNF-alpha, IFN-gamma, and IL-8 by CD3+ cells or with LPS for 9h to produce TNF-alpha, IL-6, IL-10, MCP-1, and IL-8 by CD14+ cells. RESULTS: The percentages of positive CD3+ cells stained for TNF-alpha and IFN-gamma were significantly higher and those stained for IL-8 were significantly lower in PF compared with PB, this being independent of the stage of endometriosis. In contrast, the percentages of CD14+ cells producing TNF-alpha, IL-6, IL-10, MCP-1, and IL-8 were significantly higher in PB than PF of women with endometriosis. CONCLUSIONS: Monocytes/macrophages and lymphocytes derived from the peripheral and peritoneal compartments of women with endometriosis differentially respond to stimulated cytokine synthesis induction. However, it is difficult to state whether the observed phenomenon is more related to body compartment influence per se or to the presence of endometriosis.

Serum and peritoneal evaluation of vitamin D-binding protein in women with endometriosis.

INTRODUCTION: Vitamin D-binding protein (also called DBP or Gc-globulin) is recognized as a multifunctional protein involved in the action scavenger system, the transport of vitamin D sterols, and the modulation of immune and inflammatory responses. This study evaluated total serum and peritoneal concentrations of vitamin D-binding protein in women with endometriosis, known as an inflammation-associated disease. MATERIALS/METHODS: The total concentration of DBP was measured with an enzyme-linked immunosorbent assay (ELISA) using a polyclonal antibody raised in a goat immunized with human DBP. Serum and peritoneal fluid were collected from women with endometriosis (n=26) and from patients with benign gynecological conditions serving as a control group (n=17). RESULTS: In general, the vitamin D-binding protein concentration was higher in serum than in peritoneal fluid. Women with endometriosis had higher serum but lower peritoneal levels of DBP compared with the control group; however, no significance was noted. When the endometriosis group was divided with regard to severity, an insignificantly higher serum level of DBP was observed in advanced endometriosis compared with the mild form of the disease, whereas the peritoneal concentration was not dependent on disease severity. CONCLUSIONS: It is concluded that serum and peritoneal DBP concentrations are not affected in women with endometriosis; however, based on the latest published data, it is possible that both the serum and peritoneal concentrations of vitamin D-binding protein may be dependent on Gc genotype, which results in differential modulation of monocyte/macrophage activity.

[Implantation and antigenicity of human endometrium]. / Implantacja a antygenowosc ludzkiego endometrium.

It is essential for an embryo's further development that it generate a connection with the mother. The first stage of this process is implantation, a highly coordinated event that involves both embryonic and endometrial participation. A blastocyst may attach to the endometrium only during the "implantation window", when the uterus is receptive. A description of the molecular features of a receptive endometrium is the aim of this review. During the secretory phase, the endometrium synthesizes such cytokines as LIF (leukemia inhibitory factor), HB-EGF (heparin-binding epithelial growth factor), and TGF-alpha (transforming growth factor alpha) as well as special surface structures, such as integrins. There are two types of integrins: cycle dependent and constitutionally expressed. The coexpression of cycle-dependent integrins may mark the "implantation window". The endometrium of fertile and infertile women may vary in expression of the integrins. Insufficient synthesis of integrins may be caused by a luteal phase deficiency. E-cadherin and alpha-crystalin B play an important role during implantation. The expression of pinopodes on endometrial cells during the "implantation window" marks optimal uterine receptivity. The composition of all the factors mentioned above define the unique properties of the endometrium during the "implantation window".

[Risk factors and clinical characteristic patients with vulvar cancer]. / Czynniki ryzyka i charakterystyka kliniczna chorych z rakiem sromu w materiale wlasnym.

INTRODUCTION: Vulvar cancer is very rare, accounting for about 3-5% female tract malignancies. Venereal diseases and cigarette smoking have been associated with vulvar cancer. Recently p53 gene mutation and Human Papilloma Virus (HPV) infections have been considered etiologic factors. DESIGN: The main aim of this study was the clinical analysis of patients with vulvar cancer treated in II Gynaecology Department of Medical University in Wroclaw. MATERIAL AND METHODS: We analyzed 25 women with vulvar cancer treated in our center. We focused on: choise of treatment, postoperative complications, p53 gene mutation, survival and recurrence of the disease. p53 gene mutations were detected using immunohistochemical methods with monoclonal Novocastra antibody (DO1). RESULTS: The youngest patient was 49 years old and the oldest 79 (median 70), 5 patients were younger than 60 (24%). 72% patients had overweight and 24% obese. The most often histopathological type was keratinizing squamous cell carcinoma. In 68% of cases vulvar cancer was detected in II, III or IVa stage according to FIGO classifications. In 24 patients we detected p53 gene mutation. 4 patients died because of cancer recurrence, 1 because of from radiotherapy complications. CONCLUSIONS: Obesity coexists with vulvar cancer. p53 gene mutation can be etiologic factor in vulvar cancer development. Metastases in inguinal nodes are an important prognostic factor in vulvar cancer.

[The role of matrix metalloproteinases in tumor invasion and metastasis]. / Rola metaloproteinaz macierzowych w procesie inwazji nowotworowej i przerzutowaniu.

The complicated process of invasion and metastasis consists of a long series of sequential and interrelated steps. The outcome of the process is dependent on both: the tumour cells and the properties of tissue microenvironments. Many investigators are interested in the influence of extracellular matrix components on that process. Especially matrix metalloproteinases (MMPs)--family of zinc-dependent enzymes, which take part in the coordination of extracellular matrix synthesis and breakdown seems to play crucial role in this process. A positive correlation between different type of MMPs and specific tumors has been demonstrated in many studies. In this article we summarize the current views on the role of MMPs in cancer invasion and metastasis.

Evaluation of monocyte chemotactic protein-1 levels in peripheral blood of infertile women with endometriosis.

OBJECTIVE: To test whether serum monocyte chemotactic protein-1 (MCP-1) chemokine levels correlate with endometriosis in infertile women. STUDY DESIGN: A group of women with endometriosis (n = 18, infertile) was compared with patients with uterine leiomyoma (n = 16, fertile), unexplained infertility (n = 5, infertile), and healthy women (n = 16, fertile). MCP-1 expression levels were evaluated by ELISA assay. The data obtained were statistically analyzed using the Mann-Whitney test. P-Values <0.05 were considered as significant. RESULTS: MCP-1 concentrations (median; range of values) in serum were as follows: women with endometriosis (221; 101-635 pg/ml), women with unexplained infertility (167, 114-234 pg/ml), women with uterine leiomyoma (137; 88-200 pg/ml), and healthy donors (123; 98-194 pg/ml). Significant differences were observed in the women with endometriosis compared with those with uterine leiomyoma (p = 0.02) and healthy donors (p = 0.002). Among the women with endometriosis, the level of significance in MCP-1 level at rAFS stages III-IV was higher than that at rAFS stages I-II compared with healthy donors and women with leiomyoma (p = 0.002 and p = 0.02, respectively). CONCLUSIONS: These data show that an increased level of MCP-1 can characterize infertile women with endometriosis. However, further studies are needed to be able to determine whether increased MCP-1 chemokine expression can be related to infertility or is a result of endometriosis progress.

[The presence of Mycoplasma hominis and Ureaplasma urealyticum in the cervical canal of uterus]. / Obecnosc Mycoplasma hominis i Ureaplasma urealyticum w kanale szyjki macicy kobiet.

OBJECTIVES: Mycoplasma hominis and Ureaplasma species are common commensal inhabitants of the lower genitourinary tract in adolescents and adults who are sexually active. A lot of authors points out that these microorganisms can play an important role in pathology of genital tract like pelvic inflammatory disease, sterility or non-gonococcal urethritis. MATERIALS AND METHODS: In the study samples from cervical canal of the uterus were obtained from 222 women. The first group consist of 132 women who were examined in II Gynecological Clinic in Wroclaw for different, probably infectious, gynecological pathologies (adnexitis, sterility, bacterial vaginosis). 90 women without infectious diseases were in a control group. All swabs taken from cervix were tested for Mycoplasma hominis and Ureaplasma urealyticum. RESULTS: The prevalence of Ureaplasma urealyticum was 31.8% in the first tested group (42 of 132 women were positive) and 8.8% in control group (8 of 90 were positive). 3% (4 of 132) of patients were positive to Mycoplasma hominis in the first group and only 1.1% (1 of 90) in a control group. CONCLUSIONS: Ureaplasma urealyticum was found most often in such genital tract pathologies like acute or recurrent adnexitis, sterility or bacterial vaginosis. No statistically significant correlation was found between the age of the patients and the incidence of mycoplasmas.

[Can vulvar carcinoma be a danger in the 21st century?]. / Czy w XXI wieku rak sromu moze byc niebezpieczny?

Vulvar carcinoma accounts for 3-5% of all genital cancers. The most common histology of vulvar cancer is squamous cell carcinoma. It has been suggested that vulvar cancer exists as two separate diseases--HPV-positive, occurring in young women, and p53-positive, that occurs in older women. As extensive surgery resection is gold standard of treatment, it is important to play attention for all symptoms, suggesting the beginning of disease. Understanding of the anatomy and the mechanism of lymphatic spread have made modifications in surgical technique possible, allowing less radical excisions.

[Congenital absence of the vagina--its diagnostic-therapeutic implications--case report]. / Wrodzony brak pochwy--implikacje diagnostyczno-terapeutyczne--opis przypadku.

Issues relating to diagnosis and reconstructive therapy for developmental anomalies of female genital tract are controversial. The teratogenic influence during the 6th week of intrauterine life, the time for the development of structures such as fallopian tube, uterus and cervix from the Müllerian duct may lead to their defective formation. In a 14 year old girl congenital absence of vagina, cervix developed right half of uterus (rudimentary horn?) and a pelvic kidney was diagnosed by laparoscopy and laparotomy. The attempt to connect uterus with the artificial vagina during the laparotomy was unfortunately not successful, the main reason being prolonged distance between the apex of artificial passage and the rudimentary uterus. In our opinion ultrasound is a superior diagnostic tool for diagnosis of developmental anomalies in comparison to the palpatory methods. The corrective and reconstructive surgery for the developmental anomalies of the female genital tract should be the domain of a specialized center. Increased awareness of the parents and the public, increase in environmental pollution has led to more frequent and earlier diagnosis of these malformations, which in turn has led to the shift in age for therapeutic interventions.

[Intrauterine fetal death at term--imperfection of medical supervision methods or statistical-biological inevitability--attempt for discussion based on a case report]. / Wewnatrzmaciczna smierc plodu--niedoskonalosc metod nadzoru czy nieuchronnosc statystyczno-biologiczna--próba dyskusji na kanwie opisu kazuistycznego.

There is a description of the case of unexplained intrauterine fetal death at term. The course of the pregnancy was regular. There were any sinister symptoms preceded and there were no malformations or other abnormalities observed thereafter. The preventive role of the more and more sophisticated antenatal monitoring is in the opinion of the authors questionable. Sudden prenatal and postnatal death seems to be an inevitable part of our existence. The similar conclusions from the present literature are quoted.

[Choriocarcinoma with atypical clinical course. Case report]. / Nabloniak kosmówkowy o nietypowym przebiegu.

Authors describe a case of choriocarcinoma with an atypical clinical course in 28-year old woman nine months after a normal pregnancy and labour. Diagnosis of the disease was very hard because endometrial biopsy did not show any suspected cells and two performed pregnancy tests were not positive. Diagnosis was confirmed after a hysterectomy. Authors conclude that every unclear vaginal bleeding during woman's reproductive years should be considered with a beta-HCG level measurement.

[Own experiences in salvage chemotherapy of ovarian cancer--a preliminary report]. / Doswiadczenia wlasne w ratunkowej chemioterapii raka jajnika. Doniesienie wstepne.

OBJECTIVE: To compare the efficacy and side effects of the ovarian cancer salvage treatment. MATERIALS AND METHODS: 28 patients from 2nd Department of Gynecology of Wroclaw Medical University, treated for recurrent ovarian cancer in stage III and IV were analyzed. First line treatment after complete debulking operation was based on platinum analogue (CAP). Platinum-sensitive patients were administered carboplatin with paclitaxel in the second line treatment. Platinum-resistant cases were treated with paclitaxel, topotecan or liposomal doxorubicin only. RESULTS: The effectiveness of the salvage chemotherapy was similar. Side effects depended on used agent. CONCLUSIONS: We conclude that the results of salvage treatment in ovarian cancer remain unsatisfactory. Introducing new agents into the therapy slightly improved the overall survival time.

[Using of Therma-Choice system in treatment of metrorrhagia in case of porphyria]. / Therma-Choice w leczeniu krwawien z macicy w przypadku porfirii.

The authors present the use of Uterine Balloon Therapy in the long term metrorrhagia resistant to conservative treatment, in the case of porphyria. The method was used on a 44 year old female, suffering from acute intermittent liver porphyria for 9 years.

[Urethral obstruction caused by endometriosis]. / Niedroznosc moczowodu w przebiegu endometriozy.

Two cases of unilateral urethral obstruction caused by endometriosis were reported. Two patients aged 48 and 35 years old were fully diagnosed with above mentioned abnormalities prior to a surgical operation. During the surgical operations the initial diagnosis was confirmed macroscopically, followed by the surgical amputation of the urethral parts pathologically changed. The anastomosis of urethra was finally performed after confirmation that the remaining parts were macroscopically unchanged. Histopathological examinations confirmed the initial diagnosis. After the surgical operation both patients were subjected to hormonal treatment attaining full recovery. The above presented cases--urethral endometriosis is one of rare complications caused by endometriosis. Proper and early diagnosis, followed by an effective treatment is important in obviating grievous consequences e.g. total renal failure.

[Gastric cancer in pregnancy--a case report]. / Rak zoladka w przebiegu ciazy--opis przypadku.

Authors describe a case of gastric carcinoma diagnosed during 27th week of pregnancy in 27-year-old woman with mild gastrointestinal symptoms in second and third trimester accompanied with severe anemia. Gastrofiberoscopy with a biopsy confirmed a diagnosis of diffused gastric adenocarcinoma. Sudden symptoms of premature labour in 33-rd week of pregnancy finished with a premature labor. Child died a day after and the patient died 6 days after the labour because of diffused neoplasmatic changes. Authors suggest that gastrofiberoscopy should always be considered if pregnant woman in second or third trimester has still gastrointestinal symptoms and anemia which is not explained.