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Previous studies have shown that the human capacity to gauge one's own physiological state is notoriously flawed. The cause for the mismatch between perceived and physiological stress has not yet been properly identified. In this study, we assumed that cardioceptive accuracy (CAc) is positively associated with cardiovascular reactivity, and CAc and expectation about stress might account for the discrepancy between perceived and physiological stress. In a crossover experiment, we assessed cardioceptive accuracy in two ways (mental heartbeat tracking task and perception of heart rate), and induced physiological (handgrip exercise) and mental (N-back task) stress in 64 university students (51 % male, mean age 22.2). We assessed cardiac and electrodermal activity, and expected and perceived stress. We found that indicators of cardioceptive accuracy were not associated with cardiovascular reactivity. However, heart rate perception moderated the association between the change in heart rate and perceived stress in the physical but not in the mental task. Whereas heartbeat tracking accuracy was not associated with perceived stress. Moreover, perceived stress was predicted by the expected stress but not by the change in heart rate and electrodermal activity in the mental stress task. In conclusion, heart rate perception and expectation of stress may shape perceived stress more than actual physiological changes in moderate acute stress., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Discrepancy between measured HbA 1c and HbA 1c calculated from plasma glucose is associated with higher risk for diabetic complications. However, quantification of this difference is inaccurate due to the imperfect linear conversion models. We propose to introduce a mathematical formula that correlates with the observational data and supports individualized glycemic control., Methods: We analysed 175,437 simultaneous plasma glucose and HbA 1c records stored in our laboratory database. Employing the Michaelis-Menten (MM) equation, we compared the calculated HbA 1c levels to the measured HbA 1c levels. Data from patients with multiple records were used to establish the patients' glycemic status and to assess the predictive power of our MM model., Results: HbA 1c levels calculated with the MM equation closely matched the population's average HbA 1c levels. The Michaelis constant (K m ) had a negative correlation with HbA 1c (r 2  = 0.403). Using personalized K m values in the MM equation, 85.1% of HbA 1c predictions were within 20% error (ADAG calculation: 78.4%). MM prediction also performed better in predicting pathologic HbA 1c levels (0.904 AUC vs. 0.849 AUC for ADAG)., Conclusion: MM equation is an improvement over linear models and could be readily employed in routine diabetes management. K m is a reliable and quantifiable marker to characterize variations in glucose tolerance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Pediatric acute myeloid leukemia (AML) represents a major cause of childhood leukemic mortality, with only a limited number of studies investigating the molecular landscape of the disease. Here, we present an integrative analysis of cytogenetic and molecular profiles of 75 patients with pediatric AML from a multicentric, real-world patient cohort treated according to AML Berlin-Frankfurt-Münster protocols. Targeted next-generation sequencing of 54 genes revealed 17 genes that were recurrently mutated in >5% of patients. Considerable differences were observed in the mutational profiles compared with previous studies, as BCORL1, CUX1, KDM6A, PHF6, and STAG2 mutations were detected at a higher frequency than previously reported, whereas KIT, NRAS, and KRAS were less frequently mutated. Our study identified novel recurrent mutations at diagnosis in the BCORL1 gene in 9% of the patients. Tumor suppressor gene (PHF6, TP53, and WT1) mutations were found to be associated with induction failure and shorter event-free survival, suggesting important roles of these alterations in resistance to therapy and disease progression. Comparison of the mutational landscape at diagnosis and relapse revealed an enrichment of mutations in tumor suppressor genes (16.2% versus 44.4%) and transcription factors (35.1% versus 55.6%) at relapse. Our findings shed further light on the heterogeneity of pediatric AML and identify previously unappreciated alterations that may lead to improved molecular characterization and risk stratification of pediatric AML., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety., Patients and Methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015., Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome., Conclusion: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Vasoactive intestinal polypeptide (VIP), an anti-inflammatory neuropeptide with pleiotropic cardiovascular effects, induces differentiation of hematopoietic stem cells into regulatory dendritic cells that limit graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We have previously shown that donor plasmacytoid dendritic cells (pDCs) in bone marrow (BM) donor grafts limit the pathogenesis of GVHD. In this current study we show that murine and human pDCs express VIP, and that VIP-expressing pDCs limit T-cell activation and expansion using both in vivo and in vitro model systems. Using T cells or pDCs from transgenic luciferase+ donors in murine bone marrow transplantation (BMT), we show similar homing patterns of donor pDCs and T cells to the major sites for alloactivation of donor T cells: spleen and gut. Cotransplanting VIP-knockout (KO) pDCs with hematopoietic stem cells and T cells in major histocompatibility complex mismatched allogeneic BMT led to lower survival, higher GVHD scores, and more colon crypt cell apoptosis than transplanting wild-type pDCs. BMT recipients of VIP-KO pDCs had more T helper 1 polarized T cells, and higher plasma levels of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-α than recipients of wild-type pDCs. T cells from VIP-KO pDC recipients had increasing levels of bhlhe40 transcripts during the first 2 weeks posttransplant, and higher levels of CyclophilinA/Ppia transcripts at day 15 compared with T cells from recipients of wild-type pDCs. Collectively, these data indicate paracrine VIP synthesis by donor pDCs limits pathogenic T-cell inflammation, supporting a novel mechanism by which donor immune cells regulate T-cell activation and GVHD in allogeneic BMT., (© 2022 by The American Society of Hematology.)

Human C-reactive protein (CRP), an early clinical indicator of infectious or inflammatory conditions has been recently identified as a key biomarker associated with the development of COVID-19. The rapid and accurate determination of CRP level in blood serum is an urgent need to predict timely the risk of disease worsening. The emergence of nanotechnological tools has provided an attractive perspective in designing portable bioanalytical assays with fast response time, high sensitivity and specificity, and multiplexing capability for accurate, on-site disease diagnosis and monitoring. Due to their versatile optical properties, plasmonic nanoparticles (PNPs) are appealing candidates for biosensing applications. This review summarizes the advances in the application of PNPs for CRP detection and quantification. Particularly, we review the improvements attained in the detection of CRP using aggregation-based colorimetric, localized surface plasmon resonance (LSPR), plasmon-assisted fluorescence and chemiluminescence, and surface-enhanced Raman scattering (SERS) spectroscopic methods., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Elsevier B.V. All rights reserved.)

Herein, we report the fabrication of a nanotherapeutic platform integrating near-infrared (NIR) imaging with combined therapeutic potential through photodynamic (PDT) and photothermal therapies (PTT) and recognition functionality against ovarian cancer. Owing to its NIR fluorescence, singlet oxygen generation and heating capacity, IR780 iodide is exploited to construct a multifunctional nanosystem for single-wavelength NIR laser imaging-assisted dual-modal phototherapy. We opted for loading IR780 into polymeric Pluronic-F127-chitosan nanoformulation in order to overcome its hydrophobicity and toxicity and to allow functionalization with folic acid. The obtained nanocapsules show temperature-dependent swelling and spectroscopic behavior with favorable size distribution for cellular uptake at physiological temperatures, improved fluorescence properties and good stability. The fabricated nanocapsules can efficiently generate singlet oxygen in solution and are able to produce considerable temperature increase (46 °C) upon NIR laser irradiation. Viability assays on NIH-OVCAR-3 cells confirm the successful biocompatibilization of IR780 by encapsulating in Pluronic and chitosan polymers. NIR fluorescence imaging assays reveal the ability of folic-acid functionalized nanocapsules to serve as intracellular contrast agents and demonstrate their active targeting capacity against folate receptor expressing ovarian cancer cells (NIH-OVCAR-3). Consequently, the targeted nanocapsules show improved NIR laser induced phototherapeutic performance against NIH-OVCAR-3 cells compared to free IR780. We anticipate that this class of nanocapsules holds great promise as theranostic agents for application in image-guided dual PDT-PTT and imaging assisted surgery of ovarian cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Multidrug resistant (MDR) Gram-negative bacteria are an urgent global health threat. We report on the design and evaluation of a xenosiderophore-conjugated cationic random copolymer (pGQ-DG) which exhibits selective antibacterial activity against Pseudomonas aeruginosa (P. aeruginosa) by targeting select outer membrane (OM) receptors for scavenging xenosiderophores such as deferoxamine (DFO), while possessing favorable cytocompatibility and exhibiting low hemolysis, to enhance and safely damage the bacterial OM. pGQ-DG demonstrated synergistic properties in combination with vancomycin (VAN) when evaluated in vitro against P. aeruginosa. In addition, pGQ-DG plus VAN cleared the P. aeruginosa infection and efficiently accelerated healing in a murine wound healing model as effectively as colistin, suggesting that this strategy could serve as an alternative to colistin against MDR bacteria. STATEMENT OF SIGNIFICANCE: P. aeruginosa exhibits intrinsic antibiotic resistance due to limited permeability of its outer membrane (OM). A triple combination antipseudomonal approach was investigated by 1) selectively targeting P. aeruginosa through the complex DFO:gallium, 2) disrupting the OM through a cationic random copolymer, and 3) enhancing bacteria sensitivity to VAN as a result of the OM disruption. Synthesis and characterization of the lead polymer pGQ-DG, mechanism of action, antimicrobial activity, and biocompatibility were investigated in vitro and in vivo. Overall pGQ-DG plus VAN cleared the P. aeruginosa infection and accelerated wound healing in mice as effectively as colistin, suggesting that this strategy could serve as an alternative to colistin against multidrug resistant P. aeruginosa., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Despite many hypothesized benefits of dietary isoflavone genistein (GEN) deriving from soy-based products, questions surrounding GEN's developmental effects are increasing. To understand if in utero GEN exposure modulated postnatal respiratory allergies in the middle age, we conducted a time course study in the B6C3F1 offspring (PND 240-330) using a common household allergen (house dust mites: HDM; 10 μg/mouse for PND 240 and 290, and 50 μg/mouse for PND 330, a middle age in mice) following intranasal instillation, a physiological route of allergen exposure. GEN was administered to dams by gavage from gestational day 14 to parturition at a physiologically relevant dose (20 mg/kg body weight). Female and male offspring were sensitized with HDM allergens beginning about one month prior to sacrifice followed by challenges with three weekly dosings of HDM extracts, and they were euthanized at day 3 following the final HDM exposure. In utero exposure to GEN decreased HDM allergen-induced respiratory allergy in male B6C3F1 offspring at PND 330 as reflected by decreases in airway hyperresponsiveness (e.g., Penh value), HDM-specific IgG 1 (a Th2 type Ab) and the activity of eosinophil peroxidase in the lung (an indication of eosinophil recruitment to the lungs). However, in utero exposure to GEN had minimal effects on HDM allergen-induced respiratory allergy in the middle-aged female offspring. Changes in serum total IgE, HDM-specific IgE, and lung histopathology scores in both male and female offspring were not biologically significant. Overall, in utero GEN exposure exerted a protective effect on respiratory allergy in the middle-aged male, but not female, B6C3F1 offspring following later-life HDM exposures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The specially designed chemical structure of our recently developed solvatochromic amino-isocyanonaphthalene (ICAN) dye family enables the selective detection of Hg 2+ and at the same time is able to indicate the presence of Ag + . In addition to its easy preparation and nontoxic nature, ICAN is the lowest molecular weight dye reported for ratiometric fluorescent Hg 2+ detection in water, so far. The basis of this double selectivity is the reduction of the isonitrile moiety to amine by a chemical reaction with Hg 2+ resulting in a greater than 100 nm hypsochromic shift (and switch on of fluorescence) of the emission maximum relative to ICAN, whereas the complexation of Ag + with the NC group yields an approximately 20 nm bathochromic shift (and quenching). In contrast, other common ions have little effect on the position of the emission maximum in aqueous medium. In completely aqueous medium at pH = 6, the limit of quantification was found to be lower than 17 nM and the limit of detection lower than 6 nM for Hg 2+ . The practical applicability of the method was demonstrated on dental amalgam., (Copyright © 2019. Published by Elsevier B.V.)

Our previous studies suggested that early glycation products (EGPs) generated in the first step of Maillard reaction/glycation were anti-inflammatory. The objectives of the present study were to determine the effects of EGPs derived from the whey protein isolate-glucose system on type 1 diabetes (T1D), and the underlying immunological mechanisms. In non-obese diabetic (NOD) mice, EGPs at the physiological dose of 600 mg/kg/day increased glucose metabolism, decreased non-fasting blood glucose levels and T1D incidence, decreased insulin resistance, and decreased the pancreatic immune infiltration. The protective effects were accompanied with decreases in CD4 - CD8 + thymocytes, CD8 + T cells and serum insulin autoantibody levels, and increases in splenic CD4 + CD25 + T cells, macrophage M2/M1 ratio and serum IL-10 level. However, similar treatment with EGPs produced minimal effect on the multiple low-dose streptozotocin-induced hyperglycemia. In conclusion, EGPs protected NOD mice against T1D via increasing anti-inflammatory immune responses and decreasing autoreactivity to self-antigens., Competing Interests: Conflict of interest Declarations of interest: none.

Residual chemicals on personal care and healthcare products, such as sanitary articles, sterile gauze bandages, nappies, plasters, were studied by direct analysis in real time mass spectrometry (DART-MS). We have identified around 40 compounds in seventeen different commercially available items. The tentative identification was further supported for about half of the chemicals by tandem mass spectrometric experiments (DART MS/MS). The most notable hazardous substances were tributyl phosphate, tris(2,4-di-tert-butylphenyl) phosphite, phthalic acid esters, erucamide, and nonylphenol ethoxylates (NPEs). In addition, we developed an efficient DART-MS analysis to determine the concentration of NPE in a swab sample. The quantitative result obtained by DART-MS was confirmed by liquid chromatography with mass spectrometric detection (LC-MS)., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Alterations in traditional land use practices have led to severe declines in the area of semi-natural grasslands, thereby seriously threatening plant and animal species dependent on these habitats. Small anthropogenic managed habitats, like roadsides can act as refuges and might play an important role in conserving these species. Colonization of roadside verges by endangered lizard orchids (Himantoglossum spp.) has long been known, but few studies have systematically explored the suitability of roadside habitats for these orchids and the impact of roads on them. In this paper we present results of targeted surveys of three lizard orchid taxa on roadsides from eight European countries. During these surveys we searched for lizard orchids inhabiting roadside verges and recorded their distance from road, aspects of the roadside environment, as well as vegetative and reproductive characteristics of individual plants. We found large numbers of lizard orchids on roadside verges. Distance from roads was not uniformly distributed: orchids occurred more closely to roads than expected by chance. This suggests that regular management of roadsides (e.g. mowing) might enhance colonization and survival of lizard orchids. On the other hand, we also found that close proximity to roads negatively affects reproductive success, suggesting that the immediate vicinity of roads might act as an ecological trap (i.e. favorable in terms of colonization and survival but unfavorable in terms of reproduction). Nonetheless, the fact that significant and viable populations are maintained at roadsides suggests that traditionally managed roadside verges may allow long-term persistence of lizard orchid populations and may serve as refuges in a landscape context., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The bioactive glasses doped with gold nanoparticles (AuNPs) are very attractive materials due to their potential in medical applications. In the present study Pluronic-nanogold hybrid nanoparticles were introduced during the sol-gel route of the SiO 2 -CaO-P 2 O 5 glasses preparation. The obtained samples were characterized by UV-vis spectroscopy, X-ray diffraction, FT-IR spectroscopy, transmission electron and scanning electron microscopy and afterwards they were investigated in terms of bioactivity, protein adsorption and cells viability. The in vitro bioactivity assessment shows the increase of the number of agglomerated spherical shapes of apatite layers for all Au containing samples, but apatite like structure sizes are influenced by the AuNP content. Beside the spherical shapes, three-dimensional flower-like nanostructures were observed on the surface of the glass with 0.2mol% Au 2 O. Zeta potential and fluorescence spectroscopy measurements evidenced that the amount of serum albumin adsorbed onto the composites surface increases with the AuNP content. FT-IR measurements point out that the secondary structure of the adsorbed proteins presents few minor changes, indicating biocompatibility of the AuNP doped glasses. The good proliferation rate of Human keratinocytes cells obtained in the presence of samples with 0.15 and 0.2mol% Au 2 O is comparable with the values achieved from free AuNP, fact that proves the preservation of AuNP properties after their incorporation inside the bioactive glass matrices., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Pollution of the aquatic environment by heavy metals is a great concern worldwide. Freshwater fish ingests various metals through gills, skin or diet. Our aim was to investigate the oxidative stress and histopathological injuries induced by Fe, Cu, Zn, Pb, Cd in the liver and kidney of Leuciscus cephalus. Fish samples were collected from two sites in the Tur River, NW Romania, in upstream and downstream of a pollution source. Metals were differently distributed in the liver and kidney of fish. The highest concentrations of Fe, Cu and Pb were found in liver, whereas Zn and Cd concentrations were the highest in kidney in specimens collected from the downstream site. The histopathological changes were associated with metal bioaccumulation, being more severe in kidney than liver. Malondialdehyde (MDA) and advanced oxidation protein products (AOPP) increased significantly in the liver and kidney of fish from downstream site compared to upstream one, whereas reduced glutathione (GSH) decreased. The activities of superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) increased significantly in livers, whereas SOD increased in kidney. Our study revealed that liver has a higher capacity and adaptability to counteract ROS compared to kidney. The more pronounced increase of hepatic SOD, CAT and GST activities is related milder structural changes observed in liver compared to kidney, where lesions were not reduced by antioxidant defense system., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Plasmodium chabaudi AS-infection in pregnant A/J and C57BL/6J mice results in mid-gestational pregnancy loss. Although associated with increased systemic and placental pro-inflammatory responses and coagulopathy, the molecular mechanisms that underlie poor pregnancy outcomes in these mice are not yet fully understood. This study investigates the relationships between inflammation, apoptosis and malaria-induced pregnancy loss., Methods: Infection with P. chabaudi AS in early murine pregnancy and term human placental tissues from an endemic setting were assessed by histology, immunohistochemistry, TUNEL staining, real-time PCR, flow cytometry, western blot, and ELISA., Results: Quantitative PCR reveals accumulation of lymphocytes and monocytes and upregulation of chemokines that attract these cell types in malaria-exposed mid-gestational A/J conceptuses. Monocyte accumulation is confirmed by flow cytometry and placental immunohistochemistry. Concurrent with initiation of malaria-induced abortion, markers of apoptosis are evident in the junctional zone, but not the labyrinth, of A/J placentae. In contrast, mid-gestation conceptuses in infected C57BL/6J lack evidence for monocyte accumulation, exhibiting low or no in situ placental staining despite trophoblast immunoreactivity for the monokine, CCL2. Additionally, placental apoptosis is not consistently observed, and when evident, appears after malaria-induced abortion typically initiates. Similarly, trophoblast apoptosis in term human placental malaria is not observed. Of those studied, a sole common feature of malaria-induced abortion in A/J and C57BL/6J mice is elevation of plasma tumor necrosis factor., Discussion: Consistent with our previous observations, tumor necrosis factor is likely to be a central driver of malaria-induced pregnancy loss in both strains, but likely operates through mechanisms distinct from placental apoptosis in C57BL/6J mice., (Published by Elsevier Ltd.)

In blood, the hydrogen peroxide concentration is regulated by catalase. Decreased activity of catalase may lead to increased hydrogen peroxide concentration, which may contribute to the manifestation of age-related disease. The aim of this study is to examine association of decreased blood catalase activity and catalase exon mutations in patients (n=617) with diabetes (n=380), microcytic anemia (n=58), beta-thalassemia (n=43) and presbycusis (n=136) and in controls (n=295). Overall, 51 patients (8.3%) had less than half of normal blood catalase activity. Their genomic DNA was used for mutation screening of all exons and exon/intron boundaries with polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and PCR-heteroduplex analyses, and mutations were verified with nucleotide sequencing. Seven patients (type 2 diabetes (n=3), gestational diabetes (n=1), microcytic anemia (n=2)) had four novel catalase exon mutations namely, c.106&#95;107insC, p.G36Afs*5(n=3, Hungarian type G1), c.379C>T, p.R127Y (n=2, Hungarian type H1), c.390T>C, p.R129L, (n=1, Hungarian type H2) and c.431A>T, p.N143V (n=1, Hungarian type H3). In patients with decreased blood catalase, the incidence of acatalasemia mutations was significantly high (P<0.0002) in microcytic anemia, type 2 and gestational diabetes. The four novel mutations were probably responsible for low blood catalase activity in 7/51 patients. In the remainder of the cases, other polymorphisms and epigenetic/regulatory factors may be involved., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: To examine how certain characteristics of film-presented practitioner role-models influence trainees' mentalization., Methods: In an experimental setting, psychology students watched four film clips presenting a patient-practitioner session; the clips varied in the practitioner's patient-centeredness (positive vs. negative) and gender. Participants commented on the practitioner's thoughts, emotions and intentions through the session. Analysis of 116 comments focused on the effect of patient-centeredness and gender variables on mentalization and judgment utterances., Results: Negative role-models and female role-models induced higher levels of mentalization compared to positive and male role-models. There was no gender difference in the level of mentalization; however male participants gave more judgmental responses than female participants. The patient-centeredness had a larger effect on mentalization when trainees described the opposite gender role-model., Conclusion: In a systematic comparison, students' capacity for mentalization differed according to role-models' patient-centeredness and gender, as well as the gender-match of students with role-models., Practice Implications: When working with film-presented role-models, educators should be aware of the differences in the level of mentalization elicited by positive and male role-models, as opposed to negative and female role-models. Educators should also consider the gender-match between trainees and role-models, therefore students should be exposed to both cross- and same-gender role-models., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Hydrogen peroxide was - and is still - considered toxic for a wide range of living organisms. Oxidative stress occurs when there is an excess of pro-oxidants over antioxidants and it has been implicated in several diseases. Catalase is involved in hydrogen peroxide catabolism and is important in defense against oxidative stress. Acatalasemia means the inherited near-total deficiency of catalase activity, usually in reference to red cell catalase. Acatalasemia was thought at first to be an asymptotic disorder. In the absence of catalase, neither the Japanese, or Hungarian acatalasemics nor acatalasemic mice had significantly increased blood glutathione peroxidase activity. In animal models, catalase deficient tissues show much slower rates of removal of extracellular hydrogen peroxide. In catalase knock-out mice, a decreased hydrogen peroxide removing capacity and increased reactive oxygen species formation were reported. Hydrogen peroxide may cause methemoglobinemia in patients with catalase deficiency. During anesthesia for a Japanese acatalasemic patient the disinfection with hydrogen peroxide solution caused severe methemoglobinemia. Patients with inherited catalase deficiency, who are treated with uric acid oxidase (rasburicase) may experience very high concentrations of hydrogen peroxide and may suffer from methemoglobinemia and hemolysis. The high (18.5%) prevalence of diabetes mellitus in inherited catalase deficient individuals and the earlier (10 years) manifestation of the disease may be attributed to the oxidative damage of oxidant sensitive, insulin producing pancreatic beta-cells. Ninety-seven of 114 acatalasemics had diseases related to oxidative stress and aging. The oxidative stress due to catalase deficiency could contribute to the manifestation of diabetes while for the other diseases it may be one of the factors in their causations. In summary, inherited catalase deficiency is associated with clinical features, pathologic laboratory test results, age and oxidative stress related disorders. Rather than considering it a benign condition, it should be considered as a complicating condition for aging and oxidative stress., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Catalase decreases the high, toxic concentrations of hydrogen peroxide but it lets the physiological, low concentrations in the cells mainly for signaling purposes. Its decreased activity may contribute to development of several pathological conditions. Catalase mutations occur frequently in exon 9, these were examined with different, complicated and costly methods. The aim of the current study was to evaluate a method for screening of polymorphisms in catalase exon 9. We used the slab gel electrophoresis of PCR amplicons without denaturation and silver staining for visualization of the DNA bands. We detected extra DNA bands in the 400-800 bp region of the catalase exon 9. Their single stranded nature was proved with nucleotide sequence analyses, comparison with the standard SSCP, staining with Sybr Green II and Sybr Green I, ethidium bromide, no digestion with RFLP (BstX I), and digestion with plant nuclease. We used this method for examination of polymorphisms of catalase exon 9 in microcytic anemia and beta-thalassemia patients. The lowest blood catalase activities were detected in microcytic anemia and beta-thalassemia patients with the TT genotypes of the C111T polymorphism. This method was sensitive for detection of G113A acatalasemia mutation, but poorly detected C37T and G5A acatalasemia mutations., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The enzyme catalase catalyzes the breakdown of hydrogen peroxide into oxygen and water. It is the main regulator of hydrogen peroxide metabolism. Hydrogen peroxide is a highly reactive small molecule formed as a natural byproducts of energy metabolism. Excessive concentrations may cause significant damages to protein, DNA, RNA and lipids. Low levels in muscle cells, facilitate insulin signaling. Acatalasemia is a result of the homozygous mutations in the catalase gene, has a worldwide distribution with 12 known mutations. Increased hydrogen peroxide, due to catalase deficiency, plays a role in the pathogenesis of several diseases such as diabetes mellitus. Diabetes mellitus is a disorder caused by multiple genetic and environmental factors. Examination of Hungarian diabetic and acatalasemic patients showed that an increased frequency of catalase gene mutations exists among diabetes patients. Inherited catalase deficiency may increase the risk of type 2 diabetes mellitus, especially for females. Early onset of type 2 diabetes occurs with inherited catalase deficiency. Low levels of SOD and glutathione peroxidase could contribute to complications caused by increased oxidative stress., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Anthracyclines are potent anticancer agents, but cardiotoxicity mediated by free radical generation limits their clinical use. This study evaluated the anticancer activity of phenyl-2-aminoethyl selenide (PAESe) and its potential to reduce doxorubicin (DOX)-induced cardiotoxicity. Growth inhibitory effects of PAESe with DOX, and vincristine, clinically used anticancer agents, and tert-butylhydroperoxide (TBHP), a known oxidant, on the growth of human prostate carcinoma (PC-3) cells was determined. PAESe (≤1μm) did not alter the growth of PC-3 cells, however, concomitant use of PAESe decreased the oxidative-mediated cytotoxicity of TBHP, but had limited effect on vincristine or DOX activity. Further, PAESe decreased the formation of intracellular reactive oxygen species from TBHP and DOX. The effect of PAESe on the activity of DOX was determined using a tumor (PC-3) xenograft model in mice. PAESe did not alter DOX antitumor activity and showed evidence of direct antitumor activity relative to controls. DOX treatment decreased mice body weight significantly, whereas concomitant administration of PAESe and DOX was similar to controls. Most importantly, PAESe decreased DOX-mediated infiltration of neutrophil and macrophages into the myocardium. These data suggest PAESe had in vivo antitumor activity and in combination with DOX decreased early signs of cardiotoxicity while preserving its antitumor activity., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The potential of intranasally administered carnosic acid to enhance the endogenous levels of neurotrophins [nerve growth factor and brain-derived neurotrophic factor] in the brain was investigated. Hydroxypropyl-β-cyclodextrin (HP-β-CD) was used to enhance the aqueous solubility of carnosic acid. The effect of different concentrations of chitosan on the permeation of carnosic acid was investigated across the bovine olfactory mucosa using Franz diffusion cell setup. The formulations were administered [intranasal (i.n.)/subcutaneous route] in Sprague-Dawley rats, and the neurotrophins were sampled from the brain by microdialysis after the treatment period and measured by enzyme-linked immunosorbent assay. Phase solubility studies revealed that the solubility of carnosic acid was enhanced significantly with increase in the concentration of HP-β-CD. The neurotrophin levels were enhanced significantly upon i.n. administration of carnosic acid with chitosan, which was approximately 1.5-2-fold more over the parenteral route. Nose-to-brain delivery of carnosic acid along with chitosan is a potential approach for treating disorders associated with depletion of neurotrophins., (Copyright © 2011 Wiley-Liss, Inc.)

Activation of the lipid-regulated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) modifies the immunophenotype of monocyte-derived dendritic cells (DCs). However it has not been analyzed in a systematic manner how lipid metabolism and immune regulation are connected at the transcriptional level via this receptor. Here we present the genome-wide expression analyses of PPARgamma-instructed human DCs. Receptor activation was achieved by exogenous, synthetic as well as endogenous, natural means. More than 1000 transcripts are regulated during DC development by activation of PPARgamma; half of the changes are positive effects. These changes appear to enhance and modulate the robust gene expression alterations associated with monocyte to DC transition. Strikingly, only genes related to lipid metabolism are overrepresented among early induced genes. As a net consequence, lipid accumulation appears to be diminished in these cells. In contrast, genes related to immune response are regulated after 24 hours, implying the existence of indirect mechanisms of modulation. Receptor dependence was established by using DCs of patients harboring a dominant-negative mutation of PPARgamma. Our data show that PPARgamma acts as a mostly positive transcriptional regulator in human developing DCs, acting primarily through controlling genes involved in lipid metabolism and via this, indirectly modifying the immune phenotype.

The assembly into supramolecular complexes of proteins having complementary activities is central to cellular function. One such complex of considerable biological and industrial significance is the plant cell wall-degrading apparatus of anaerobic microorganisms, termed the cellulosome. A central feature of bacterial cellulosomes is a large non-catalytic protein, the scaffoldin, which contains multiple cohesin domains. An array of digestive enzymes is incorporated into the cellulosome through the interaction of the dockerin domains, present in the catalytic subunits, with the cohesin domains that are present in the scaffoldin. By contrast, in anaerobic fungi, such as Piromyces equi, the dockerins of cellulosomal enzymes are often present in tandem copies; however, the identity of the cognate cohesin domains in these organisms is unclear, hindering further biotechnological development of the fungal cellulosome. Here, we characterise the solution structure and function of a double-dockerin construct from the P. equi endoglucanase Cel45A. We show that the two domains are connected by a flexible linker that is short enough to keep the binding sites of the two domains on adjacent surfaces, and allows the double-dockerin construct to bind more tightly to cellulosomes than a single domain and with greater coverage. The double dockerin binds to the GH3 beta-glucosidase component of the fungal cellulosome, which is thereby identified as a potential scaffoldin.

Ivermectin is a potent antiparasitic drug from macrocyclic lactone (ML) family, which interacts with the ABC multidrug transporter P-glycoprotein (Pgp). We studied the interactions of ivermectin with the multidrug resistance proteins (MRPs) by combining cellular and subcellular approaches. The inhibition by ivermectin of substrate transport was measured in A549 cells (calcein or 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein, BCECF) and in HL60-MRP1 (calcein). Ivermectin induced calcein and BCECF retention in A549 cells (IC(50) at 1 and 2.5microM, respectively) and inhibited calcein efflux in HL60-MRP1 (IC(50)=3.8microM). The action of ivermectin on the transporters ATPase activity was followed on membranes from Sf9 cells overexpressing human Pgp, MRP1, 2 or 3. Ivermectin inhibited the Pgp, MRP1, 2 and 3 ATPase activities after stimulation by their respective activators. Ivermectin showed a rather good affinity for MRPs, mainly MRP1, in the micromolar range, although it was lower than that for Pgp. The transport of BODIPY-ivermectin was followed in cells overexpressing selectively Pgp or MRP1. In both cell lines, inhibition of the transporter activity induced intracellular retention of BODIPY-ivermectin. Our data revealed the specific interaction of ivermectin with MRP proteins, and its transport by MRP1. Although Pgp has been considered until now as the sole active transporter for this drug, the MRPs should be taken into account for the transport of ivermectin across cell membrane, modulating its disposition in addition to Pgp. This could be of importance for optimizing clinical efficacy of ML-based antiparasitic treatments. This offers fair perspectives for the use of ivermectin or non-toxic derivatives as multidrug resistance-reversing agents.

Hip-Arg-Phe-, Hip-Phe-Arg- and Hip-His-Leu-cleaving dipeptidyl carboxypeptidase activities were measured in the supernatant (S2) and pellet (P2) fractions obtained by ultracentrifugation of human adrenal tumor preparations. Negligible enzyme activity was found in cortical tumor whereas highly significant activities were present in the P2 fractions of the two pheochromocytoma specimens. The hydrolysis rates, expressed in terms of the percent of added substrate were 58-66%/60 min for Hip-Phe-Arg, 55-58%/60 min for Hip-Arg-Phe and 19-30%/60 min for Hip-His-Leu. The angiotensin-converting enzyme inhibitor, captopril, differentially inhibited the enzyme splitting Hip-His-Leu versus the one cleaving Hip-Arg-Phe; Hip-Phe-Arg is probably the substrate of both. It is concluded that the Hip-Arg-Phe-cleaving enzyme in adrenomedullary tumor is probably identical to the purportedly novel dipeptidyl carboxypeptidase that we detected earlier in rabbit ear artery wall, which converts (Met5)-enkephalin-Arg6,Phe7 to (Met5)-enkephalin.

We have studied the process of retinal regeneration in Rana catesbienna tadpoles using a recently developed monoclonal antibody (2D3) directed against frog neurons and germinitive neuroepithelium. We have found that, following retinal degeneration induced by devascularization, new retina is generated in the posterior eye from transdifferentiating pigment epithelial (RPE) cells and in the anterior eye from increased proliferation at the normal growth zone in the ora serrata. This demonstrates that the anuran retina regenerates in a manner similar to that observed previously in urodeles. In addition, the use of MAb-2D3 has allowed us to study the process of RPE transdifferentiation more accurately than was previously possible, and consequently we have found a high degree of association of migratory pigment cells with the retinal vascular membrane at the time of the initial RPE transdifferentiation to retinal neuroblasts.

During a severe drought Port-au-Prince, Haiti, lost hydroelectric power for 10 weeks. This led to water shortages in areas of the city dependent on water supplied from electrically driven pumps. In a study of the impact of water restriction on disease, 400 families were randomly selected from two urban areas differentially affected by the water shortage. Disease in children was found to be related to quantity of water used, socioeconomic status, employment of head of household, and family size. The methods used in this study are recommended for the investigation of the relationship between water quantity and health.