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Beneficial genetic or environmental factors that influence the length and quality of life can be evaluated while studying supercentenarians. The oldest-old can withstand serious/fatal illnesses more than their peers and/or their aging rate is decreased. Supercentenarians are an interesting group of individuals whose lifestyle is not particularly healthy according to the common guidelines, namely some of them seem to have similar harmful behaviors, but still manage to stay healthier for longer, and while eventually dying from the same degenerative diseases as the general population, they develop symptoms 20-30 years later. As there are not many supercentenarians by definition, it is worthwhile to diligently collect their data to enable future meta-analyses on larger samples; much can be learned from supercentenarians' habits and lifestyle choices about the aging process. Contributions of genetics, lifestyle choices, and epigenetics to their extended life span are discussed here.

Purpose: AI and its machine learning algorithms have proven useful in several fields of medicine, including medically assisted reproduction. The purpose of the study was to construct several predictive models based on clinical data and select the best models to predict IUI procedure outcomes., Methods: Clinical data (patient baseline characteristics, sperm quality, hormonal status, and cycle data) from 1029 IUI procedures performed in 413 couples stimulated by clomiphene citrate, letrozole, or gonadotropins were used to build several models to predict clinical pregnancy. The models included ANN, random forest, PLS, SVM, and linear models using the caret package in R. The models were evaluated using ROC analysis by means of random CV on test data., Results: Out of the best performing models, the random forest model achieved an AUC of 0.66, a sensitivity of 0.432, and a specificity of 0.756. This performance was followed by the PLS model, which achieved a sensitivity of 0.459 and specificity of 0.734. The other models achieved significantly lower AUCs. When adjusting the predictive cutoff value, confusion matrices show that clinical pregnancy is twice as likely in the case of positive prediction., Conclusion: Among the compared methods, the random forest and PLS models demonstrated superior performance in predicting the clinical outcome of IUI. With additional research and clinical validation, AI methods may be successfully used in improving patient selection and consequently lead to better clinical results., (© 2021. The Author(s).)

Background: Given the high prevalence of internalizing disorders among adolescents, it is necessary to define the factors affecting the development and course of psychopathology. Nolen Hoeksema demonstrated the effect of rumination on the development of various forms of psychopathology in adults, while recent data suggest that cognitive control may be a factor underlying this relationship. The aim of this study is to investigate the relation between cognitive control impairments and symptoms of depression through rumination in adolescents suffering from internalizing psychiatric disorders., Subjects and Methods: The study included 100 adolescents of both genders diagnosed with internalizing psychiatric disorders at the Unit for Child and Adolescent Psychiatry at University Hospital Center Osijek. During psychodiagnostic assessment, subjects completed Youth self report, CANTAB Intra-dimensional/extra-dimensional (IED) task, The Ruminative Response Scale, and Beck Depression Inventory-II., Results: The results indicate a clinically significant level of internalizing symptoms and a clinically and subclinically high level of depressive symptoms. The results also show a high positive correlation between internalizing symptoms, rumination, and depressive symptoms, as well as a positive correlation between female gender and internalizing symptoms, rumination, and depressive symptoms. Significant predictors of depression are female gender and rumination while cognitive control has not been detected as a significant predictor., Conclusion: The results of the study emphasize the importance of rumination in the prediction of depressive symptoms in internalizing psychiatric disorders among adolescents and, accordingly, the importance of rumination as a clinical variable in terms of implications in the prevention and treatment of internalizing psychopathology.

The loss and/or modification of natural antioxidants during various food processing techniques and storage methods, like heat/thermal, UV, pulsed electric field treatment, drying, blanching and irradiation is well described. Antioxidants in their reduced form are modified mainly by oxidation, and less by pyrolysis and hydrolysis. Thus, they are chemically converted from the reduced to an oxidized form. Here we describe the neglected role of the oxidized forms of antioxidants produced during food processing and their effect on health. While natural antioxidants in their reduced forms have many well studied health-promoting characteristics, much less is known about the effects of their oxidized forms and other metabolites, which may have some health benefits as well. The oxidized forms of natural antioxidants affect cell signaling, the regulation of transcription factor activities and other determinants of gene expression. Very low doses may trigger hormesis, resulting in specific health benefits by the activation of damage repair processes and antioxidative defense systems. Functional studies determining the antioxidants' effects on the organisms are important, especially as reduced or oxidized antioxidants and their metabolites may have additional or synergistic effects.

We present a 26-year-old primigravida with rudimentary horn pregnancy rupture at 14 weeks of pregnancy. Uterine anomaly was first diagnosed at the time of nuchal translucency scan and was presumed to be a bicornuate uterus with normal intrauterine pregnancy in the right horn. One day later, she was admitted to our department with abdominal pain, shortly leading to massive hemoperitoneum and hypovolemic shock. Uterine rupture was confirmed ultrasonically, followed by immediate laparotomy. Ruptured rudimentary horn with already expulsed pregnancy was encountered during surgery. Despite significant advances in ultrasonography, diagnosis of prerupture stage remains controversial. However, high mortality of the condition should ensure low threshold for surgical exploration., (© 2020 Japan Society of Obstetrics and Gynecology.)

The aim of our study was to investigate whether the experience of objects' implicit features would change if we observe it as a real 3D object or as a photograph or a drawing. In our experiment 46 participants estimated their impression of 10 objects shown in four different presentations. As stimuli, we used 3D objects, their virtual reality models, photographs and drawings from four different viewing directions, created by architecture students. As a measure of implicit features experience we used 12 bipolar adjectives grouped into four factors (attractiveness, regularity, arousal, and calmness) and 3 adjectives forming aesthetic experience factor. Results show significant differences between types of object presentations on four factors of implicit features experience, but not on the aesthetic experience factor. Real 3D objects were experienced as more attractive and calm, while VR presentation showed reduced arousal than other presentation types. On regularity VR and real 3D objects were experienced as same and more regular then drawings and photographs., (Copyright © 2020. Published by Elsevier B.V.)

Remarkable immunomodulatory abilities of mesenchymal stem cells, also called multipotent mesenchymal stromal cells or medicinal signaling cells (MSCs), have entailed significant advances in veterinary regenerative medicine in recent years. Despite positive outcomes from MSC therapies in various diseases in dogs and cats, differences in MSC characteristics between small animal veterinary patients are not well-known. We performed a comparative study of cells' surface marker expression, viability, proliferation, and differentiation capacity of adipose-derived MSCs (ADMSCs) from dogs and domestic cats. The same growth media and methods were used to isolate, characterize, and culture canine and feline ADMSCs. Adipose tissue was collected from 11 dogs and 8 cats of both sexes. The expression of surface markers CD44, CD90, and CD34 was detected by flow cytometry. Viability at passage 3 was measured with the hemocytometer and compared to the viability measured by flow cytometry after 1 day of handling. The proliferation potential of MSCs was measured by calculating cell doubling and cell doubling time from second to eighth passage. Differentiation potential was determined at early and late passages by inducing cells toward adipogenic, osteogenic, and chondrogenic differentiation using commercial media. Our study shows that the percentage of CD44 + CD90 + and CD34 -/- cells is higher in cells from dogs than in cells from cats. The viability of cells measured by two different methods at passage 3 differed between the species, and finally, canine ADMSCs possess greater proliferation and differentiation potential in comparison to the feline ADMSCs., Competing Interests: GM is a partial owner of Animacel Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Voga, Kovač and Majdic.)

In this review, we describe the role of oxidized forms of nicotinamide adenine dinucleotide (NAD + ) as a molecule central to health benefits as the result from observing selected healthy lifestyle recommendations. Namely, NAD + level can be regulated by lifestyle and nutrition approaches such as fasting, caloric restriction, sports activity, low glucose availability, and heat shocks. NAD + is reduced with age at a cellular, tissue, and organismal level due to inflammation, defect in NAMPT-mediated NAD + biosynthesis, and the PARP-mediated NAD + depletion. This leads to a decrease in cellular energy production and DNA repair and modifies genomic signalling leading to an increased incidence of chronic diseases and ageing. By implementing healthy lifestyle approaches, endogenous intracellular NAD + levels can be increased, which explains the molecular mechanisms underlying health benefits at the organismal level. Namely, adherence to here presented healthy lifestyle approaches is correlated with an extended life expectancy free of major chronic diseases., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2020 Borut Poljsak et al.)

Compositions of stainless steel, nickel-titanium, cobalt-chromium and β-titanium orthodontic alloys were simulated with mixtures of Fe, Ni, Cr, Co, Ti and Mo metal ions as potential oxidative stress-triggering agents. Wild-type yeast Saccharomyces cerevisiae and two mutants ΔSod1 and ΔCtt1 were used as model organisms to assess the cytotoxicity and oxidative stress occurrence. Metal mixtures at concentrations of 1, 10, 100 and 1000 µM were prepared out of metal chlorides and used to treat yeast cells for 24 h. Every simulated orthodontic alloy at 1000 µM was cytotoxic, and, in the case of cobalt-chromium alloy, even 100 µM was cytotoxic. Reactive oxygen species and oxidative damage were detected for stainless steel and both cobalt-chromium alloys at 1000 µM in wild-type yeast and 100 µM in the ΔSod1 and ΔCtt1 mutants. Simulated nickel-titanium and β-titanium alloy did not induce oxidative stress in any of the tested strains.

Our aim of the study was to evaluate the efficacy and complication rate of our inpatient medical management protocol for missed miscarriages. Three-hundred and ninety women hospitalised at our tertiary centre because of a missed miscarriage/anembryonic pregnancy in 2012-2013 were included in this retrospective study. The women underwent either a low (until 9 + 0 weeks of gestation) or high gestational age (from 9 + 1 until 15 + 6 weeks of gestation) management protocol. The success rate, curettage in the first 48 hours after the procedure, the complication rate and the factors that might influence these outcomes were evaluated. The overall success rate was 83.3%. The curettage in the first 48 hours after the procedure was performed in 7.4% of the patients and was more often in the high gestational age protocol. Complications that required another outpatient visit or hospitalisation occurred in 9% of the patients. Higher beta-hCG values 14 days after the procedure and the absence of evacuation of products of conception during hospitalisation were associated with a higher complication rate. IMPACT STATEMENT What is already known on this subject? As much as 10-20% of clinically recognised pregnancies end in a spontaneous abortion. A missed miscarriage and a blighted ovum represent a form of spontaneous abortion, which has long been treated with surgical evacuation. However, nowadays, medical management represents a well-established alternative with very high success rates and is considered as an equivalent and safe method that is also very well accepted by patients. What do the results of this study add? According to our results, a medical management of a first trimester missed miscarriage and a blighted ovum is very effective with an overall success rate of 83.3% and a very low percentage of curettage in the first 48 hours after the procedure (7.4%). Our study was also able to identify higher beta-hCG values 14 days after procedure and absence of evacuation of products of conception during hospitalisation as risk factors for complication occurrence. What are the implications of these findings for clinical practice and/or further research? Our study helps to identify patients who are at greater risk for developing complications after the medical management of a first trimester missed miscarriage.

Background: Profound clinical, conceptual and ideological differences between child and adult mental health service models contribute to transition-related discontinuity of care. Many of these may be related to psychiatry training., Methods: A systematic review on General Adult Psychiatry (GAP) and Child and Adult Psychiatry (CAP) training in Europe, with a particular focus on transition as a theme in GAP and CAP training., Results: Thirty-four full-papers, six abstracts and seven additional full text documents were identified. Important variations between countries were found across several domains including assessment of trainees, clinical and educational supervision, psychotherapy training and continuing medical education. Three models of training were identified: i) a generalist common training programme; ii) totally separate training programmes; iii) mixed types. Only two national training programs (UK and Ireland) were identified to have addressed transition as a topic, both involving CAP exclusively., Conclusion: Three models of training in GAP and CAP across Europe are identified, suggesting that the harmonization is not yet realised and a possible barrier to improving transitional care. Training in transition has only recently been considered. It is timely, topical and important to develop evidence-based training approaches on transitional care across Europe into both CAP and GAP training.

Background: Femoral stems with bimodular (head-neck as well as neck-body) junctions were designed to help surgeons address patients' hip anatomy individually. However, arthroplasty registers have reported higher revision rates in stems with bimodular junctions than in stems with modularity limited to the head-neck trunnion. However, to our knowledge, no epidemiologic study has identified patient-specific risk factors for modular femoral neck fractures, and some stems using these designs still are produced and marketed., Questions/purposes: The purposes of this study were (1) to establish the survival rate free from aseptic loosening of one widely used bimodular THA design; (2) to define the proportion of patients who experienced a fracture of the stem's modular femoral neck; and (3) to determine factors associated with neck fracture., Methods: In this retrospective, nationwide, multicenter study, we reviewed 2767 bimodular Profemur® Z stems from four hospitals in Slovenia with a mean followup of 8 years (range, 3 days to 15 years). Between 2002 and 2015, the four participating hospitals performed 26,132 primary THAs; this implant was used in 2767 of them (11%). The general indications for using this implant were primary osteoarthritis (OA) in 2198 (79%) hips and other indications in 569 (21%) hips. We followed patients from the date of the index operation to the date of death, date of revision, or the end of followup on March 1, 2018. We believe that all revisions would be captured in our sample, except for patients who may have emigrated outside the country, but the proportion of people immigrating to Slovenia is higher than the proportion of those emigrating from it; however, no formal accounting for loss to followup is possible in a study of this design. There were 1438 (52%) stems implanted in female and 1329 (48%) in male patients, respectively. A titanium alloy neck was used in 2489 hips (90%) and a cobalt-chromium neck in 278 (10%) hips. The mean body mass index (BMI) at the time of operation was 29 kg/m (SD ± 5 kg/m). We used Kaplan-Meier analysis to establish survival rates, and we performed a chart review to determine the proportion of patients who experienced femoral neck fractures. A binary logistic regression model that controlled for the potential confounding variables of age, sex, BMI, time since implantation, type of bearing, diagnosis, hospital, neck length, and neck material was used to analyze neck fractures., Results: There were 55 (2%) aseptic stem revisions. Survival rate free from aseptic loosening at 12 years was 97% (95% confidence interval [CI] ± 1%). Fracture of the modular neck occurred in 23 patients (0.83%) with a mean BMI of 29 kg/m (SD ± 4 kg/m.) Twenty patients with neck fractures were males and 19 of 23 fractured necks were long. Time since implantation (odds ratio [OR], 0.55; 95% CI 0.46-0.66; p < 0.001), a long neck (OR, 6.77; 95% CI, 2.1-22.2; p = 0.002), a cobalt-chromium alloy neck (OR, 5.7; 95% CI, 1.6-21.1; p = 0.008), younger age (OR, 0.91; 95% CI, 0.86-0.96; p < 0.001), and male sex (OR, 3.98; 95% CI, 1.04-14.55; p = 0.043) were factors associated with neck fracture., Conclusions: The loosening and neck fracture rates of the Profemur® Z stem were lower than in some of previously published series. However, the use of modular femoral necks in primary THA increases the risk for neck fracture, particularly in young male patients with cobalt-chromium long femoral necks. The bimodular stem we analyzed fractured unacceptably often, especially in younger male patients. For most patients, the risks of using this device outweigh the benefits, and several dozen patients had revisions and complications they would not have had if a different stem had been used., Level of Evidence: Level III, therapeutic study.

Background: Malignant mesothelioma (MM) is a rare, but fatal disease with few treatment options. The diagnosis and treatment response are challenging in MM. Therefore, the search for novel diagnostic and prognostic biomarkers is ongoing. The aim of our study was to investigate matrix metalloproteinase 9 (MMP9) as a potential serum biomarker of treatment response and survival in MM. We also investigated the influence of genetic polymorphisms on MMP9 serum levels., Methods: We included 110 patients with MM that have been previously genotyped for common MMP9 polymorphisms. Serum samples were collected before treatment, at the end of chemotherapy, and at the time of progression. MMP9 serum levels were measured using enzyme-linked immunosorbent assay kits. The role of serum MMP9 and MMP9 polymorphisms in treatment response was determined using the nonparametric tests and logistic or Cox regression., Results: Median serum MMP9 was 706.7 (499.6-1224.9) ng/ml before treatment, 440.5 (255.9-685.2) ng/ml after chemotherapy, and 502.8 (307.2-851.4) ng/ml at disease progression. After chemotherapy, 87 (79.8%) patients had lower serum MMP9, with the median change of -286.3 (-607.3 to -70.2) ng/ml ( P < 0.001). At disease progression, 47 (65.3%) patients had lower serum MMP9 compared to pretreatment values, with the median change of -163.7 (-466.6 to 108.6) ng/ml ( P = 0.001). Patients with higher performance status had higher serum MMP9 before treatment ( P = 0.010). Among investigated polymorphisms, only rs17576 was associated with serum MMP9 levels before treatment ( P = 0.041)., Conclusion: Median serum MMP9 levels differed significantly before and after treatment of MM, but failed to reach significance as a standalone biomarker. The contribution of MMP9 serum levels and MMP9 polymorphisms to a composite diagnostic and prognostic biomarker should be further tested.

Purpose: To analyze and clarify conflicting aspects of fusion and total disc replacement (TDR) surgery in literature., Method: Using keywords, 23 literature reviews, 41 studies accepted by "importance criteria" from the Internet, and 16 articles "published in 2018" were chosen. Altogether 80 studies., Results: General assessment was mentioned as affirmative for TDR in 40 papers, five were negative, 24 without clear decision. Long term results TDR seven affirmative, four nondecisive. Comparison to fusion (general, ALIF, 360 0 , BAK cage) 18 found as better, nine equal, one nondecisive. Complications TDR 3-50%. Adjacent disc degeneration disease recognized in 14 papers, denied existence in four. Cost-benefit effective in three papers comparing to fusions, ALIF, 360 0 . Nonimbursement from the state mentioned as problem in three papers. Salvage surgery seven papers, rare but extremely problematic. Anterior approach 16 challenging surgery, one 10% minor, one 38.5% transient complications, one 1.8% retrograde ejaculations, one 6.6% vascular injuries, two access surgeon needed. Construct judgment two no importance, 22 wear and durability problems, two inadequate biomechanics and biomaterials, three construct and lateral approach. Impact of TDR upon spine surgery is decreasing, currently is less than 2%., Conclusion: It is concluded that problems with anterior surgery, imbursement policy, and potential problems with salvage surgery are major reasons for loosing popularity of TDR surgery.

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive thoracic malignancy that is difficult to cure. Dynamic contrast-enhanced (DCE) MRI is a functional imaging technique used to analyze tumor microvascular properties and to monitor therapy response. Purpose of this study was to compare two tracer kinetic models, the extended Tofts (ET) and the adiabatic approximation tissue homogeneity model (AATH) for analysis of DCE-MRI and examine the value of the DCE parameters to predict response to chemotherapy in patients with MPM., Method: This prospective, longitudinal, single tertiary radiology center study was conducted between October 2013 and July 2015. Patient underwent DCE-MRI studies at three time points: prior to therapy, during and after cisplatin-based chemotherapy. The images were analyzed using ET and AATH models. In short-term follow-up, the patients were classified as having disease control or progressive disease according to modified response evaluation criteria in solid tumors (mRECIST) criteria. Receiver operating characteristic curve analysis was used to examine specificity and sensitivity of DCE parameters for predicting response to therapy. Comparison tests were used to analyze whether derived parameters are interchangeable between the two models., Results: Nineteen patients form the study population. The results indicate that the derived parameters are not interchangeable between the models. Significant correlation with response to therapy was found for AATH-calculated median pre-treatment efflux rate (k ep ) showing sensitivity of 83% and specificity of 100% (AUC 0.9). ET-calculated maximal pre-treatment k ep showed 100% sensitivity and specificity for predicting treatment response during the early phase of the therapy and reached a favorable trend to significant prognostic value post-therapy., Conclusion: Both models show potential in predicting response to therapy in MPM. High pre-treatment k ep values suggest MPM disease control post-chemotherapy.

BACKGROUND Ovarian hyperstimulation syndrome (OHSS) is a potentially serious complication of ovulation stimulation. Modest vulvar edema is frequently seen in a severe form of OHSS; however, cases of massive bilateral vulvar edema are rare and pathogenesis is uncertain. CASE REPORT We report a 31-year-old patient with massive vulvar edema and severe OHSS after IVF treatment with GnRH antagonist and gonadotropins. Five days after embryo transfer, she was hospitalized because of severe clinical manifestation of OHSS and on the fifth day after admission she developed a massive bilateral vulvar edema. After conventional medical therapy of OHSS, vulvar edema spontaneously resolved. CONCLUSIONS Hypoproteinemia with low oncotic pressure and certain personal tissue characteristics may play the main role in the pathogenesis of massive vulvar edema in OHSS.

Alginate hydrogels are often used for immobilization of plant-derived bioactive compounds by fast and simple ionic gelation technique. However, the structure of alginate gel network is very porous and mostly result with high-diffusion rates of encapsulated compound, what limits its application as delivery vehicle. In order to prevent losses of bioactives and prepare efficient encapsulation systems, the aim of this study was to evaluate a potential of new natural fillers, cocoa powder (CP) and carob (C) for structuring alginate network aimed for encapsulation of aqueous dandelion (Taraxacum officinale L.) leaf extract using ionic gelation. Whey protein isolates served as a standard filler. The influence of different concentrations of gelling medium (2% and 3% calcium chloride) on encapsulation properties of alginate systems was also evaluated. Calcium concentration affected morphological properties (more acceptable when using 3% CaCl 2 ), while textural properties and encapsulation efficiency of polyphenols and retained antioxidant capacity were more influenced by selected delivery materials. Alginate-whey protein isolates beads were scored with the highest loading capacity of polyphenols (>93%), while newly formulated binary mixtures (alginate-cocoa powder and alginate-carob) also enabled highly efficient entrapment of polyphenols (>88%). The slowest release of polyphenols in simulated gastrointestinal fluids were obtained when alginate was combined with CP and C, where system alginate-cocoa powder prepared with lower concentration of calcium chloride (2% CaCl 2 ) enabled the most extended release of total polyphenols and hydroxycinnamic acids. Obtained results strongly justified implementation of new plant-derived functional fillers (cocoa powder and carob) for encapsulation purposes and opened new directions for designing of binary carrier's., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Prion protein (PrP) is a biomolecule that is involved in neuronal signaling, myelinization, and the development of neurodegenerative diseases. In the cell, PrP is shed by the ADAM10 protease. This process generates PrP molecules that lack glycophosphatidylinositol anchor, and these molecules incorporate into toxic aggregates and neutralize toxic oligomers. Due to this dual role, these molecules are important biomarkers for neurodegenerative diseases. In this review, we present shed PrP as a potential biomarker, with a focus on PrP226*, which may be the main biomarker for predicting neurodegenerative diseases in humans., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Suicide and mood disorders (especially major depressive disorder (MDD) and bipolar affective disorder (BD)) represent a significant global health burden. Major depressive disorder and bipolar affective disorder have been associated with increased risk for suicide. Some specific suicide risk factors might be found in underlying individual personality traits. Specific personality features may predispose an individual to mood disorders (MDD or BD) hence increased suicide risk. The specificity of this research is in the assessment of personality features during the acute phase of illness immediately after suicide attempt which resulted in psychiatric inpatient treatment., Subjects and Methods: The study included 119 unrelated Caucasian participants with MDD-severe depressive episode without psychotic symptoms (MDD) and BD-severe depressive episode without psychotic symptoms (BD-sDE). Both groups of patients with MDD and BD-sDE were divided into the suicide attempters and non-suicidal group. The diagnoses of the severe depressive episode without psychotic symptoms in major depressive disorder (MDD; F32.2) and bipolar disorder (BD-sDE; F31.4) were made according to ICD-10 (WHO 1992) diagnostic criteria. Methods of suicide attempts were also assessed according to ICD-10 and a self-report questionnaire, the Temperament and Character Inventory (TCI) was applied., Results: The participants who exhibited suicide attempt had significantly higher scores on harm-avoidance (HA) (p<0.001), significantly lower score on persistence (PS) (p=0.037) and lower score, however not statistically significant, on novelty-seeking (NS) (p=0.319) regarding temperament dimensions. In character dimensions, the patients with suicidal attempt had significantly lower scores on self-directedness (SD) (p<0.001) and significantly lower scores on cooperativeness (CO) (p=0.001)., Conclusion: Patients who had suicide attempt may have some significantly different personality traits than non-suicidal patients with mood disorders. The combination of high harm-avoidance (HA) and low self-directedness (SD) may be specific for depressive episode while the combination of high HA, novelty-seeking (NS), and self-transcendence (ST) with low SD may be related to suicide attempts during the depressive episode in bipolar disorder. The novelty-seeking (NS), self-transcendence (ST) and self-directedness (SD) may be specific for suicidal group of bipolar patients.

Purpose: The purpose of this study was to find out the most important prognostic factors for achieving a pregnancy after in vitro fertilization (IVF) in women with history of repeated unsuccessful IVF attempts., Methods: We analyzed factors affecting pregnancy rate in a retrospective study including 429 IVF/ICSI cycles performed in women younger than 40 years with at least three previous consecutive failed IVF/ICSI attempts., Results: Clinical pregnancy was observed in 140/429 (32.6%) cycles. Clinical pregnancy rate (CPR) was significantly higher in cycles with LEI compared to cycles without LEI before embryo transfer (44.4 vs 26.54%, p = 0.007). The CPR was also higher in cycles with day 5 blastocyst- compared with day 3 cleavage-stage embryo transfers (45.51 vs 26.54%, p < 0.001). In multivariate logistic regression model, only transfer of at least one good quality embryo (OR = 4.32, 95% CI 2.41-7.73), local endometrial injury (OR = 1.73, 95% CI 1.02-2.92), and transfer on day 5 (OR = 3.02, 95% CI 1.53-5.94) remained important independent prognostic factors for clinical pregnancy., Conclusions: These results suggest that hysteroscopy with local injury to the endometrium prior to ovarian stimulation for IVF/ICSI can improve implantation and pregnancy rates in women experiencing recurrent IVF failure. However, large studies are needed to confirm these findings.

Large interindividual differences in treatment outcome are observed in cancer patients undergoing chemotherapy. Our aim was to develop and validate clinical-pharmacogenetic prediction models of gemcitabine/cisplatin or pemetrexed/cisplatin treatment outcome and develop an algorithm for genotype-based treatment recommendations in malignant mesothelioma (MM). We genotyped 189 MM patients for polymorphisms in gemcitabine, pemetrexed and cisplatin metabolism, transport and drug target genes and DNA repair pathways. To build respective clinical-pharmacogenetic models, pharmacogenetic scores were assigned by rounding regression coefficients. Gemcitabine/cisplatin model was based on training group of 71 patients and included CRP, histological type, performance status, RRM1 rs1042927, ERCC2 rs13181, ERCC1 rs3212986, and XRCC1 rs25487. Patients with higher score had shorter progression-free (PFS) and overall survival (P < 0.001). This model's sensitivity was 0.615 and specificity 0.812. In independent validation group of 66 patients the sensitivity and specificity were 0.667 and 0.641, respectively. Pemetrexed/cisplatin model was based on 57 patients and included CRP, MTHFD1 rs2236225, and ABCC2 rs2273697. Patients with higher score had worse response and shorter PFS (P < 0.001). This model's sensitivity was 0.750 and specificity 0.607. In independent validation group of 20 patients the sensitivity and specificity were 0.889 and 0.500, respectively. The proposed algorithm based on these models could enable the choice of the most effective chemotherapy for 85.5% of patients and lead to improved treatment outcome in MM.

In the brain of patients with transmissible spongiform encephalopathies, besides PrP Sc aggregates, deposition of truncated PrP molecules was described. Jansen et al. reported two clinical cases with deposition of C-terminally truncated PrP, one of them ending with Tyr226. We have previously described the discovery of monoclonal antibody V5B2 that selectively recognizes this version of the prion protein, which we called PrP226*. Using monoclonal antibody V5B2 we showed that accumulation of PrP226* is characteristic for most types of human and animal TSEs. Its distribution correlates to the distribution of PrP Sc aggregates. To gain insight into the structural basis of its presence and distribution in PrP aggregates, we have determined the NMR structure of recombinant PrP226*. The structure of the protein consists of a disordered N-terminal part (residues 90-125) and a structured C-terminal part (residues 126-226). The C-terminal segment consists of four α-helices and a short antiparallel β-sheet. Our model predicts a break in the C-terminal helix and reorganized hydrophobic interactions between helix α 3 and β 2 -α 2 loop due to the shorter C-terminus. The structural model gives information on the possible role of the protein in the development of amyloid disease and can serve as a foundation to develop tools for prevention and treatment of prion diseases., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Malignant pleural mesothelioma (MPM) is a rare disease with a relatively short overall survival (OS). Metalloproteinases (MMPs) have a vast biological effect on tumor progression, invasion, metastasis formation, and apoptosis. MMP expression was previously associated with survival in MPM. Our aim was to evaluate if genetic variability of MMP genes could also serve as a prognostic biomarker in MPM., Methods: We genotyped 199 MPM patients for ten polymorphisms: rs243865, rs243849 and rs7201, in MMP2; rs17576, rs17577, rs20544, and rs2250889 in MMP9 ; and rs1042703, rs1042704, and rs743257 in MMP14 . We determined the influence on survival using Cox regression., Results: Carriers of polymorphic MMP9 rs2250889 allele had shorter time to progression (TTP) (6.07 versus 10.03 months, HR = 2.45, 95% CI = 1.45-4.14, p = 0.001) and OS (9.23 versus 19.2 months, HR = 2.39, 95% CI = 1.37-4.18, p = 0.002). In contrast, carriers of at least one polymorphic MMP9 rs20544 allele had longer TTP (10.93 versus 9.40 months, HR = 0.57, 95% CI = 0.38-0.86 p = 0.007) and OS (20.67 versus 13.50 months, HR = 0.56, 95% CI = 0.37-0.85, p = 0.007). MMP14 rs1042703 was associated with nominally shorter TTP (8.7 versus 9.27 months, HR = 2.09, 95% CI = 1.06-4.12, p = 0.032)., Conclusions: Selected MMP SNPs were associated with survival and could be used as potential genetic biomarkers in MPM.

Prion diseases are a group of fatal neurodegenerative diseases caused by scrapie form of prion protein, PrP Sc . Prion protein (PrP) is bound to the cell via glycophosphatidylinositol (GPI) anchor. The role of GPI anchor in PrP Sc replication and propagation remains unclear. It has been shown that anchorless and truncated PrP accelerate the formation and propagation of prions in vivo and further increases the risk for transmission of prion diseases among species. To explain the role of anchorless forms of PrP in the development of prion diseases, we have prepared five C-terminal PrP truncated variants, determined their thermodynamic properties and analyzed the kinetics of conversion into amyloid fibrils. According to our results thermodynamic and kinetic properties are affected both by pH and truncation. We have shown that the shortest variant was the most destabilized and converted faster than other variants in acidic pH. Other variants converted with longer lag time of fibrillization than WT despite comparable or even decreased stability in acidic pH. Our results indicate that even the change in length for 1 amino acid residue can have a profound effect on in vitro conversion., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Osteosarcoma patients are commonly treated with cisplatin-based preoperative and postoperative chemotherapy. Cisplatin binds to DNA and forms both intrastrand and interstrand crosslinks, inhibiting DNA replication. Glutathione-S-transferases (GSTs) participate in cisplatin detoxification, while several independent DNA repair mechanisms repair cisplatin-induced lesions. The aim of our study was to investigate the influence of genetic variability of DNA repair mechanisms and GSTs on efficacy and toxicity of cisplatin-based chemotherapy in osteosarcoma patients., Methods: A total of 66 osteosarcoma patients were genotyped for ERCC1, ERCC2, NBN, RAD51, XRCC3, and GSTP1 polymorphisms, as well as GSTM1 and GSTT1 gene deletion. We determined the influence of polymorphisms on survival and treatment outcome using Cox regression and logistic regression., Results: Carriers of at least one polymorphic ERCC2 rs1799793 allele had longer event-free survival (EFS) (P=0.006; hazard ratio (HR)=0.28; 95% confidence interval (CI)=0.11-0.70). Polymorphic GSTP1 rs1138272 allele was associated with both shorter EFS and OS (P=0.005; HR=3.67; 95%CI=1.47-9.16; and P=0.004; HR=3.52; 95%CI=1.51-8.22, respectively). Compared to the reference NBN CAA haplotype, NBN CGA haplotype was associated with shorter EFS (P=0.001; HR=4.12; 95%CI=1.77-9.56)., Conclusions: Our results suggest that DNA repair polymorphisms and GST polymorphisms could be used as predictive factors for cisplatin-based chemotherapy in osteosarcoma patients and could contribute to treatment personalization., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Cytotoxic activity of most chemotherapeutic agents is based on their ability to induce DNA damage. Interstrand crosslinks are among the most detrimental forms of DNA damage as both DNA strands are affected. As translesion polymerases participate in their repair, they may be important for response to chemotherapeutic agents that induce such lesions, including commonly used cisplatin. Altered expression of translesion polymerase genes REV1 and REV3L may modify sensitivity to cisplatin. As osteosarcoma patients are commonly treated with cisplatin-based chemotherapy, our aim was to investigate if REV1 and REV3L polymorphisms influence survival of osteosarcoma patients treated with cisplatin-based chemotherapy. We determined the genotypes of common functional tag REV1 and REV3L polymorphisms in 66 osteosarcoma patients. Cox regression was used for survival analysis. Carriers of at least one polymorphic REV1 rs3087403 allele had significantly shorter EFS and overall survival (OS) (p = 0.004; HR = 3.79; 95%CI = 1.53-9.35 and p < 0.001; HR = 4.44; 95%CI = 1.92-10.27, respectively). Combination of REV1 rs3087403 and REV3L rs462779 polymorphisms was also significantly associated with shorter OS (ptrend<0.001) and shorter EFS (ptrend = 0.003). The results of this first study on polymorphisms in translesion polymerase genes in osteosarcoma suggest they could help predict outcome of cisplatin-based chemotherapy in osteosarcoma patients.

Background: Survivin is an inhibitor of apoptosis protein involved in the regulation of cell proliferation that could be used as a marker for cancer diagnosis or prognosis. Our aim was to evaluate whether serum survivin levels influence the outcome of cisplatin-based chemotherapy in patients with malignant mesothelioma (MM)., Methods: Serum survivin levels were determined using human survivin enzyme-linked immunosorbent assay in 78 MM patients before chemotherapy, after chemotherapy, and at disease progression. The influence on tumor response and survival was evaluated using nonparametric tests and Cox regression., Results: A median serum survivin level at diagnosis was 4.1 (0-217.5) pg/mL. Patients with a progressive disease had significantly higher survivin levels before chemotherapy (p = 0.041). A median serum survivin level after chemotherapy was 73.1 (0-346.2) pg/mL. If survivin levels increased after chemotherapy, patients had, conversely, better response (p = 0.001, OR = 5.40, 95% CI = 1.98-14.72). Unexpectedly, patients with increased survivin levels after chemotherapy also had longer progression-free (p < 0.001, HR = 0.33, 95% CI = 0.20-0.57) and overall survival (p = 0.001, HR = 0.29, 95% CI = 0.14-0.58)., Conclusions: These results suggest that serum survivin levels before and during chemotherapy could serve as a biomarker predicting MM treatment response.

Objectives: Osteosarcoma is the most common primary bone malignancy that occurs mostly in adolescents. Treatment protocols usually include multiagent preoperative and postoperative chemotherapy based on methotrexate, cisplatin, doxorubicin and ifosfamide. Despite a favourable prognosis, there are considerable interindividual differences in treatment outcome. Genetic variability of enzymes involved in the metabolism and transport of methotrexate could contribute towards observed differences in response to chemotherapy. Our aim was to evaluate how polymorphisms in the folate pathway and transporter genes influence treatment outcome in osteosarcoma patients., Patients and Methods: In total, 44 osteosarcoma patients treated with methotrexate were genotyped for eleven polymorphisms in four folate pathway and five folate transporter genes. Cox regression was used in survival analysis. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity and nonparametric tests were used to determine the influence on serum methotrexate levels., Results: Polymorphic SLCO1B1 rs4149056 and rs11045879 alleles were associated with significantly higher serum methotrexate area under the curve (P=0.001 and 0.011, respectively). Carriers of at least one polymorphic SLCO1B1 rs4149056 and rs11045879 allele tended to have longer event-free survival compared with patients with two wild-type alleles [P=0.040, hazard ratio (HR)=0.26, 95% confidence interval (CI)=0.07-0.94; and P=0.034, HR=0.20, 95% CI=0.05-0.89, respectively]. Compared with the most common haplotype, carriers of both polymorphic alleles had significantly longer event-free survival (P=0.009, HR=0.27, 95% CI=0.10-0.72)., Conclusion: We have shown that SLCO1B1 polymorphisms influence methotrexate disposition and survival in methotrexate-treated osteosarcoma patients and therefore might serve as pharmacogenetic markers of treatment outcome.

Aim: We evaluated the influence of genetic variability in translesion polymerases REV1 and REV3L on the outcome of cisplatin treatment in malignant mesothelioma patients., Materials & Methods: In total, 139 malignant mesothelioma patients were genotyped for seven tag SNPs in REV1 and REV3L. Logistic regression and Cox regression were used to assess the influence of SNPs on treatment outcome., Results: Polymorphic REV1 rs3087403 allele and REV1 TGT haplotype were associated with increased risk for leukopenia (p = 0.013 and p = 0.047, respectively) and neutropenia (p = 0.048 and p = 0.024, respectively). REV3L rs465646, rs462779 and REV3L CCGG haplotype were significantly associated with longer overall survival (p = 0.007, p = 0.022 and p = 0.013, respectively)., Conclusion: Our results suggest for the first time that REV1 and REV3L SNPs might serve as potential predictive markers of outcome of cisplatin-based chemotherapy. Original submitted 7 October 2013; Revision submitted 15 January 2014.

Conjoint liquid chromatography (CLC) on monolithic convective interaction media (CIM) disks coupled on-line to UV and inductively coupled plasma mass spectrometry (ICP-MS) detectors was used for the first time in speciation analysis of Pt in human serum spiked with Pt-based chemotherapeutics. CIM Protein G and CIM DEAE disks were assembled together in a single housing forming a CLC monolithic column. Such a set-up allows rapid two-dimensional separation by affinity and ion-exchange (IE) modes to be carried out in a single chromatographic run. By applying isocratic elution with Tris-HCl-NaHCO3 buffer (pH 7.4) in the first minute, followed by gradient elution with 1 mol L(-1) NH4Cl (pH 7.4) in the next 9 min, immunoglobulins (IgG) were retained by the Protein G disk enabling subsequent separation of unbound Pt from Pt bound to transferrin (Tf) and albumin (HSA) on the CIM DEAE disk. Further elution with acetic acid (AcOH) in the next 3 min allowed separation of Pt associated with IgG. Separated Pt species were quantified by post-column isotope dilution-ICP-MS. Pt recovery on the CLC column was close to 100%. In comparison to commonly applied procedures that involve separation of protein peaks by size-exclusion chromatography (SEC) followed by IE separation of metal-based chemotherapeutic fractions bound to serum proteins, the CLC method developed is much faster and simpler. Its sensitivity (LOQs adequate for quantification of all separated Pt species, lower than 2.4 ng Pt mL(-1)), good selectivity and method repeatability (RSD±3%) enabled investigation of the kinetics of interaction of Pt-based chemotherapeutics with serum proteins and the distribution of Pt species in spiked human serum. Pt species present in spiked serum were bound preferentially to HSA. The proportion of Pt associated with IgG and Tf was lower than 13%. Cisplatin and especially oxaliplatin react rapidly with serum proteins, while carboplatin much less. The method developed may be reliably applied in preclinical and clinical studies of the kinetics of the interaction and distribution of different metallodrugs with proteins in blood serum., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Malignant pleural mesothelioma is an incurable cancer strongly associated with asbestos exposure and characterised by poor response to treatment. The inhibitor-of-apoptosis protein family member survivin is involved in apoptosis and proliferation and is expressed in cancer cells only. The aims of the present study were to elucidate whether survivin expression is associated with tumour cell apoptosis and proliferation and to assess the prognostic and predictive value of survivin expression in malignant pleural mesothelioma. Archival pleural mesothelioma tissue samples from 101 patients were immunohistochemically analysed for nuclear expression of survivin, for proliferation with the use of Ki-67 as marker and for apoptosis using active caspase-3 as a marker. Staining results and clinical data were included in a survival analysis. Survivin was highly expressed in tumour cell nuclei in all samples and this correlated positively with both apoptosis and proliferation, but did not have a significant prognostic value. We found significantly higher survivin expression in patients who responded to chemotherapy compared to patients with progressive disease. Survivin expression might contribute to treatment response prediction, but survivin expression in malignant pleural mesothelioma did not have prognostic significance.

Introduction: Genetic polymorphisms that affect DNA repair capacity can modulate the efficacy and toxicity of cytotoxic agents. Therefore, the aim of our study was to evaluate the influence of genetic variability in DNA repair genes on treatment outcome in patients with malignant mesothelioma (MM) treated with gemcitabine-platinum combination chemotherapy., Methods: In total, 109 patients with MM were genotyped for 10 polymorphisms in XRCC1, NBN, RAD51, and XRCC3 genes. The influence of selected polymorphisms on tumor response and occurrence of treatment-related toxicity was determined by logistic regression analysis, whereas their influence on survival was estimated by Cox proportional hazards model., Results: There were no associations between the investigated polymorphisms and tumor response, but we observed a significant association between XRCC1 399Gln allele and reduced overall survival (hazards ratio = 1.70; 95% confidence interval [CI] 1.06-2.73; p = 0.028). Interaction between XRCC1 399Gln allele and C-reactive protein levels revealed that carriers of at least one XRCC1 399Gln allele with C-reactive protein levels above median had significantly shorter overall survival time compared with other patients (12.9 months versus 25.3 months, log-rank p < 0.001). We also observed an association between XRCC1 399Gln and lower frequency of leukopenia (odds ratio [OR] = 0.25; 95% CI 0.09-0.67; p = 0.006), neutropenia (OR = 0.24; 95% CI 0.09-0.68; p = 0.007), and thrombocytopenia (OR = 0.27; 95% CI 0.09-0.84; p = 0.024). In addition, NBN 3474A>C, XRCC3 -316A>G, and Thr241Met polymorphisms showed significant associations with treatment-related toxicity., Conclusions: Our results support the hypothesis that DNA repair gene polymorphisms, particularly XRCC1 Arg399Gln, may modify the response to gemcitabine-platinum combination chemotherapy and, for the first time, show this effect in patients with MM.

Objective: To compare blood coagulation parameters between pregnant women with vaginal bleeding in the first trimester of pregnancy and pregnant women with normal pregnancy in the first trimester., Methods: A prospective controlled study of 98 women in the first trimester of vital pregnancy was conducted at the University Medical Centre Maribor, Slovenia. The study group comprised women with vaginal bleeding (n=50) while the control group women with normal pregnancy, admitted for artificial abortion (n=48). Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen concentration, number of platelets, hemogram, coagulation factor VIII (FVIII) and von Willebrand factor (VWF) activity were compared between the 2 groups., Results: No significant between-group differences were detected in mean PT, fibrinogen concentration, FVIII, and VWF activity. Mean aPTT was significantly higher in the control group than the study group (32.47 versus 30.46 seconds; P<0.05). The mean number of platelets was significantly lower in the study group than the control group (181.69 versus 203.52×10(9)/L; P<0.05). All measured coagulation parameters, except VWF activity, were within normal ranges., Conclusion: Coagulation abnormalities are rarely the cause of vaginal bleeding in the first trimester of pregnancy among women with no previous symptoms of bleeding disorders., (Copyright © 2012 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: Identification of biomarkers that could predict gemcitabine efficacy and toxicity is a key issue in the development of individualized therapy. The aim of our study was to evaluate the influence of gemcitabine pathway polymorphisms on treatment outcome in patients with malignant mesothelioma (MM)., Methods: In total, 107 patients with MM, treated with gemcitabine-platinum chemotherapy, were genotyped for 11 polymorphisms in deoxycytidine kinase, ribonucleotide reductase M1 (RRM1), and cytidine deaminase genes using KASPar assays. Binary logistic regression was used to evaluate the influence of selected polymorphisms on tumor response and occurrence of treatment-related toxicity, while their influence on survival was estimated by Cox proportional hazards model. A haplotype analysis was carried out to assess the combined effect of RRM1 polymorphisms., Results: Deoxycytidine kinase and cytidine deaminase polymorphisms did not influence treatment outcome in patients with MM. In multivariable analysis, RRM1 2927A>C polymorphism significantly decreased overall survival probability [hazard ratio (HR)=2.02; 95% confidence interval (CI)=1.11-3.65; P=0.021]. Two promoter polymorphisms, RRM1 -524T>C and -37C>A, decreased the odds of nausea/vomiting grade≥2 occurrence [odds ratio (OR)=0.25; 95% CI=0.10-0.60; P=0.002 and OR=0.26; 95% CI=0.11-0.63; P=0.003, respectively]. RRM1 TTCCA haplotype was associated with worse tumor response (OR=16.67; 95% CI=2.38-100.00; P=0.004) and worse overall survival (HR=2.97; 95% CI=1.46-6.06; P=0.003) compared with the most frequent TTCAA haplotype, while TCACA haplotype influenced nausea/vomiting grade≥2 occurrence (OR=0.27; 95% CI=0.12-0.60; P=0.001)., Conclusion: RRM1 polymorphisms as well as haplotypes showed an association with gemcitabine treatment efficacy and toxicity; therefore, they should be validated as potential markers for the prediction of clinical outcome in patients with MM.

In the title compound, [Fe(C(5)H(5))(C(20)H(14)NO(3))], the cyclo-penta-dienyl rings deviate by 9.3 (2)° from an eclipsed conformation, defined by C-Cg(1)-Cg(2)-C pseudo-torsion angles ranging from 8.8 (1) to 9.85 (1)°. The coordination at the N atom is slightly pyramidal, as indicated by the angular sum around it of 352.6°. The amide group is inclined at 17.86 (9) and 27.27 (11)° with respect to the aromatic rings. In the crystal, mol-ecules are linked by one C-H⋯O hydrogen bond and one C-H⋯π inter-action into a two-dimensional framework parallel to the b axis.