Monte Carlo Optimization Method Based QSAR Modeling of Placental Barrier Permeability.

PURPOSE: In order to ensure that drug administration is safe during pregnancy, it is crucial to have the possibility to predict the placental permeability of drugs in humans. The experimental method which is most widely used for the said purpose is in vitro human placental perfusion, though the approach is highly expensive and time consuming. Quantitative structure-activity relationship (QSAR) modeling represents a powerful tool for the assessment of the drug placental transfer, and can be successfully employed to be an alternative in in vitro experiments. METHODS: The conformation-independent QSAR models covered in the present study were developed through the use of the SMILES notation descriptors and local molecular graph invariants. What is more, the Monte Carlo optimization method, was used in the test sets and the training sets as the model developer with three independent molecular splits. RESULTS: A range of different statistical parameters was used to validate the developed QSAR model, including the standard error of estimation, mean absolute error, root-mean-square error (RMSE), correlation coefficient, cross-validated correlation coefficient, Fisher ratio, MAE-based metrics and the correlation ideality index. Once the mentioned statistical methods were employed, an excellent predictive potential and robustness of the developed QSAR model was demonstrated. In addition, the molecular fragments, which are derived from the SMILES notation descriptors accounting for the decrease or increase in the investigated activity, were revealed. CONCLUSION: The presented QSAR modeling can be an invaluable tool for the high-throughput screening of the placental permeability of drugs.

Integrating in silico with in vivo approach to investigate phthalate and bisphenol A mixture-linked asthma development: Positive probiotic intervention.

The aim of this study was to explore the mechanisms of bis(2- ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and bisphenol A (BPA) mixture-induced asthma development and test probiotic as a potential positive intervention. Comparative Toxicogenomics Database (CTD) and ToppGene Suite were used as the main tools for in silico analysis. In vivo 28-day experiment was conducted on rats - seven groups (n = 6): (1) Control: corn oil, (2) P: probiotic (8.78 * 108 CFU/kg/day); (3) DEHP: 50 mg/kg b.w./day, (4) DBP: 50 mg/kg b.w./day, (5) BPA: 25 mg/kg b.w./day; (6) MIX: DEHP + DBP + BPA; (7) MIX + P. Lungs, thymus and kidneys were extracted and prepared for redox status and essential metals analysis. By conducting additional in vitro experiment, probiotic phthalate and BPA binding ability was explored. There were 24 DEHP, DBP and BPA asthma-related genes, indicating the three most probable mechanisms - apoptosis, inflammation and oxidative stress. In vivo experiment confirmed that significant changes in redox status/essential metal parameters were either prominent, or only present in the MIX group, indicating possible additive effects. In vitro experiment confirmed the ability of the multy-strain probiotic to bind DEHP/DBP/BPA mixture, while probiotic administration ameliorated mixture-induced changes in rat tissue.

Cesarean Scar Pregnancy Successfully Managed to Term: When the Patient Is Determined to Keep the Pregnancy.

Cesarean scar pregnancy (CSP) is a rare form of ectopic pregnancy, defined as the implantation of the gestational sac at the uterine incision scar of the previous cesarean section. This condition is associated with severe maternal and fetal/neonatal complications, including severe bleeding, rupture of the uterus, fetal demise, or preterm delivery. In view of these, early diagnosis allows the option of termination of pregnancy. In this case report, we present a patient with a cesarean scar pregnancy who was diagnosed at the sixth week of gestation but declined early termination of the pregnancy and was managed to the 38th week. Placenta previa was confirmed in the second trimester. A planned cesarean section was performed that resulted in the birth of a live full-term neonate. Intraoperatively, placenta percreta was diagnosed, and due to uncontrollable bleeding, a hysterectomy was performed. The postoperative course was uneventful. In cases where an early diagnosis of CSP is made, women should be counseled that this will almost certainly evolve to placenta previa, and the associated risks should be explained. Close follow-up of CSP is mandatory if expectant management is selected. Further studies are needed for definitive conclusions and to determine the risks of expectant management.

T lymphocytes in the third trimester decidua in preeclampsia.

OBJECTIVE: The aim of study was to conduct immunohistochemical quantification of CD3+ and CD8+ decidual lymphocytes in preeclampsia. METHODS: A study group included 30 cases of preeclampsia and a control group included 20 healthy pregnant women, all delivered by Cesarean section. Samples of placental bed were analyzed after immunohistochemical staining of CD45+, CD3+ and CD8+ cells. RESULTS: The group with preeclampsia included a significantly higher number of CD3+ (p < 0.01) and CD8+ (p < 0.05) T lymphocytes. CONCLUSION: It is certain that thebalance dysregulation of T cell of the immune milieu of deciduais of importance in etiopathogenesis and manifestations of preeclampsia.

Metastatic malignant melanoma of the uterus diagnosed by colposcopy.

Introduction: Primary and metastatic malignant melanomas represent a rare diagnosis with a small number of described cases. The aggressive nature of the tumor, non-specific symptoms, difficult diagnosis, and no official protocol about the treatment result in poor disease prognosis. Case Outline: The authors presented a 41-year-old multigravida patient. She had an operation of malignant melanoma in the occipital area of the head. She went to her gynecologist because of increased pale pink vaginal secretion. Gynecological examination didn't show any significant abnormalities apart from a slightly enlarged uterus. Papanicolaou test and vaginal secretion examination were normal. Colposcopically, a significant dark brown hyperpigmented area around 1 cm in size was observed on the posterior lip of the cervix, near the orifice and cervical canal, suspicious of melanoma, which was proven on targeted biopsy of the hyperpigmented change on the cervix, and by magnetic resonance imaging of the lesser pelvis. Classic hysterectomy with adnexectomy and regional pelvic lymphadenectomy were performed. Conclusion: This case report pointed out the significance of applying colposcopy in diagnosing suspected metastatic melanoma of the uterine cervix, along with other diagnostic methods and anamnestic data.

ALTERNATIVES OF MENOPAUSAL HORMONE THERAPY.

INTRODUCTION: It has been generally accepted that the benefits of menopausal hormone therapy outweigh the risks. but there are still some concerns about the administration of menopausal hormone therapy, which has introduced alternative treatments. Pharmacological Alternatives. Central alpha-2 agonist clonidine is only marginally more effective than placebo, and significantly less effective than estrogen. Antiepileptic drug gabapentin reduces hot flashes; however, it is less effective than estrogen. Selective serotonin reuptake inhibitors (paroxetine and fluoxetine) and selective noradrenaline reuptake inhibitors (venlafaxine) reduce vasomotor symptoms and improve depression, anxiety and sleep. Results of studies about dehydroepiandrosterone effects on menopausal symptoms are inconsistent and additional investigations are needed. Non-Pharmacological Alternatives. Stellatum ganglion blockade is a successful treatment for reducing vasomotor symptoms in patients with contraindications for menopausal hormone therapy. Efficacy of acupuncture, homeopathy and reflexology Should be proved by adequate studies. Phytoestrogens could reduce vasomotortymptoms but to a lesser extent than conventional menopausal hormone therapy. However, they have not been proved yet to pro-ide cardiovascular protection and prevention of osteoporosis. nor they could be recommended instead of traditional menopausal hor-one therapy. There is a concern about their undesirable effects. Adequate diet, unchanging body weight Nwthin ideal values and adequate physical activities have beneficial long-term effects, first of all onlpreservation of bone density Alternatives for Atrophic Changes of Vaginal Epithelium. Menopausal symptoms resulting from vaginal atrophy could be resolved by use of hydrophilic prep- arations, lubricants and topical lidocaine creamn r 4% lidocaine water solution for dyspareunia. CONCLUSION: If there are contrain-ications to menopausal hormone therapy or patients are unwilling to take hormone therapy, alternative treatments, which canlalso solve menopausal symptoms, should be considered.

MENOPAUSAL HORMONE THERAPY BENEFITS AND DIFFERENT FORMS.

INTRODUCTION: Declining of ovarian hormone production can seriously disturb the quality of woman's life, with physical and emotional consequences and to potentiate the development of additional health risks such as cardiovascular diseases and osteoporosis which are already present in women of older age. Benefits of Menopausal Hormone Therapy. Menopausal hormone therapy ameliorates the quality of life by resolving the atrophic symptoms and vasomotor problems, protecting from the osteoporosis, maintaining the skin and connective tissue turgor, as well as by improving libido, mood and depression during the menopausal transition. Forms of Menopausal Hormone Therapy. There are several possibilities to treat menopausal problems: estrogen, combination of estrogen and progestogen, androgens, selective estrogen receptor modulators, tissue selective estrogen complex, tibolon and alternatives. Initiating, Monitoring and Discontinuing Menopausal Hormone Therapy. Menopausal hormone therapy should be started when the problems due to menopausal symptoms appear. It is important to have on mind that the effects of hormones depend on age and actual condition of the woman's organism. The goal is effective treatment at the lowest dose and during the shortest interval needed for symptom control. The therapy must be reevaluated every year and potential risks must be discussed as well. CONCLUSION: Menopausal hormone therapy ameliorates the quality of woman's life in perimenopause. Type, doses and duration of the menopausal hormone therapy should be individualized.

EARLY PRIMARY ABDOMINAL PREGNANCY IMPLANTED IN THE VESICOUTERINE POUCH - A CASE REPORT.

INTRODUCTION: An abdominal pregnancy is a rare form of ectopic pregnancy and potentially life-threatening condition. It is difficult to make an early diagnosis of abdominal pregnancy. CASE REPORT: We present a case of early primary abdominal pregnancy, diagnosed at 6th gestational week, located in thevesicouterine pouch and treated laparoscopically. Despite the rapidly decreasing serum ß-human chorionic gonadotropin levels, the presence of the intraperitoneal blood allowed neither expectant management nor medical treatment, although the patient was hemodinamically stable at that moment. The absence of significant bleeding during the surgery and histopathological finding of placental villi with necrosis confirmed that, in this case, the abdominal pregnancy was already the subject of spontaneous involution. CONCLUSION: High index of suspicion and carefully interpreted clinical and ultrasound findings are crucial for timely diagnosis of early abdominal pregnancy before the occurrence of massive and potentially fatal intraperitoneal bleeding.

Stages of endometriosis: does it affect in vitro fertilization outcome.

OBJECTIVE: Women with endometriosis often need in vitro fertilization (IVF) to conceive. There are conflicting data on the results of IVF in patients with endometriosis. The present study was undertaken to investigate whether or not the stage of endometriosis affects the IVF outcome in order to give the best patient counseling MATERIALS AND METHODS: We compared IVF outcome measures between 40 patients with surgically confirmed minimal and mild endometriosis (American Society for Reproductive Medicine Stage I/II) and 38 patients with moderate and severe endometriosis (Stage III/IV). Each group was also compared with a control group of 157 patients with tubal factor infertility. Outcome measures included number of follicles, number of oocytes, mean number of ampoules of gonadotropins, cumulative pregnancy, and live birth rates RESULTS: Higher cancelation rates, higher total gonadotropin requirements, and lower oocyte yield were found in women with endometriosis Stage III and IV compared with both the Stage I/II and control groups. The fertilization rate was higher in Stage III/IV endometriosis compared to Stage I/II. Clinical pregnancy and live birth rates were comparable between patients with endometriosis Stage I/II and control group, whereas they were significantly lower in patients with endometriosis Stage III/IV compared to other two groups. CONCLUSION: The American Society for Reproductive Medicine classification of endometriosis is useful in predicting IVF outcome. Advanced endometriosis means a worse prognosis for IVF treatment compared to milder stages or tubal factor infertility. The decreased fertilization rate in Stage I/II endometriosis might be a cause of subfertility in these women, as a result of a hostile environment caused by the disease.

[Pregnancy after conservative surgical treatment of ovarial mucinous adenocarcinoma].

BACKGROUND: Epithelial ovarian cancer (EOC) accounts for 25% of all malignancies in the female genital tract and it is the most common cause of death among women who develop gynecologic malignancies. According to recent reports at least 20% of EOC are diagnosed at stage I of the disease. Because women tend to give birth to their first child at an older age, and due to the usage of more sensitive diagnostic procedures, the diagnosis of EOC during reproductive age has become more frequent. Therefore, the demand for fertility-sparing surgery in early-stage of EOC is increased. CASE REPORT: We presented the case of accomplished reproduction at 41 after the conservative treatment of mucinous ovarian cancer. In the absence of a complete surgical staging, her decision was to spare her fertility capacities opposed to the treatment recommendations of the oncological council. The bottom-line of this report was to give its contribution to the ongoing controversies in the decision to recommend the conservative surgical treatment of the EOC and also to reveal the need of reconsideration of the necessity of a complete surgical staging in patients with stage I of mucinous ovarian cancer. CONCLUSION: The profile of EOC cases in which a conservative surgical approach is the appropriate one has not yet been defined. Correct surgical staging is still an indispensable guideline for that kind of clinical decision. In the case of stage I of mucinous ovarian cancer with the low tumor grade, the necessity of a complete surgical staging should be reconsidered.

Organophosphate induced delayed polyneuropathy in man: an overview.

About 80 years have passed since the first cases of organophosphate induced delayed polyneuropathy (OPIDP), as the consequence of human poisoning with certain organophosphorus compounds, were described in the literature. OPIDP is a relatively rare neurodegenerative disorder in humans characterized by loss of function, ataxia and paralysis of distal parts of sensory and motor axons in peripheral nerves and ascending and descending tracts of spinal cord appearing 2-3 weeks after exposure or later. The molecular target for OPIDP is considered to be an enzyme in the nervous system known as neuropathy target esterase (NTE). This review discusses OPIDP in man with emphasis on clinical presentation, pathogenesis, molecular mechanisms, and possibilities for prevention/therapy.

[Characteristics of endometrial carcinoma in obese women].

INTRODUCTION: In most developed countries, endometrial cancer appears as most frequent invasive neoplasm of genital tract. Obesity is one of most important risk factors. Aim of study was to establish characteristics endometrial cancer in obese women. MATERIAL AND METHODS: The study included 50 surgically treated women with endometrial cancer. According body mass index they were divided into two groups--group A (30 obese women), group B (20 non-obese women). RESULTS AND DISCUSSION: Non-obese women with endometrial cancer are statistically significantly older than obese. Menopausal status, parity are not statistically significant. The obese group most frequently includes endometrioid type of tumor, while non-obese group most frequently includes non-endometrioid types of endometrial cancer. Over 50% thick myometrial invasion is statistically more frequent in non-obese group than in obese group. In obese group, less than 50% thick myometrial invasion, is statistically significant in comparison to nonobese group. High-differentiated endometrial cancer (G1) is statistically significantly more present in obese women than non-obese. Low-differentiated endometrial cancer is statistically more frequent in non-obese women than in obese. Most frequent in both groups is NG2. According to FIGO stage I, disease is statistically significantly more frequent in obese group than in non-obese. In non-obese group, total number of diseased in higher stages (II and III) is statistically significantly higher than in stage I. CONCLUSION: Endometrial cancer present in obese women is mostly endometroid type I, with slow myometrial invasion, with histological grade I, nuclear grade II in FIGO stage I of disease. In non-obese women, non-endometrioid cancer-- type II is more frequent, with faster myometrial invasion, histological grade II and III, nuclear grade II, in FIGO stage II of disease.

Insulin resistance and C-reactive protein in preeclampsia.

Preeclampsia is referred to as the "disease of the theories" because of the multiple hypotheses proposed to explain is occurrence. Despite considerable research, the causes of preeclampsia remain unclear. Preeclampsia is likely to be multifactorial in origin, and recent research has focused on endothelial dysfunction as a central abnormality in preeclampsia. Insulin resistance and inflammation may contribute to the onset of preeclampsia. They could also be correlated. The aim of the study was to evaluate the presence and relationship between insulin resistance and its markers and C-reactive protein as a marker of inflammation. During their third trimester, 17 preeclamptic women and 20 normotensive controls underwent oral glucose tolerance test, basic biochemical analyses and SHBG. Preeclamptic women were more insulin resistant (p=0,004), and they had higher triglycerides levels (p=0,006), uric acid (p=0,002). However, the study groups did not differ in C-reactive protein (CRP), sex hormone-binding globulin (SHBG), high and low-density lipoproteins (HDL-cholesterol and LDL-cholesterol). In multiple regression analysis only SHBG (p=0,014) and triglycerides (p=0,003) were associated with insulin sensitivity independently of the body mass index (BMI), weight gain, HDL and LDL, and CRP. Preeclampsia is a state of increased insulin resistance, and CRP as the marker of inflammation was not increased in our research, and not associated with established preeclampsia.

[Color Doppler imaging and measurements of intraovarian and intrauterine vascularization on basal ultrasound examination in spontaneous ovulatory and anovulatory cycles].

BACKGROUND/AIM: Any organs functioning directly depends on vascularization. It applies also to the uterus and ovary which go through changes of vascularization during a menstruation cycle. The aim of this investigation was to determine differences in intrauterine and ovarian stromal arterioral blood flow on basal ultrasound examination (day 2-4) between spontaneous ovulatory and anovulatory cycles. METHODS: This prospective clinical investigation included 205 patients divided into two groups: with ovulatory and with anovulatory cycles. RESULTS: Resistance to ovarian arterioral stromal blood flow was significantly lower in the patients with ovulatory cycles (pulsatile index--PI 0.97 +/- 0.4 vs 1.93 +/- 1.37; p = 0.001737; and (resistance index - RI 0.55 +/- 0.12 vs 0.68 +/- 0.14; p = 0.040033). There. were no statistically significant differences in arcuate arterioral blood flow in the pateints with ovulatory and anovulatory cycles (PI 1.21 +/- 0.34 vs 61 +/- 0,61 p = 0.136161 and RI 0.64 +/- 0.11 vs 0.74 +/- 0.07; p = 0.136649). The patients with ovulatory cycles had lower uterine radial arterioral blood flow than the patients with anovulatory cycles (PI 1.001 +/- 0.22 vs 1.61 +/- 0.23 p = 0.007501 and RI 0.55 +/- 0.08 vs 0.71 +/- 0.12; p = 0,0460113). The patients with ovulatory cycles had lower subendometrial arterioral blood flow resistance (PI 0.69 0.19 vs 1.385 +/- 0.09; p = 0.00622 and RI 0.44 +/- 0.09 vs 0.65 +/- 0.02; p = 0.027458). CONCLUSION: Color Doppler ultrasuond imaging and measurements of intrauterine and ovarian stromal arterioral blood flow on basal ultrasound examination (day 2-4), showed lower resistance to blood flow in ovulatory than in anovulatory cycles.

[Acute abdomen in a patient with Mayer-Rokitansky-Kuster-Hauser syndrome].

BACKGROUND: Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a malformation of female genital tract (incidence 1 in 4000 female newborn children). It appears as a result of a disorder in the development of Millerian cannals. Etiology is unknown. Syndrome MRKH is the most frequent cause of primary amenorrhoea (90%). Patients with MRKH have a normal female phenotype, with normal pubic hairness and thelarche, and female karyotype (46XX) followed by primary amenorrhoea. Hormonal status corresponds to healthy women, where the appearance of ovarian tumors and tumors on rudiment parts of uterus is possible. CASE REPORT: We presented a case of acute abdomen in a patient with previously not diagnosed MRKH. The diagnosis was done during the operation. Small pelvis and an abdominal part were filled with torquated tumor lump, where ovaries, oviducts, uterus or something resembling rudiment of uterus were not recognized through careful examination. Furthemore, the patient had a short, dead-end vagina. Tumorectomy was done and hystopathological finding showed the presence of vascular leiomyoma. CONCLUSION: The diagnosis of complex syndromes, such as MRKH, can, despite modern diagnostics, be absent for non-medical and psycho-social reasons. We can expect ovarian and uterine pathology on hypoplastic structures in these patients, as well as in healthy women. Vascular leiomyoma in the patients with MRKH was not found in the available literature.