[The differentiation and clinical significance of follicular helper T cells during acute exacerbation in asthma patients].
To observe the differentiation of follicular helper T (Tfh) cells in asthma patients during acute exacerbation and post-treatment periods, and explore the clinical significance of Tfh cells in asthma. We detected the percentages of CD4⁺CXCR5⁺, CD4⁺ICOS⁺, CD4⁺CXCR5⁺ICOS⁺ T cells in peripheral blood mononuclear cells (PBMCs) by flow cytometry, the level of Bcl-6 mRNA in CD4⁺ T cells by reverse transcription PCR, and the level of interleukin 21 (IL-21) in plasma by ELISA in healthy controls and asthma patients during acute exacerbation and post-treatment release periods. The linear regression analysis was used to analyze the correlations of the level of IL-21 in plasma with forced expiratory volume in one second/forced vital capacity (FEV1/FVC) and forced expiratory volume in one second/prediction (FEV1/Pre) in acute exacerbation period of asthma patients. The percentages of CD4⁺CXCR5⁺, CD4⁺CXCR5⁺ICOS⁺ T cells in PBMCs, the level of Bcl-6 mRNA in CD4⁺T cells, and the level of IL-21 in plasma increased in acute exacerbation of the asthma patients compared to the healthy controls. After treatment, the percentages of CD4⁺CXCR5⁺, CD4⁺ICOS⁺, CD4⁺CXCR5⁺ICOS⁺ T cells in PBMCs, the level of Bcl-6 mRNA in CD4⁺T cells, and the level of IL-21 in plasma in asthma patients were all reduced as compared with the acute exacerbation period. There were negative correlations between IL-21 and lung function parameters such as FEV1/FVC and FEV1/Pre. The differentiation of Tfh cells was enhanced in acute exacerbation of asthma patients, and ameliorated after treatment. Tfh cells may participate in the inflammatory reaction of asthma, and the differentiation degree of Tfh cells may reflect the extent of airway limitation in asthma patients.


Transforming mental healthcare in higher education through scalable mental health interventions.
A significant number of young people throughout the world are experiencing mental health concerns. Many young people will develop their first mental health concerns or will be managing their symptoms while enrolled in institutions of higher education. Although many colleges and universities are aware of the significant mental health needs among their students, the mental health and psychosocial needs of students often exceed the availability of resources and cultural and contextual barriers, such as stigma, may further impede access to care. Such gaps and barriers in mental health may lead to poor prognosis as well as negative educational and social outcomes. We propose that non-specialist delivered mental health and psychosocial interventions may play a critical role in reducing the gaps in care for students in higher education. In particular, non-specialist delivered care can complement existing specialized services to provide stepped models of care. Importantly, the adaptation and implementation of non-specialist delivered mental health and psychosocial support interventions in higher education may lead to innovative strategies for increasing access to care in this context, but may lead to adaptations that could apply to contexts outside of higher education as well.


Semiconducting eutectic materials for photocatalysis and photoelectrochemistry applications: a perspective.
The world of semiconductors has drastically improved human lifestyle due to its versatile applications. The demand for new efficient semiconductors is increasing day by day, giving birth to the idea of new synthesis methods. Here, the importance of semiconductor eutectic materials has been presented, as one of the potential candidates for solar-based devices such as photo-anodes for water splitting, along with the micro (μ) pulling method (as a synthesis method for semiconductor eutectic materials). A comparison of the efficiency of the present devices with the eutectic composites has been made, showing semiconductor eutectic materials as a better alternative. In addition, possible changes that can be achieved using the μ-pulling method to enhance the photo(electro)chemical (PEC) properties have focused on semiconducting eutectic materials in this article.


Pathophysiological role of osteopontin in hepatic inflammation, toxicity, and cancer.
Osteopontin (OPN) is a highly modified integrin-binding extracellular matrix glycophosphoprotein produced by cells of the immune system, epithelial tissue, smooth muscle cells, osteoblasts, and tumor cells. Extensive research has elucidated the pivotal role of OPN in cell signaling that controls inflammation, tumor progression, and metastasis. OPN interaction with the integrin receptors expressed on inflammatory cells through its arginine-glycine-aspartate (RGD) and non-RGD motifs promote migration and adhesion of cells. In the liver, it has been reported that hepatic Kupffer cells secrete OPN facilitating macrophage infiltration into necrotic areas following carbon tetrachloride liver toxicity. Recent work has highlighted the role of OPN in inflammatory liver diseases such as alcoholic and nonalcoholic liver disease and T-cell-mediated hepatitis. The role of OPN in hepatocellular carcinoma (HCC) has also generated significant interest, especially with regards to its role as a prognostic factor. OPN therefore appears to play an important role during liver inflammation and cancer. In this review we will present data to demonstrate the key role played by OPN in mediating hepatic inflammation (neutrophils, monocytes/macrophages, and lymphocytes) and its role in HCC. Greater understanding of the pathophysiologic role of OPN in hepatic inflammation and cancer may enable development of novel inflammation and cancer treatment strategies.


Human smooth muscle autoantibody. Its identification as antiactin antibody and a study of its binding to "nonmuscular" cells.
When human serum containing smooth muscle autoantibodies (SMA) is incubated with extracts containing thrombosthenin (the contractile material of platelets) or thrombosthenin-A (the actin-like moiety of thrombosthenin), it loses its ability to bind to smooth muscle. Such binding is also diminished when SMA serum is incubated with lysed platelets; this effect is not seen if the SMA serum is incubated with intact platelets. The incubation of other autoantibodies (such as antimitochondrial or antinuclear antibodies) with thrombosthenin does not affect their binding to the specific antigens. It appears that SMA is directed against the actin fraction of thrombosthenin-ie, SMA is an antiactin antibody. Hence the name of antiactin autoantibody (AAA) seems more appropriate than smooth muscle autoantibody (SMA). A study of the distribution of antiactin autoantibody binding in rat, rabbit and man shows that several "nonmuscular" structures contain actin under normal conditions; these include megakaryocytes and platelets, normal rat hepatocytes, the brush borders of renal tubules, the periphery of epithelial cells of the intestine, polymorphs and lymphocytes in lymph nodes (but not thymic cortical lymphocytes). In addition, certain cell types (such as granulation tissue fibroblasts, cultivated fibroblasts, hepatocytes or regenerating liver and epidermal cells growing over a skin wound) can reversibly acquire a massive network of actin-containing microfilaments resembling those in smooth muscle.


Physical activity buffers the negative relationship between multimorbidity, self-rated health and life satisfaction.
This study aimed to examine the relationship between multimorbidity, self-rated health and life satisfaction, and to test the moderating effect of physical activity on the relationship between multimorbidity, self-rated health and life satisfaction. This is a cross-sectional study based on data from the European Social Survey 2014. Participants were 25 713 adults (12 830 men), aged 18-64 years old, from 18 European countries and Israel. Self-reported information regarding chronic diseases, health perception, life satisfaction and physical activity was collected through interview. Multimorbidity was defined as the co-occurrence of ≥ 2 chronic diseases. Linear regression models were used to estimate the effects of multimorbidity, physical activity and the interaction effect of multimorbidity × physical activity on self-rated health and life satisfaction. Multimorbidity was negatively related to self-rated health (d = 0.03) and life satisfaction (d = 0.03). Physical activity was positively related to self-rated health and life satisfaction. There was a significant interaction effect between multimorbidity and physical activity with regard to self-rated health (β = 0.01, P < 0.001) and life satisfaction (β = 0.04, P < 0.001). Physical activity buffered the negative relationship between multimorbidity, self-rated health and life satisfaction; contributing to better self-rated health and life satisfaction.


[Secondary appearance of a carcinoma in an excluded native bladder: Report of three cases].
The management of congenital urological malformations is sometimes complex and may require urinary diversion. Cystectomy is usually performed, but sometimes the bladder is left in place due to the presence of a pelvic cloaca and the morbidity related to this type of surgery. The authors report three cases of patients treated by urinary diversion for a congenital malformation without primary resection of the bladder In the absence of any infectious complications, bladder carcinoma on an excluded native bladder was diagnosed at the age of 3 years, 4 years and 38 years, respectively. Histological examination showed transitional cell carcinoma in two cases and gastrointestinal-type adenocarcinoma of the bladder in 1 case. The risk of secondary development of carcinoma in an excluded bladder during management of (congenital urological malformations is not negligible. Primary cystectomy therefore appears to be preferable. In the presence of a pelvic cloaca making this surgical resection unreasonable, it appears important to exclude the formation of a pyocyst by annual abdominal ultrasound. The authors also recommend cystoscopy and urine cytology with lavage to detect degeneration of the bladder mucosa.


Does the vaginal microbiota play a role in the development of cervical cancer?
Persistent infection with oncogenic human papillomavirus (HPV) is necessary but not sufficient for the development of cervical cancer. The factors promoting persistence as well those triggering carcinogenetic pathways are incompletely understood. Rapidly evolving evidence indicates that the vaginal microbiome (VM) may play a functional role (both protective and harmful) in the acquisition and persistence of HPV, and subsequent development of cervical cancer. The first studies examining the VM and the presence of an HPV infection using next-generation sequencing techniques identified higher microbial diversity in HPV-positive as opposed to HPV-negative women. Furthermore, there appears to be a temporal relationship between the VM and HPV infection in that specific community state types may be correlated with a higher chance of progression or regression of the infection. Studies describing the VM in women with preinvasive disease (squamous intraepithelial neoplasia [SIL]) consistently demonstrate a dysbiosis in women with the more severe disease. Although it is plausible that the composition of the VM may influence the host's innate immune response, susceptibility to infection, and the development of cervical disease, the studies to date do not prove causality. Future studies should explore the causal link between the VM and the clinical outcome in longitudinal samples from existing biobanks.


Cancellation of elective surgeries in a Brazilian public hospital: reasons and estimated reduction.
To characterize cancellations of elective surgeries according to clinical and non-clinical reasons, as well as to verify seasonal influence and determine the estimated reduction of the index. Quantitative, descriptive and retrospective study with secondary data extracted from the Public Hospital of the State of São Paulo database. Out of the 8,443 (100%) elective surgeries scheduled, 7,870 (93.21%) were performed and 573 (6.79%) were canceled. Out of these 573 (100%) people, 48.33% were canceled for clinical reasons and 46.40% were for non-clinical reasons. Among the non-clinical reasons for surgery cancellations, those related to medical reasons stood out: at the request of the surgeon/change of approach (17.93%), followed by non-hospitalized patient (8.96%). There was no indication of seasonality regarding the reasons for cancellation in the assessed period. Although the rate of elective surgeries cancellations is lower than that of other hospitals with similar characteristics, it is still possible to reduce it from 6.79% to 1.36%, considering that 80% of the reasons for cancellation are avoidable.


Quantification of Ag-NOR proteins using Ag-NOR staining on western blots.
Ribosomal genes are associated with a set of silver-stained nucleolar proteins, the Ag-NOR proteins, whose amount is directly related to the duration of the cell cycle. Quantification of Ag-NOR proteins by image analysis is presently used to evaluate the rate of proliferation of cancer cells and nucleolar activity. Our objective was to establish a procedure to quantify independently each major Ag-NOR protein in cell extracts. Computerized densitometry established that the specific silver staining of Ag-NOR proteins (Ag-NOR staining) performed on Western blots makes it possible to quantify Ag-NOR proteins. Using purified Ag-NOR proteins, nucleolin, and protein B23, we observed that the intensity of Ag-NOR staining is proportional to the amount of protein. A linear relationship exists between the intensity of Ag-NOR staining and the amount of nucleolin, in the range of 0.2-1.6 micrograms. Using total nuclear extracts prepared from mammalian cells, the proportionality was maintained for total Ag-NOR-stained proteins or for a particular protein. We also determined the levels of nuclear proteins suitable for quantitative analysis. Individual Ag-NOR proteins can be quantified by computerized densitometry in nuclear extracts after Ag-NOR staining on Western blots. This procedure can be applied to establish the contribution of each Ag-NOR protein in general staining, estimate the variability of each Ag-NOR protein in normal and pathological conditions, and quantify each Ag-NOR protein contained per cell.


The 80-hour workweek restriction: How are OB/GYN resident procedure numbers affected?
To evaluate the surgical caseload in a military obstetrics and gynecology residency program, prior to and after implementation of an 80-hour workweek. A retrospective cohort study evaluating data submitted to the Accreditation Council for Graduate Medical Education (ACGME) for cumulative resident procedures in obstetrics and gynecology for the years before (July 2001-June 2002) and after (July 2002-June 2003) 80-hour workweek implementation. Total obstetric and gynecology procedures were examined using both the Student's paired t-test and a two-way mixed factor analysis of variance. Between July 2001 and June 2002 there were 822 gynecological cases and 3958 deliveries done by 17 OB/GYN residents; these were compared with 827 cases and 3504 deliveries done by 18 OB/GYN residents between July 2002 and June 2003 (p=0.189). The total numbers of obstetric and gynecology cases pre- and post-80-hour workweek intervention were similar when evaluated by month (July through June of 2001/2 vs. 2002/3; p=0.908). There was a significantly greater number of obstetrics cases compared with gynecological cases (p < 0.001) in the pre- vs. post-80-hour workweek groups; the number of gynecological cases remained constant in the post-80-hour workweek group while the obstetric numbers dropped (p=0.001). The 80-hour workweek restriction resulted in similar total numbers of obstetrics and gynecology cases, although the total number of obstetric cases per resident declined after implementation.


Identification of biomarkers for the transition from low-grade glioma to secondary glioblastoma by an integrated bioinformatic analysis.
Secondary glioblastoma (sGBM) is a type of glioblastoma multiforme that evolves from low-grade glioma (LGG). However, the mechanism of this transition still remains poorly understood. In this study, we used weighted gene co-expression network analysis (WGCNA) on the gene expression profiles of glioma samples from the Chinese Glioma Genome Atlas (CGGA) database to identify key genetic module related to distinguish histological characteristics. Here, the brown module was highly correlated with histological characteristics and was selected as the hub module. By applying functional annotation analysis, we found that biological processes related to the cell-cycle and DNA-replication were enriched in the genes of the brown module. After constructing a protein-protein interaction (PPI) network, validation of differential gene expression, and survival analyses, we ultimately identified five hub genes: CCNB2 (Cyclin B2), KIF2C (Kinesin Family Member 2C), CDC20 (Cell Division Cycle 20), TPX2 (TPX2 Microtubule Nucleation Factor), and PLK1 (Polo Like Kinase 1). In addition, a computational risk model was developed for predicting the clinical outcomes of sGBM patients by combining gene expression levels. This gene signature was demonstrated to be an independent predictor of survival by univariate and multivariable Cox regression analysis. Finally, we used the Genomics of Drug Sensitivity in Cancer (GDSC) database to predict the responses of sGBM patients to routine chemotherapeutic drugs. Patients from the high-risk group were more sensitive to common chemotherapies during clinical treatment. Our findings based on comprehensive analyses might advance the understanding of sGBM transition and aid the development of novel biomarkers for diagnosing and predicting the survival of sGBM patients.


Advances in epigenetic modification affecting anthocyanin synthesis.
Anthocyanins are a class of important flavonoid compounds widely present in plants, and play important roles in plant growth, metabolism and stress responses. In the process of growth and development, anthocyanin renders the flowers and fruits of plants displaying rich colors, attracts insect pollination and animal feeding, thereby facilitating seed spreading and dissemination. In metabolic stress, anthocyanin can resist low temperature, drought, fungal infection, ultraviolet damage, insect pests and other stress-resistant processes. The anthocyanin biosynthesis is co-regulated by related structural genes as well as transcription factor genes. Recent studies have showed that the anthocyanin biosynthesis-related genes in plants are epigenetically regulated, thus affecting the synthesis of anthocyanin glycosides. Epigenetics is one of the hot topics in the field of biological sciences. In this review, we summarize the advances of epigenetic modifications in anthocyanin biosynthesis and the application of genome editing in epigenetics, thereby providing new ideas for flower color breeding improvement by epigenetic regulation.


[Interferon therapy for brain tumor patients (author's transl)].
Nine cases of recurrent and metastatic brain tumors were treated by Hu-IFN-alpha. It was given intramuscularly and singly to those who finished the usual treatments of surgical removal and 60Co irradiation more than 6 months before, to exclude their effects on tumors. They were divided into 2 groups of small dosage (fifty thousands units weekly) and large dosage (3 million units every other day). The total dosage of IFN varied from about 2 million units for the small dosage group to 264 million units for the large dosage group. No side effects were noted. In two cases of six which were followed up over 4 months, the tumors regressed about 50% on serial CT. However, IFN was not effective on the tumors which had already showed a rapid growth before IFN administration. Almost all the patients showed improvements in their general condition, PPD and PHA skin test, peripheral lymphocyte counts and natural killer cell activities.


Elucidation of cladofulvin biosynthesis reveals a cytochrome P450 monooxygenase required for anthraquinone dimerization.
Anthraquinones are a large family of secondary metabolites (SMs) that are extensively studied for their diverse biological activities. These activities are determined by functional group decorations and the formation of dimers from anthraquinone monomers. Despite their numerous medicinal qualities, very few anthraquinone biosynthetic pathways have been elucidated so far, including the enzymatic dimerization steps. In this study, we report the elucidation of the biosynthesis of cladofulvin, an asymmetrical homodimer of nataloe-emodin produced by the fungus Cladosporium fulvum A gene cluster of 10 genes controls cladofulvin biosynthesis, which begins with the production of atrochrysone carboxylic acid by the polyketide synthase ClaG and the β-lactamase ClaF. This compound is decarboxylated by ClaH to yield emodin, which is then converted to chrysophanol hydroquinone by the reductase ClaC and the dehydratase ClaB. We show that the predicted cytochrome P450 ClaM catalyzes the dimerization of nataloe-emodin to cladofulvin. Remarkably, such dimerization dramatically increases nataloe-emodin cytotoxicity against mammalian cell lines. These findings shed light on the enzymatic mechanisms involved in anthraquinone dimerization. Future characterization of the ClaM enzyme should facilitate engineering the biosynthesis of novel, potent, dimeric anthraquinones and structurally related compound families.


Clinical evaluation of interferons in malignant melanoma.
The evaluation of interferons in the treatment of malignant melanoma has been mainly in the treatment of advanced disease using interferons as the sole agent or in combination with other agents. Studies of the value of interferons as adjuvant therapy in high-risk primary melanoma patients are necessary, but no results have been published to date. Human interferon alpha produces low response rates as a sole agent, but in combination with cimetidine, a 30% response rate has been achieved. Recombinant alpha interferons give responses of 15%-20% in advanced melanomas, and combination with cimetidine does not enhance the response rate. Recombinant alpha interferons have been used in combination with other interferons, cimetidine, monoclonal antibodies, and cytotoxics, with either no or small improvement in response rates. DTIC with recombinant interferon alpha-2a has been shown to produce objective response rates of 26%, with low toxicity and maintenance of quality of life. A randomized trial with DTIC as the sole agent, compared with combination treatment, is being conducted to determine the significance of this finding.


Quantitative Live Imaging of Zebrafish Scale Regeneration: From Adult Fish to Signaling Patterns and Tissue Flows.
In regeneration, a damaged body part grows back to its original form. Understanding the mechanisms and physical principles underlying this process has been limited by the difficulties of visualizing cell signals and behaviors in regeneration. Zebrafish scales are emerging as a model system to investigate morphogenesis during vertebrate regeneration using quantitative live imaging. Scales are millimeter-sized dermal bone disks forming a skeletal armor on the body of the fish. The scale bone is deposited by an adjacent monolayer of osteoblasts that, after scale loss, regenerates in about 2 weeks. This intriguing regenerative process is accessible to live confocal microscopy, quantifications, and mathematical modeling. Here, I describe methods to image scale regeneration live, tissue-wide and at sub-cellular resolution. Furthermore, I describe methods to process the resulting images and quantify cell, tissue, and signal dynamics.


Prevalence of HIV-1 infection in a rural medical clinic in Haiti.
To estimate the prevalence of the human immunodeficiency virus type 1 (HIV-1) among the patients attending the out-patient Medicine Clinic of the Hôpital Albert Schweitzer in Haiti, the serum samples of 535 consecutive patients were examined for HIV-1 antibodies by enzyme immunoassay. One hundred and twelve sera (20.9%) tested positive (19.3% of the in-district patients and 27.6% of the out-district patients). We concluded that HIV-1 infection has already spread to rural areas in Haiti and that we should prepare ourselves for the impact that the increasing number of infected patients will have.


Impact of ultra-low emission technology retrofit on the mercury emissions and cross-media transfer in coal-fired power plants.
China has applied the ultra-low emission technology in coal-fired power plants to control traditional air pollutants and to reduce Hg emissions synergically. In this study, we applied field experiment, model calculation, and literature review to evaluate the Hg control effect of ultra-low emission technology and the potential cross-media effect comprehensively. The dominant ultra-low emission technology significantly improves the atmospheric Hg removal efficiency from 75% to 87%. Such improvement mainly comes from the effect of dust removal devices. Based on the calculated distribution characteristic of Hg content of wastes, we find out that the improvement of Hg control effect of air pollution control devices significantly increase the Hg content of fly ash, which rises from 0.16 mg/kg to 0.33 mg/kg. However, the Hg content of gypsum decreases from 0.75 mg/kg to 0.51 mg/kg. Whether or not to carry out ultra-low emission retrofits, Hg contents of wastes from coal-fired power plants are overall lower than the limit of 25 mg/kg which is intended to be set as the limit for Hg-containing wastes. However, the embodied more than two hundreds of tons Hg in these wastes still require policies to guide the disposal of these wastes.


Hypoxia activation of mitophagy and its role in disease pathogenesis.
Mitochondria utilize most of the oxygen to produce adenosine triphosphate via electron transfer coupled with oxidative phosphorylation. Hypoxia undoubtedly induces reduced energy production via decreased mitochondrial metabolic activity or altered hypoxia-inducible factor-1- and peroxisome proliferator-activated receptor gamma coactivator 1-dependent mitochondrial biogenesis. Hypoxia may also activate mitophagy to selectively remove damaged or unwanted mitochondria for both mitochondrial quantity and quality control. Increasing evidence has shown that the accumulation of damaged mitochondria is a characteristic of aging and aging-related diseases, such as metabolic disorder, cancer, and neurodegenerative disease. Both receptor-dependent and PTEN-induced putative kinase 1-PARKIN-dependent mitophagy have been described. Mitophagy receptors include Atg32 in yeast, as well as NIX/BNIP3L, B-cell lymphoma 2/adenovirus E1B 19-kDa-interacting protein 3 and FUN14 domain containing 1 in mammals. In response to hypoxia or mitochondrial oxidative stress, receptor-mediated mitophagy was found to be activated via both transcriptional and post-translational modification. To date, the molecular mechanisms by which hypoxia triggers mitophagy and by which mitophagy contributes to the pathogenesis of aging-related diseases remain to be explored. An improved understanding of the regulation of mitochondrial quality may provide a strategy for treating aging-related diseases by targeting mitochondria and mitophagy pathways.


Edible Film Casting Techniques and Materials and Their Utilization for Meat-Based Product Packaging.
According to a profusion of academic studies on the use of organic materials or biopolymers as key components, the current trajectory of food packaging techniques is showing a positive inclination. Notably, one such biopolymer that has attracted much attention is edible film. The biopolymers that have been stated as constitutive components are composed of polysaccharides, lipids, proteins, or a combination of these, which work together to reinforce one another's properties and create homogenous mixtures. An edible film provides a clear, thin layer that encases foodstuffs, including their packaging. The production and use of edible film have recently been the focus of much research in the field of food polymers. Extending the shelf life of food goods is the goal of this research. Given their great susceptibility to change brought on by outside forces or pollutants, which may result in oxidative rancidity, the proper storage of nutrient-dense food items, particularly meat products, deserves careful study. Many edible films have been found to contain active ingredients, such antimicrobials or antioxidants, that can successfully prevent the spoiling of meat products, a process that can happen in a short amount of time. Surprisingly, a number of scholarly examinations reveal that edible film may be cooked alongside meat because of its organic makeup. We hope that the use of edible film will lead to a more environmentally responsible method of food packaging than has previously been possible.


Dynamic range enhancement of self-referenced spectral interferometry with extended time excursion method by the cascaded Kerr lens process.
Self-referenced spectral interferometry with extended time excursion (SRSI-ETE) is a powerful method for single-shot characterization of the temporal contrast of a high peak power laser, which has high temporal resolution but a low dynamic range. Here, a temporal contrast reduction method is proposed that uses the cascaded Kerr lens process in two thin glass plates. Combined with the SRSI-ETE method, the measurement dynamic range of the method is increased about two orders of magnitude while having a 20 fs temporal resolution and a 40 ps time window in single shot.


Clinical, endoscopical and morphological efficacy of mesalazine in patients with irritable bowel syndrome.
The aim of this study was to analyze the clinical efficacy and cytomorphologic changes of colon mucosa following the treatment of patients suffering from irritable bowel syndrome (IBS) with mesalazine (5-aminosalicylic acid [5-ASA]). In this controlled, randomized, blind clinical trial, a total of 360 patients with varying subtypes of IBS were randomly treated with 500 mg of mesalazine qid or by standard therapy without mesalazine for a period of 28 days. Pre- and post-treatment pain intensity, pain duration, meteorism, stool abnormalities and endoscopic parameters were monitored, and biopsies or brush biopsies were examined histologically. Treatment of IBS patients with mesalazine significantly reduced intensity and duration of pain in all subtypes of IBS, except for duration of pain in the subtype "undifferentiated", where the difference was not significant. In addition, in patients with diarrhea type and undifferentiated type of IBS, mesalazine also significantly reduced the abnormal stool pattern. In comparison to the control group, administration of mesalazine reduced the incidence of endoscopic and cytomorphologic changes of the bowel mucosa, including changes in colon mucus, mucus production, cytologic or histologic parameters, epithelial cell degeneration, appearance of leukocytes and macrophages and cell infiltrations. Mesalazine was effective in reducing several symptoms characteristic of IBS. It significantly reduced pain intensity and duration and improved cytohistologic parameters of the bowel mucosa.


Enhanced expression of tumour suppressor RAR-β by DSPC nano-formulated lipo-ATRA in the lung of B16F10 cell-implanted C57BL6 mice and in A549 cells.
All Trans Retinoic acid (ATRA) is an efficient drug for leukemia, but is not efficient therapy for solid cancers. Hence we have used 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol lipo-ATRA to investigate its molecular therapeutic effect on lung cancer. The objective was to find whether it could enhance ATRA receptor, RAR-β expression in lung cells as it was lost in majority of cancers including lung cancer. The study was made in an experimental C57BL/6 mice model developed by tail vein injection of B16F10 cells and in A549 human lung cancer cells. The RAR-β protein expression was studied by Immunohistochemistry/Immunocytochemistry and the mRNA expression was studied by RT-PCR and qPCR methods. Both free and lipo-ATRA treatments showed an enhancement of RAR-β protein and gene expressions, indicating its induction on RAR β. However, lipo-ATRA treatment has shown significant induction when compared with free ATRA treatment. Our results implies that the DSPC lipo-ATRA treatment might have accumulated more ATRA in to the target cells which might have resulted in the induction of its receptor RAR-β expression in a hypothesis of ligand induced receptor expression.


Fidelity of the representation of value in decision-making.
The ability to make optimal decisions depends on evaluating the expected rewards associated with different potential actions. This process is critically dependent on the fidelity with which reward value information can be maintained in the nervous system. Here we directly probe the fidelity of value representation following a standard reinforcement learning task. The results demonstrate a previously-unrecognized bias in the representation of value: extreme reward values, both low and high, are stored significantly more accurately and precisely than intermediate rewards. The symmetry between low and high rewards pertained despite substantially higher frequency of exposure to high rewards, resulting from preferential exploitation of more rewarding options. The observed variation in fidelity of value representation retrospectively predicted performance on the reinforcement learning task, demonstrating that the bias in representation has an impact on decision-making. A second experiment in which one or other extreme-valued option was omitted from the learning sequence showed that representational fidelity is primarily determined by the relative position of an encoded value on the scale of rewards experienced during learning. Both variability and guessing decreased with the reduction in the number of options, consistent with allocation of a limited representational resource. These findings have implications for existing models of reward-based learning, which typically assume defectless representation of reward value.


Conferring aldosterone synthesis to human CYP11B1 by replacing key amino acid residues with CYP11B2-specific ones.
Performing residue-swapping experiments between the highly conserved human steroidogenic proteins CYP11B1 and CYP11B2 we recently demonstrated that replacement of specific residues at position 301, 302 and 320 in the aldosterone-producing CYP11B2 protein for such residues that were specific for the highly similar cortisol-producing CYP11B1 protein elevated the 11beta-hydroxylase activity dramatically. Conversely, aldosterone synthesis in the triple mutant was severely impaired. Here we provide evidence that in a reciprocal experiment, CYP11B2-specific amino acids at position 320 and 335 endowed CYP11B1 with an 18-oxidase function amounting to 20% of the CYP11B2 wild-type activity, thus changing the specificity of steroid hydroxylation by only one point mutation. Combining substitutions at positions 296, 301, 302, 320, 335 and 339 did, however, not result in further enhancement. Paradoxically, 11beta-hydroxylation was not or only marginally affected in CYP11B1 mutants, indicating an alternative structural basis for this activity in CYP11B1 compared with the engineered CYP11B2 variant. Our results suggest that the sequence spanned by amino acids 301 and 335 constitutes part of the substrate-binding site in CYP11B1 and CYP11B2 as well. By constructing chimeric proteins we further investigated the effect of the C-terminal portions of both proteins and found that diverging residues at positions 471, 472, 492, 493 and 494 were insignificant for the stereospecificity and regiospecificity of steroid hydroxylation.


Assessment of air sampling methods and size distribution of virus-laden aerosols in outbreaks in swine and poultry farms.
Swine and poultry viruses, such as porcine reproductive and respiratory syndrome virus (PRRSV), porcine epidemic diarrhea virus (PEDV), and highly pathogenic avian influenza virus (HPAIV), are economically important pathogens that can spread via aerosols. The reliability of methods for quantifying particle-associated viruses as well as the size distribution of aerosolized particles bearing these viruses under field conditions are not well documented. We compared the performance of 2 size-differentiating air samplers in disease outbreaks that occurred in swine and poultry facilities. Both air samplers allowed quantification of particles by size, and measured concentrations of PRRSV, PEDV, and HPAIV stratified by particle size both within and outside swine and poultry facilities. All 3 viruses were detectable in association with aerosolized particles. Proportions of positive sampling events were 69% for PEDV, 61% for HPAIV, and 8% for PRRSV. The highest virus concentrations were found with PEDV, followed by HPAIV and PRRSV. Both air collectors performed equally for the detection of total virus concentration. For all 3 viruses, higher numbers of RNA copies were associated with larger particles; however, a bimodal distribution of particles was observed in the case of PEDV and HPAIV.


Proceed™ mesh for laparoscopic ventral hernia repair.
Laparoscopic technique to repair ventral hernia offers advantages over conventional open surgery such as shorter recovery time, decreased pain, and lower recurrence rates. There are a myriad of meshes available for laparoscopic repair of ventral hernias. This study evaluated the outcomes of laparoscopic repair of ventral hernias with Proceed mesh (Ethicon, Somerville, NJ, USA) in a single academic institution. An institutional review board-approved retrospective review was performed for 100 consecutive patients with ventral hernia who underwent a laparoscopic approach at our institution from August 2006 to February 2009. All patients were operated on by a single surgeon using a standard technique with transabdominal suture fixation and tacks. The study included 100 consecutive patients (57 female and 43 male patients). The mean age was 55 years (range, 16-78 years), and the mean body mass index was 33.3 kg/m(2) (range, 19.6-68.9 kg/m(2)). Of the repairs, 27% were performed for a recurrent hernia. The mean and median size of the defect were 128 cm(2) and 119.5 cm(2) (range, 4-500 cm(2)), respectively. To ensure appropriate mesh overlap, the mean size of mesh was 253 cm(2) (range, 36-700 cm(2)). There were 4 conversions. The mean operative time was 117 minutes (range, 35-286 minutes). The mean length of stay was 1.9 days. There were no major abdominal complications. With a mean follow-up period of 50 months (range, 38-68 months), we have not recorded any recurrences. No mesh-related complications have been documented. The laparoscopic approach to ventral hernia repairs using Proceed mesh is associated with a low conversion rate and no major complications. At 50 months of follow-up, the recurrence rate is 0%. There were no mesh-related complications.


Epidemiologic studies on Eskimos and fish intake.
Chronic diseases such as coronary heart disease and diabetes mellitus are uncommon in Eskimos. Total cholesterol levels are generally low, whereas HDL cholesterol levels are higher than those in an age- and sex-matched Danish population. It is frequently assumed that this is mainly due to their dietary pattern, especially with its high content of n-3 polyunsaturated fatty acids, derived from fish and other seafoods. Dietary surveys have shown that the intake of n-3 polyunsaturated fatty acids in Eskimos is about 14 g/day, whereas it is 3 g/day in Denmark and about 0.2 g/day in the United States. However, the Eskimo diet also differs from the Western diet in other aspects, especially in the intake of saturated fatty acids which is low (9 energy-%). The intake of dietary cholesterol is rather high because of the large consumption of seafood. Individually based studies are better suited to disentangle the health effects of different nutrients, inasmuch as confounding factors can be taken into account. Several cohort studies have now shown that the consumption of 1-2 fish meals per week is associated with a reduction in the risk of coronary heart disease. Recently, similar results concerning glucose intolerance and stroke were also reported. These combined data suggest that a diet low in saturated fatty acids, in combination with a low or moderate level of fish consumption, may be of importance in the prevention of diseases such as coronary heart disease, ischemic stroke, and diabetes mellitus.


Endocannabinoid signaling and memory dynamics: A synaptic perspective.
Memory acquisition is a key brain feature in which our human nature relies on. Memories evolve over time. Initially after learning, memories are labile and sensitive to disruption by the interference of concurrent events. Later on, after consolidation, memories are resistant to disruption. However, reactivation of previously consolidated memories renders them again in an unstable state and therefore susceptible to perturbation. Additionally, and depending on the characteristics of the stimuli, a parallel process may be initiated which ultimately leads to the extinction of the previously acquired response. This dynamic aspect of memory maintenance opens the possibility for an updating of previously acquired memories but it also creates several conceptual challenges. What is the time window for memory updating? What determines whether reconsolidation or extinction is triggered? In this review, we tried to re-examine the relationship between consolidation, reconsolidation and extinction, aiming for a unifying view of memory dynamics. Since cellular models of memory share common principles, we present the evidence that similar rules apply to the maintenance of synaptic plasticity. Recently, a new function of the endocannabinoid (eCB) signaling system has been described for associative forms of synaptic plasticity in amygdala synapses. The eCB system has emerged as a key modulator of memory dynamics by adjusting the outcome to stimuli intensity. We propose a key function of eCB in discriminative forms of learning by restricting associative plasticity in amygdala synapses. Since many neuropsychiatric disorders are associated with a dysregulation in memory dynamics, understanding the rules underlying memory maintenance paves the path to better clinical interventions.


Risk factors for septicemia-associated mortality in older adults.
Septicemia is the 10th leading cause of death among older adults in the United States; its mortality rate has steadily increased over the past decades. Little is known about factors which predispose to septicemia mortality in the elderly. The authors investigated risk factors for septicemia-associated mortality in 10,269 older adults as part of a longitudinal study of three communities (East Boston, MA; New Haven, CT; and Iowa and Washington Counties, IA). During 6 years of followup, 177 persons (3.2 per 1,000 person-years) had septicemia ICD9 038 (International Classification of Diseases, ninth revision) reported on their death certificate. In a multivariate proportional-hazards model, septicemia mortality was significantly (P < 0.05) and independently associated with age, male sex, history of diabetes, history of cancer requiring hospitalization, smoking one pack of cigarettes per day or more, not drinking alcohol in the year prior to baseline, disability in activities of daily living, cognitive impairment, and missing cognitive testing score. These factors might be useful in developing an at-risk population for testing septicemia treatment or prevention strategies in a community setting. Further investigation is needed to explain underlying mechanisms of increased risk of subsequent septicemia.


Isolated aortitis: a rare cause of febrile illness.
Febrile illness often presents a challenge for the clinician. The main causes of febrile illness are infections, solid or haematological malignancies and connective tissue disorders, including vasculitis. A 49-year-old woman sought medical attention because of intermittent fever that lasted 2 weeks. She presented no further symptoms or physical signs to suggest the aetiology. The epidemiological context was irrelevant. Analyses revealed anaemia of chronic disease and significant elevations of inflammatory parameters. A comprehensive study was performed, which revealed presence of an aortitis. Investigation of infectious and immunological causes was negative. We arrived at the definitive diagnosis of isolated aortitis. She was treated with corticosteroid and methotrexate, with resolution of symptoms and clinical abnormalities.


Hierarchical-Structured Fe2O3 Anode with Exposed (001) Facet for Enhanced Lithium Storage Performance.
The hierarchical structure is an ideal nanostructure for conversion-type anodes with drastic volume expansion. Here, we demonstrate a tin-doping strategy for constructing Fe2O3 brushes, in which nanowires with exposed (001) facets are stacked into the hierarchical structure. Thanks to the tin-doping, the conductivity of the Sn-doped Fe2O3 has been improved greatly. Moreover, the volume changes of the Sn-doped Fe2O3 anodes can be limited to ~4% vertical expansion and ~13% horizontal expansion, thus resulting in high-rate performance and long-life stability due to the exposed (001) facet and the unique hierarchical structure. As a result, it delivers a high reversible lithium storage capacity of 580 mAh/g at a current density of 0.2C (0.2 A/g), and excellent rate performance of above 400 mAh/g even at a high current density of 2C (2 A/g) over 500 cycles, which is much higher than most of the reported transition metal oxide anodes. This doping strategy and the unique hierarchical structures bring inspiration for nanostructure design of functional materials in energy storage.


Non-vitamin K antagonist oral anticoagulants for the prevention of recurrent venous thromboembolism.
Venous thromboembolism (VTE) is associated with a risk of recurrence that depends on factors specific to index event and patient. A first unprovoked VTE increases the risk of a recurrent event, particularly during the first year after anticoagulation cessation. Determining a strategy for the long-term prevention of recurrent VTE poses challenges that stem from a lack of agreement on recommended therapy duration and varying treatment burden for the patient. Oral anticoagulants, including vitamin K antagonists and non-vitamin K antagonist oral anticoagulants (NOACs), are the main treatment options for the long-term prevention of recurrent VTE. However, the risk of VTE recurrence must be balanced against the risk of bleeding in each patient. Phase III clinical trials have evaluated rivaroxaban, apixaban and dabigatran for extended treatment and prevention of VTE versus placebo, and versus warfarin in the case of dabigatran. Compared with placebo treatment, each NOAC showed superior efficacy together with an acceptable safety profile during extended treatment periods of 6-18months. Patients receiving long-term NOAC therapy will still require regular risk factor assessment, but these agents may permit longer treatment duration with an improved benefit-risk profile.


Possible contribution of (pro)renin receptor to development of gestational diabetes mellitus.
(Pro)renin receptor [(P)RR], a receptor for renin and prorenin, was first cloned in 2002. Since then, the pathophysiological roles of (P)RR have been growing concerns. (P)RR binds renin and prorenin, with two important consequences, nonproteolytic activation of prorenin, leading to the tissue renin-angiotensin system activation and the intracellular signalings. It is now also known to play an important role as vacuolar H(+)-ATPase associated protein, involving in Wnt signaling, main component of embryonic development. Extracellular domain of full-length (P)RR is cleaved in golgi-complex forming soluble (P)RR [s(P)RR]. The s(P)RR is now possible to be measured in human blood and urine. It is now measured in different pathophysiological states, and recent study showed that elevated plasma s(P)RR levels in the early stage of pregnancies are associated with higher incidence of gestational diabetes mellitus later in the pregnancies. Plasma s(P)RR levels of neonates are known to be higher than that of adults. It was also shown that, increased s(P)RR concentrations in cord blood, associated with a lower small for gestational age birth likelihood. These data suggests the involvement of (P)RR in embryo's growth. In this review article, we attempt to figure out the possible pathophysiological roles of the (P)RR in maternal glucose intolerance and embryo's growth, through reviewing previous studies.


Deletion of Type 2 Metabotropic Glutamate Receptor Decreases Sensitivity to Cocaine Reward in Rats.
Cocaine users show reduced expression of the metabotropic glutamate receptor (mGluR2), but it is not clear whether this is a predisposing trait for addiction or a consequence of drug exposure. In this study, we found that a nonsense mutation at the mGluR2 gene decreased mGluR2 expression and altered the seeking and taking of cocaine. mGluR2 mutant rats show reduced sensitivity to cocaine reward, requiring more cocaine to reach satiation when it was freely available and ceasing their drug-seeking behavior sooner than controls when the response requirement was increased. mGluR2 mutant rats also show a lower propensity to relapse after a period of cocaine abstinence, an effect associated with reduced cocaine-induced dopamine and glutamate overflow in the nucleus accumbens. These findings suggest that mGluR2 polymorphisms or reduced availability of mGluR2 might be risk factors for the initial development of cocaine use but could actually protect against addiction by reducing sensitivity to cocaine reward.


Acidic phosphoproteins of the 60-S ribosomal subunits from HeLa cells.
Two-dimensional analysis of the ribosomal proteins from 60-S subunits of HeLa cells revealed a triplet of acidic proteins, L40a, L40b and L40c, of identical molecular weight (13,700), which can be separated only on the basis of their charge differences. Two of the spots, L40b and L40c, become labeled after incubation of the cells with inorganic [32P]phosphate. The electrophoretic behavior and molecular weights of these proteins support the notion that the proteins L40b and L40c, are phosphorylated forms of the protein L40a. The same proteins can be phosphorylated also in vitro by a HeLa protein kinase on 60-S subunits but not on 80-S ribosomes. The inaccessibility of L40 proteins to the phosphorylation in vitro on 80-S ribosomes suggests that they are located in the interface between the 40-S and 60-S subunits.


α9-Containing Nicotinic Receptors in Cancer.
Neuronal nicotinic acetylcholine receptors containing the α9 or the α9 and α10 subunits are expressed in various extra-neuronal tissues. Moreover, most cancer cells and tissues highly express α9-containing receptors, and a number of studies have shown that they are powerful regulators of responses that stimulate cancer processes such as proliferation, inhibition of apoptosis, and metastasis. It has also emerged that their modulation is a promising target for drug development. The aim of this review is to summarize recent data showing the involvement of these receptors in controlling the downstream signaling cascades involved in the promotion of cancer.


Simulation of the ligand-leaving process of the human heat shock protein.
The human heat shock protein plays a critical role in various diseases and is an important target for pharmacological modulation. Simulation of conformational changes and free energy profiles of the human heat shock protein derived by the ligand-leaving process is a challenging issue. In this work, steered molecular dynamics simulation was adopted to simulate the ligand-leaving process. Two composite systems of heat shock protein NHSP90 and small molecules 6FJ and 6G7 are selected as research objects. The free energy during the leaving of ligand small molecules is calculated using conventional molecular dynamics simulation, steered molecular dynamics simulation (SMD), and the umbrella sampling method. We found that the a slower pulling velocity (0.001 nm ns-1) will result in 2.19 kcal mol-1, and the umbrella sampling method gives a value of 3.26 kcal mol-1 for the free energy difference for the two systems, which reasonably agrees with experimental results. A faster-pulling velocity (0.01 nm ns-1) leads to a large overestimation of free energy. At the same time, the conformational analysis indicated that the faster pulling velocity may lead to the conformational change of NHSP90, which was proved to be false by the slower pulling velocity and the umbrella sampling method.


Bilinguals' twisted tongues: Frequency lag or interference?
Though bilinguals know many more words than monolinguals, within each language bilinguals exhibit some processing disadvantages, extending to sublexical processes specifying the sound structure of words (Gollan & Goldrick, Cognition, 125(3), 491-497, 2012). This study investigated the source of this bilingual disadvantage. Spanish-English bilinguals, Mandarin-English bilinguals, and English monolinguals repeated tongue twisters composed of English nonwords. Twister materials were made up of sound sequences that are unique to the English language (nonoverlapping) or sound sequences that are highly similar-yet phonetically distinct-in the two languages for the bilingual groups (overlapping). If bilingual disadvantages in tongue-twister production result from competition between phonetic representations in their two languages, bilinguals should have more difficulty selecting an intended target when similar sounds are activated in the overlapping sound sequences. Alternatively, if bilingual disadvantages reflect the relatively reduced frequency of use of sound sequences, bilinguals should have greater difficulty in the nonoverlapping condition (as the elements of such sound sequences are limited to a single language). Consistent with the frequency-lag account, but not the competition account, both Spanish-English and Mandarin-English bilinguals were disadvantaged in tongue-twister production only when producing twisters with nonoverlapping sound sequences. Thus, the bilingual disadvantage in tongue-twister production likely reflects reduced frequency of use of sound sequences specific to each language.


[Association between cigarette smoking and hypertension in men: a dose response relationship analysis].
To estimate the dose response relationship between cigarette smoking and hypertension in men based on restricted cubic spline method. Under the proportion to the population size, 38 520 subjects were randomly selected from May to August 2012 with cluster sampling method in urban and rural areas of Kunshan, China.Each participant received face-to-face interview with the standardized questionnaire, and physical examination.Restricted cubic spline was employed to estimate the dose response relation of cigarette smoking on the risk of hypertension. The overall prevalence of cigarette smoking was 22.6% (8 691/38 520), prevalence of cigarette smoking in men was 46.1% (8 499/18 454). Multiple logistic regression analysis showed that current smoking (OR = 1.16, 95%CI:1.05-1.28) and previous cigarette smoking (OR = 1.32, 95%CI:1.07-1.63) were associated with hypertension after adjusted confounding factors (age, sex, body mass index, education, family income per month, urban or rural areas, physical activity and physical exercise) in men. After further adjusting drinking status, only previous cigarette smoking was associated with hypertension (OR = 1.28, 95%CI:1.04-1.58). The restricted cubic spline model indicated a linear dose-response relation between hypertension and cigarette smoking per day in men (non-linearity test P = 0.604 1).However, a non-linear dose response relation was found between duration of smoking (non-linearity test P < 0.000 1), smoking index (non-linearity test P = 0.009 9) and hypertension. Long-term and heavy cigarette smoking is associated with hypertension in men.


Developing high-power hybrid resonant gain-switched thulium fiber lasers.
In this paper, we propose hybrid-pumped resonant gain-switched thulium fiber lasers to realize high-average-power and high-pulse-energy 2-μm laser emissions. Based on numerical simulation, laser dynamics (pulse peak power, pulse energy, pulse duration, etc.) of this kind of laser system are investigated in detail. By taking advantages of the 793 nm continuous wave pump and the 1900 nm pulsed pump, performance of the laser emission can be significantly improved, with the highest average power of 28 W, peak power of 3.5 kW, pulse energy of 281 μJ, and narrowest pulse duration of 92 ns, all of which can be further optimized through designing the cavity parameters and the pumping circumstance. Compared with the pump pulses, two times improvement in pulse energy and average power has been achieved. This hybrid resonant gain-switched system has an all-fiber configuration and high efficiency (low heat load), and can be steadily extended into the cladding pump scheme, thus paving a new way to realize high power (>100 W average power) and high pulse energy (>1 mJ) 2 μm thulium fiber lasers.


Different DRB1*03:01-DQB1*02:01 haplotypes confer different risk for celiac disease.
Celiac disease is associated with the HLA-DR3-DQA1*05:01-DQB1*02:01 and DR4-DQA1*03:01-DQB1*03:02 haplotypes. In addition, there are currently over 40 non-HLA loci associated with celiac disease. This study extends previous analyses on different HLA haplotypes in celiac disease using next generation targeted sequencing. Included were 143 patients with celiac disease and 135 non-celiac disease controls investigated at median 9.8 years (1.4-18.3 years). PCR-based amplification of HLA and sequencing with Illumina MiSeq technology were used for extended sequencing of the HLA class II haplotypes HLA-DRB1, DRB3, DRB4, DRB5, DQA1 and DQB1, respectively. Odds ratios were computed marginally for every allele and haplotype as the ratio of allelic frequency in patients and controls as ratio of exposure rates (RR), when comparing a null reference with equal exposure rates in cases and controls. Among the extended HLA haplotypes, the strongest risk haplotype for celiac disease was shown for DRB3*01:01:02 in linkage with DQA1*05:01-DQB1*02:01 (RR = 6.34; P-value < .0001). In a subpopulation analysis, DRB3*01:01:02-DQA1*05:01-DQB1*02:01 remained the most significant in patients with Scandinavian ethnicity (RR = 4.63; P < .0001) whereas DRB1*07:01:01-DRB4*01:03:01-DQA1*02:01-DQB1*02:02:01 presented the highest risk of celiac disease among non-Scandinavians (RR = 7.94; P = .011). The data also revealed 2 distinct celiac disease risk DR3-DQA1*05:01-DQB*02:01 haplotypes distinguished by either the DRB3*01:01:02 or DRB3*02:02:01 alleles, indicating that different DRB1*03:01-DQB1*02:01 haplotypes confer different risk for celiac disease. The associated risk of celiac disease for DR3-DRB3*01:01:02-DQA1*05:01-DQB1*02:01 is predominant among patients of Scandinavian ethnicity.


[Effect of lead on learn and memory and release of intracellular free Ca2+ from calcium pool in dissociated mouse hippocampal neurons].
To study effect of lead on learn and memory and the release of intracellular free Ca2+ from calcium pool in dissociated mouse hippocampal neurons. Using a water maze we measured the ability of spatial learning of mouses. Digesting with low concentration of trypsin and gently triturating mode were used to dissociate hippocampal neurons. Using inositol 1,4,5-triphosphate (IP3) sensitive calcium store antagonist-heparine and non-IP3 sensitive calcium store (ryanodine) antagonist-procaine to stimulate hippocampal neurons, and observed the effect of Pb2+ on [Ca2+]i of hippocampal neurons by Fura-2 double wavelength fluoremetry. In the Morris water maze task, results indicated that mouses having drink lead water displayed significant impairment in their performance, and this extent of impairment showed in lead concentration dependent manner. Compared with control group, in condition of none of extracellular free calcium, 25 micromol x L(-1) of Pb2+ induced markedly increase of intracellular free calcium of hippocampal neurons in mouse. Heparin (IP3 sensitive calcium store antagonist) of 30 microg x ml(-1) and procaine (non-IP3 sensitive calcium store atagonist) of 0.1 mg x ml(-1) blocked the increases of [Ca2+]i in mouse hippocampal neurons elicited by 25 micromol x L(-1) of Pb2+. Chronic exposure to lead (Pb2+) reduces the ability of spatial learing and memory of mice. High level of Pb2+ facilitated release of intracellular free calcium from IP3 sensitive and non-IP3 sensitive calcium store and induced the increases of intracellular free calcium in mouse hippocampal neurons.


Impact of Sports Participation on Achievement of Clinically Relevant Outcomes 2 Years After ACL Reconstruction.
Clinically relevant threshold values associated with patient-reported outcome measures after orthopaedic procedures such as anterior cruciate ligament reconstruction (ACLR) are important for relating these scores to meaningful postoperative improvement. The purpose of this study was to determine the Patient Acceptable Symptom State (PASS) for the Patient-Reported Outcomes Measurement Information System Computer Adaptive Test (PROMIS-CAT) after ACLR. It was hypothesized that preoperative sport participation would have an impact on PASS achievement. Case series; Level of evidence, 4. Included were consecutive patients who underwent primary assisted ACLR between January 4 and August 1, 2016. Patients were administered the PROMIS-CAT Physical Function (PF) and Pain Interference domains preoperatively and at a minimum 2 years postoperatively, with external anchor questions used to determine the PASS. Receiver operating characteristic (ROC) curves were constructed for the entire study population as well as separately for athletes and nonathletes to determine PROMIS PASS thresholds for each population. A previously published PROMIS-PF minimal clinically important difference was used to evaluate postoperative improvement. A post hoc multivariate nominal logistic multivariate analysis was constructed to assess the effects of preoperative patient characteristics on the likelihood of attaining both the minimal clinically important difference and PASS. In total, 112 patients were included in the study, with 79 (71%) having recreational or higher levels of athletic participation. The PASS for the study population was 56.0 (area under the ROC curve, 0.86) and was unaffected by baseline PROMIS-PF scores but was affected by preoperative athletic participation (56.0 for athletes, 49.0 for nonathletes). A post hoc analysis found 57 patients (51%) achieved the PASS for the PROMIS-PF (cutoff, 56.0), but when the athlete and nonathlete thresholds were applied to their respective patient groups, 66% of athletes and 64% of nonathletes achieved the PASS postoperatively. The multivariate analysis found that sport participation (odds ratio, 6.2; P = .001) but not age, sex, body mass index, or preoperative PROMIS affected the likelihood of achieving the PASS on the PROMIS-PF. Preoperative athletic participation significantly affected the ability to achieve PASS.


Depression and memory narrative type.
Research with autobiographical memories has distinguished between memory narratives of specific events and summaries of many events blended together. Depression has been associated with a reduced ability to retrieve and orally relate specific positive memories. This study explored the hedonic bias in memory through collection of written autobiographical memories from 90 nonclinical college students whose mood was assessed for depression. Participants with higher depression scores recalled significantly more summary memories in response to a request for a positive self-defining memory than did participants with lower depression scores. There were no significant differences in the number of single-event and summary memories when participants were asked for a negative memory. We used J. A. Singer and K. H. Moffitt's (1991-1992) scoring system to distinguish between summarized and specific memory narratives.


[Risk assessment for eating disorders in a high school: a study based on the Eating Attitudes Test 26].
Disordered eating behaviours can lead to clinically evident and serious eating disorders (ED). Aim of this paper is to determine their extent among adolescents and to evaluate the associated characteristics. All students of a high school (age 14-18) have been asked to fill up the Eating Attitudes Test (EAT-26) anonymously. EAT-26 is a self-reported questionnaire identifying subjects at risk for ED. This questionnaire included also an integrative section, aimed at investigating some ED-related variables (family composition, diet among relatives, social relationships, spare time activities, self-esteem). Collected data have been analyzed using EpiInfo6. The study involved all the 902 students of the school; 833 questionnaires have been distributed and 701 were collected (89.4% from girls, 10.3% from boys). The percentage of EAT-26 positive boys (i.e. scoring = or > 20) is 3%, while for girls is 13.7%. A positive test significantly correlates with low self-esteem (OR = 46.67, CI = 13.16-182.04), contentious relationships with the mother (OR = 2.20, CI = 1.12-4.29) and the father (OR=2.45, CI=1.24-4.80). No significant correlation has been found for being an only child, living in a single-parent family having limited/not having social relationships, having unsatisfactory social relationships, spending spare time mostly alone, watching TV more than 2 h per day. Our data suggest an increasing diffusion in the risk for ED among adolescents. Personal characteristics and behaviours related to this risk are good start points to program projects focusing on primary and secondary prevention of ED in high schools.


Prolonged Ischemia Triggers Necrotic Depletion of Tissue-Resident Macrophages To Facilitate Inflammatory Immune Activation in Liver Ischemia Reperfusion Injury.
Although mechanisms of immune activation against liver ischemia reperfusion (IR) injury (IRI) have been studied extensively, questions regarding liver-resident macrophages, that is, Kupffer cells (KCs), remain controversial. Recent progress in the biology of tissue-resident macrophages implicates homeostatic functions of KCs. This study aims to dissect responses and functions of KCs in liver IRI. In a murine liver partial warm ischemia model, we analyzed liver-resident versus infiltrating macrophages by FACS and immunofluorescence staining. Our data showed that liver immune activation by IR was associated with not only infiltrations/activations of peripheral macrophages, but also necrotic depletion of KCs. Inhibition of receptor-interacting protein 1 (RIP1) by necrostatin-1s protected KCs from ischemia-induced depletion, resulting in the reduction of macrophage infiltration, suppression of proinflammatory immune activation, and protection of livers from IRI. The depletion of KCs by clodronate liposomes abrogated the effect of necrostatin-1s. Additionally, liver reconstitutions with KCs postischemia exerted anti-inflammatory/cytoprotective effects against IRI. These results reveal a unique response of KCs against liver IR, that is, RIP1-dependent necrosis, which constitutes a novel mechanism of liver inflammatory immune activation in the pathogenesis of liver IRI.


Pressure pain sensitivity and hardness along human normal and sensitized muscle.
The spatial distribution of pressure sensitivity and muscle hardness was examined on normal muscle tissue and muscle tissue after induction of delayed onset muscle soreness (DOMS). The pressure sensitivity and muscle hardness were assessed at nine sites on the tibialis muscle from the proximal to distal tendon on two separate days. In total 37 healthy volunteers participated in three experiments. In the first experiment pressure pain threshold (PPT) and pressure pain tolerance (PPTO) were assessed. Decreased PPT and PPTO were found on day 2, 7 days after day 1. Proximal and distal stimulation sites were harder compared to muscle belly sites. In a second experiment two different probe sizes were used. Variation in PPT between the nine sites was found for the large probe with muscle belly being less sensitive to pressure stimulation compared to proximal and distal sites. The most proximal stimulation site was harder compared to muscle belly sites. In a third experiment PPT and muscle hardness were assessed before and 48 h after eccentric exercise. PPT at two muscle belly sites was significantly decreased during DOMS. No specific sites were harder during DOMS, the average muscle hardness across sites was however significantly increased. Decreased PPT and increased muscle hardness did not correlate. In conclusion, within subjects the pressure sensitivity varies along the musculoskeletal unit. In DOMS, specific muscle belly sites were more sensitive to pressure stimulation. Muscle-tendon sites were harder compared to muscle belly sites.


Fine needle aspiration cytology, in relationships to clinical examination and mammography in the diagnosis of a solid breast mass.
The accuracy of clinical examination, mammography and fine needle aspiration cytology in identifying malignancy has been assessed in 1655 breast masses from two time periods. Clinical examination and mammography remained consistent at identifying malignancy but 9 per cent of all breast carcinomas were considered benign by both techniques (sensitivity 91 per cent). Fine needle aspiration cytology, when performed by multiple aspirators in the first study period, had a sensitivity of only 66 per cent for malignancy. During the second period of study, when all aspirates were performed by a single aspirator, sensitivity rose to 99 per cent. The two patients with false negative cytology in this latter period had both clinical and mammographic evidence of malignancy. No patient with malignant cytology was subsequently shown to have benign disease. It is concluded that a combination of clinical examination and mammography, with fine needle aspiration cytology performed by committed individuals with aptitude for the technique and interpreted by experienced pathologists, can identify all patients with breast cancer before surgery.


The ND10 Component Promyelocytic Leukemia Protein Acts as an E3 Ligase for SUMOylation of the Major Immediate Early Protein IE1 of Human Cytomegalovirus.
Previous studies identified the nuclear domain 10 (ND10) components promyelocytic leukemia protein (PML), hDaxx, and Sp100 as factors of an intrinsic immune response against human cytomegalovirus (HCMV). This antiviral function of ND10, however, is antagonized by viral effector proteins like IE1p72, which induces dispersal of ND10. Furthermore, we have shown that both major immediate early proteins of HCMV, IE1p72 and IE2p86, transiently colocalize with ND10 subnuclear structures and undergo modification by the covalent attachment of SUMO. Since recent reports indicate that PML acts as a SUMO E3 ligase, we asked whether the SUMOylation of IE1p72 and IE2p86 is regulated by PML. To address this, PML-depleted fibroblasts, as well as cells overexpressing individual PML isoforms, were infected with HCMV. Western blot experiments revealed a clear correlation between the degree of IE1p72 SUMO conjugation and the abundance of PML. On the other hand, the SUMOylation of IE2p86 was not affected by PML. By performing in vitro SUMOylation assays, we were able to provide direct evidence that IE1p72 is a substrate for PML-mediated SUMOylation. Interestingly, disruption of the RING finger domain of PML, which is proposed to confer SUMO E3 ligase activity, abolished PML-induced SUMOylation of IE1p72. In contrast, IE1p72 was still efficiently SUMO modified by a SUMOylation-defective PML mutant, indicating that intact ND10 bodies are not necessary for this effect. Thus, this is the first report that the E3 ligase PML is capable of stimulating the SUMOylation of a viral protein which is supposed to serve as a cellular mechanism to compromise specific functions of IE1p72.IMPORTANCE The major immediate early proteins of human cytomegalovirus, termed IE1p72 and IE2p86, have previously been shown to undergo posttranslational modification by covalent coupling to SUMO moieties at specific lysine residues. However, the enzymatic activities that are responsible for this modification have not been identified. Here, we demonstrate that the PML protein, which mediates an intrinsic immune response against HCMV, specifically serves as an E3 ligase for SUMO modification of IE1p72. Since SUMO modification of IE1p72 has previously been shown to interfere with STAT factor binding, thus compromising the interferon-antagonistic function of this viral effector protein, our finding highlights an additional mechanism through which PML is able to restrict viral infections.


Prediction of response to neoadjuvant chemotherapy by sequential F-18-fluorodeoxyglucose positron emission tomography in patients with advanced-stage ovarian cancer.
The aim of this study was to evaluate sequential F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) to predict patient outcome after the first and third cycle of neoadjuvant chemotherapy in advanced-stage (International Federation of Gynecology and Obstetrics stages IIIC and IV) ovarian cancer. Thirty-three patients received three cycles of carboplatin-based chemotherapy, followed by cytoreductive surgery. Quantitative FDG-PET of the abdomen and pelvis was acquired before treatment and after the first and third cycle of chemotherapy. Changes in tumoral FDG uptake, expressed as standardized uptake values (SUV), were compared with clinical and histopathologic response; overall survival served as a reference. A significant correlation was observed between FDG-PET metabolic response after the first (P = .008) and third (P = .005) cycle of chemotherapy and overall survival. By using a threshold for decrease in SUV from baseline of 20% after the first cycle, median overall survival was 38.3 months in metabolic responders compared with 23.1 months in metabolic nonresponders. At a threshold of 55% decrease in SUV after the third cycle median overall survival was 38.9 months in metabolic responders compared with 19.7 months in nonresponders. There was no correlation between clinical response criteria (P = .7) or CA125 response criteria (P = .5) and overall survival. There was only a weak correlation (P = .09) between histopathologic response criteria and overall survival. Sequential FDG-PET predicted patient outcome as early as after the first cycle of neoadjuvant chemotherapy and was more accurate than clinical or histopathologic response criteria including changes in tumor marker CA125. FDG-PET appears to be a promising tool for early prediction of response to chemotherapy.


Chronic and Episodic Stress in Children of Depressed Mothers.
The goal of this study was to examine chronic and episodic stress in children of mothers with and without a history of major depressive disorder (MDD) during the children's lives. Participants were 255 mothers selected according to their history of MDD (present vs. absent during child's life) and their children (age 8-14; 53% girls, 81% Caucasian). Mothers' and children's histories of MDD were assessed using diagnostic interviews, and their depressive symptoms were assessed via self-report measures. Children's levels of chronic and episodic stress were assessed using a semistructured contextual threat interview. Children of mothers with a history of recurrent MDD, compared to single MDD or no depression, experienced more chronic stress within several domains including peers, mother-child relations, and other family member relations as well as greater episodic dependent interpersonal stress. Each of these group differences was maintained after excluding children with a history of MDD themselves and controlling for their current depressive symptoms. However, only the group difference in chronic peer stress was maintained when controlling for mothers' current depression. The results suggest that children exposed to recurrent maternal MDD experience higher levels of both chronic and episodic stress, at least some of which they contribute to themselves (dependent interpersonal stress) and which is at least partially independent of the effects of children's depression. In addition, much of this stress is associated primarily with current depression in the mother, though it appears that chronic peer stress may remain elevated even after the remission of maternal depression.


Oral administration of haloperidol at clinically recommended doses elicits smaller parkinsonian effects but more tardive dyskinesia in rats.
The present study was designed to monitor extrapyramidal symptoms (EPS) elicited by the oral administration of haloperidol at clinically recommended doses and to compare it with EPS produced when the drug is injected intraperitoneally at doses used in animal research. Rats injected with haloperidol at a dose of 1 mg/kg daily for 5 weeks exhibited akinesia in an open field and impaired motor coordination. Effects of the drug on motor coordination but not on open field akinesia were attenuated gradually from 2-5 weeks of treatment. Oral administration of haloperidol in drinking water at clinically recommended dose exhibited decreased exploratory activity without producing akinesia. Motor coordination was impaired maximally after 3 weeks and tolerance was developed in the drug induced motor impairment after 5 weeks of treatment. Intensity of vacuous chewing movements (VCMs) and tardive VCMs was greater by oral administration than intraperitoneal injections of haloperidol. The present results showed that oral administration of haloperidol expected to produce sustained effect may result in tolerance in acute parkinsonian like effects but more intensity of tardive dyskinesia. We suggest that drugs which may helpful in alleviating tardive dyskinesia may be more useful if person is on oral drug therapy.


Altered brain lipid composition in cyclooxygenase-2 knockout mouse.
Cyclooxygenase (COX)-2 plays an important role in brain arachidonic acid (20:4n-6) metabolism, and its expression is upregulated in animal models of neuroinflammation and excitotoxicity. Our hypothesis was that brain lipid composition would be altered in COX-2 knockout (COX-2(-/-)) compared with wild-type (COX-2(+/+)) mice, reflecting the important role of COX-2 in brain lipid metabolism. Concentrations of different lipids were measured in high-energy microwaved brain from COX-2(-/-) and COX-2(+/+) mice. Compared with the COX-2(+/+) mouse brain, the brain of the COX-2(-/-) mouse had a statistically significant 15% increase in phosphatidylserine (PtdSer) and significant 37, 27, and 32% reductions in triacylglycerol and cholesterol concentrations and in the cholesterol-to-phospholipid ratio, respectively. The normalized concentration of palmitic acid (16:0) was increased in PtdSer, as was the brain concentration of unesterified arachidic acid (20:0). A lifetime absence of COX-2 produces multiple changes in brain lipid composition. These changes may be related to reported changes in fatty acid kinetics and in resistance to neuroinflammation and excitotoxicity in the COX-2(-/-) mouse.


Monte Carlo simulation of focused helium ion beam induced deposition.
The details of a Monte Carlo helium ion beam induced deposition simulation are introduced and initial results for reaction rate and mass transport limited growth regimes are presented. Reaction rate limited growth leads to fast vertical growth from incident primary ions and minimal lateral broadening, whereas mass transport limited growth has lower vertical growth velocity and exhibits broadening due to scattered ions and secondary electrons. The results are compared to recent experiments and previous electron beam induced deposition simulations.


A ganglionic stimulant, 1,1-dimethyl-4-phenylpiperazinium, caused both cholinergic and adrenergic responses in the isolated mouse atrium.
An isolated atrial preparation of the mouse is useful for analyzing the actions of drugs on the myocardium, autonomic neurons and endocardial endothelium. The aim of the present study was to examine the functions of intrinsic neurons of the atrium using a ganglionic stimulant, 1,1-dimethyl-4-phenylpiperazinium (DMPP). DMPP (1-100 μM) caused a negative chronotropic action followed by a positive chronotropic action in spontaneously beating right atria and also caused biphasic inotropic actions consisting of initial inhibition followed by potentiation of electrical field stimulation (EFS)-induced contraction in the left atria. Inotropic actions in the left atria induced by DMPP were characterized using some autonomic drugs and M2 and/or M3 muscarinic receptor knockout (M2R-KO, M3R-KO and M2M3R-KO) mice. Atropine and hexamethonium decreased the initial negative inotropic actions of DMPP. In the atria from pertussis toxin-treated, M2R-KO and M2/M3R-KO mice, the negative inotropic actions were abolished. On the other hand, the following positive inotropic actions were decreased by hexamethonium, atropine and atenolol. In the atria from reserpine-treated mice, positive inotropic actions were also decreased. The positive inotropic action induced by DMPP was almost the same in M2R-KO mice but was reduced in both M3R-KO mice and M2/M3R-KO mice. In conclusion, DMPP caused biphasic inotropic/chronotropic actions in the mouse atrium through activation of intrinsic cholinergic and adrenergic neurons. M2 and M3 muscarinic receptors and β1-adrenoceptor are thought to be involved in these actions.


The mechanism of lowering cholesterol absorption by calcium studied by using an in vitro digestion model.
Studies in humans show that a calcium-enriched diet leads to lower cholesterol in blood serum. This phenomenon is usually explained in the literature with a reduced cholesterol absorption in the small intestine. Our study aims to clarify the effect of calcium on the solubilisation of cholesterol and fatty acid in the dietary mixed micelles (DMM), viz. on the bioaccessibility of these lipophilic substances in the gut. We use an in vitro digestion model which mimics very closely the intestinal pH-profile and the composition of the intestinal fluids. We quantified the effects of Ca(2+) concentration on the lipid solubilization for fats and oils with different saturated/unsaturated fatty acid (FA) contents. We found that the increase of calcium significantly decreases the solubilization of cholesterol, FA and MG. Most importantly, we observe a clear positive correlation between the amounts of solubilized cholesterol, on one side, and solubilized free fatty acids and monoglycerides, on the other side. The main conclusion is that Ca(2+) ions strongly affect the bioaccessibility of both cholesterol and saturated FA. Therefore, calcium may decrease the serum cholesterol via two complementary mechanisms: (1) fatty acid precipitation by calcium ions reduces the solubilisation capacity of the DMM, thus decreasing the levels of solubilised (bioaccessible) cholesterol; (2) the observed strong decrease of the bioaccessible saturated FA, in its own turn, may suppress the cholesterol synthesis in the liver.


Suppression of genetic recombination in the pseudoautosomal region and at subtelomeres in mice with a hypomorphic Spo11 allele.
Homologous recombination is the key process that generates genetic diversity and drives evolution. SPO11 protein triggers recombination by introducing DNA double stranded breaks at discreet areas of the genome called recombination hotspots. The hotspot locations are largely determined by the DNA binding specificity of the PRDM9 protein in human, mice and most other mammals. In budding yeast Saccharomyces cerevisae, which lacks a Prdm9 gene, meiotic breaks are formed opportunistically in the regions of accessible chromatin, primarily at gene promoters. The genome-wide distribution of hotspots in this organism can be altered by tethering Spo11 protein to Gal4 recognition sequences in the strain expressing Spo11 attached to the DNA binding domain of the Gal4 transcription factor. To establish whether similar re-targeting of meiotic breaks can be achieved in PRDM9-containing organisms we have generated a Gal4BD-Spo11 mouse that expresses SPO11 protein joined to the DNA binding domain of yeast Gal4. We have mapped the genome-wide distribution of the recombination initiation sites in the Gal4BD-Spo11 mice. More than two hundred of the hotspots in these mice were novel and were likely defined by Gal4BD, as the Gal4 consensus motif was clustered around the centers in these hotspots. Surprisingly, meiotic DNA breaks in the Gal4BD-Spo11 mice were significantly depleted near the ends of chromosomes. The effect is particularly striking at the pseudoautosomal region of the X and Y chromosomes - normally the hottest region in the genome. Our data suggest that specific, yet-unidentified factors influence the initiation of meiotic recombination at subtelomeric chromosomal regions.


Non-inhibition of acetylcholinesterase by cycloSal nucleotides.
An acetylcholinesterase (AChE) assay based on the Rappaport method was established to investigate the behaviour of several cycloSal nucleotides against AChE from electrophorus electricus and human sources (purified enzymes). AChE is a physiologically essential enzyme as it catalyzes the hydrolysis of the neurotransmitter acetylcholine. No inhibition was observed in any of the cases.


The Global Spine Care Initiative: public health and prevention interventions for common spine disorders in low- and middle-income communities.
The purpose of this study was to develop recommendations for prevention interventions for spinal disorders that could be delivered globally, but especially in underserved areas and in low- and middle-income countries. We extracted risk factors, associations, and comorbidities of common spinal disorders (e.g., back and neck pain, spinal trauma, infection, developmental disorders) from a scoping review of meta-analyses and systematic reviews of clinical trials, cohort studies, case control studies, and cross-sectional studies. Categories were informed by the Global Spine Care Initiative (GSCI) classification system using the biopsychosocial model. Risk factors were clustered and mapped visually. Potential prevention interventions for individuals and communities were identified. Forty-one risk factors, 51 associations, and 39 comorbidities were extracted; some were associated with more than one disorder. Interventions were at primary, secondary, tertiary, and quaternary prevention levels. Public health-related actions included screening for osteopenia, avoiding exposure to certain substances associated with spinal disorders, insuring adequate dietary intake for vitamins and minerals, smoking cessation, weight management, injury prevention, adequate physical activity, and avoiding harmful clinical practices (e.g., over-medicalization). Prevention principles and health promotion strategies were identified that were incorporated in the GSCI care pathway. Interventions should encourage healthy behaviors of individuals and promote public health interventions that are most likely to optimize physical and psychosocial health targeting the unique characteristics of each community. Prevention interventions that are implemented in medically underserved areas should be based upon best evidence, resource availability, and selected through group decision-making processes by individuals and the community. These slides can be retrieved under Electronic Supplementary Material.


A cell cycle study of human mammary epithelial cells.
The growth regulation of human mammary epithelial cells (HMEC) cultured in a growth factor/hormone-enriched (e.g. EGF, insulin) medium with bovine pituitary extract as the only undefined supplement was studied. The doubling times of the cultures, in which the cells appear in colonies, was 55-72 h, and a considerable intercolonial heterogenecity in proliferative activity could be demonstrated. However, every colony, irrespective of the size of the growth fraction, comprised a sub-population of rapidly growing cells which had a mean generation time of approximately 22 h. When insulin was removed from the culture medium, HMEC proliferation was inhibited. This growth inhibition was shown to be a result of a cell cycle-specific block.


Hypoxia inducible factor 3α plays a critical role in alveolarization and distal epithelial cell differentiation during mouse lung development.
Lung development occurs under relative hypoxia and the most important oxygen-sensitive response pathway is driven by Hypoxia Inducible Factors (HIF). HIFs are heterodimeric transcription factors of an oxygen-sensitive subunit, HIFα, and a constitutively expressed subunit, HIF1β. HIF1α and HIF2α, encoded by two separate genes, contribute to the activation of hypoxia inducible genes. A third HIFα gene, HIF3α, is subject to alternative promoter usage and splicing, leading to three major isoforms, HIF3α, NEPAS and IPAS. HIF3α gene products add to the complexity of the hypoxia response as they function as dominant negative inhibitors (IPAS) or weak transcriptional activators (HIF3α/NEPAS). Previously, we and others have shown the importance of the Hif1α and Hif2α factors in lung development, and here we investigated the role of Hif3α during pulmonary development. Therefore, HIF3α was conditionally expressed in airway epithelial cells during gestation and although HIF3α transgenic mice were born alive and appeared normal, their lungs showed clear abnormalities, including a post-pseudoglandular branching defect and a decreased number of alveoli. The HIF3α expressing lungs displayed reduced numbers of Clara cells, alveolar epithelial type I and type II cells. As a result of HIF3α expression, the level of Hif2α was reduced, but that of Hif1α was not affected. Two regulatory genes, Rarβ, involved in alveologenesis, and Foxp2, a transcriptional repressor of the Clara cell specific Ccsp gene, were significantly upregulated in the HIF3α expressing lungs. In addition, aberrant basal cells were observed distally as determined by the expression of Sox2 and p63. We show that Hif3α binds a conserved HRE site in the Sox2 promoter and weakly transactivated a reporter construct containing the Sox2 promoter region. Moreover, Hif3α affected the expression of genes not typically involved in the hypoxia response, providing evidence for a novel function of Hif3α beyond the hypoxia response.


Identification of a meiosis-specific protein as a member of the class of cancer/testis antigens.
Little is known about the function of human cancer/testis antigens (CTAs), such as MAGE, BAGE, GAGE, HOM-MEL-40, and NY-ESO-1, the expression of which is restricted to human malignancies and testis. When screening a cDNA expression library enriched for testis-specific representative long transcripts for reactivity with high-titered IgG antibodies from the serum of a patient with renal cell carcinoma, one repeatedly detected antigen, designated HOM-TES-14, turned out to be encoded by the synaptonemal complex protein 1 (SCP-1) gene. SCP-1 is known to be selectively expressed during the meiotic prophase of spermatocytes and is involved in the pairing of homologous chromosomes, an essential step for the generation of haploid cells in meiosis I. Investigation of a broad spectrum of normal and malignant tissues revealed expression of SCP-1 transcripts and antigen selectively in a variety of neoplastic tissues and tumor cell lines. Immunofluorescence microscopy analysis with specific antiserum showed a cell cycle phase-independent nuclear expression of SCP-1 protein in cancer cells. SCP-1 differs from other members of the class of CTA by its localization on chromosome 1 and its frequent expression in malignant gliomas, breast, renal cell, and ovarian cancer. The aberrant expression of SCP-1 in tumors might contribute to their genomic instability and suggests that the functional role of other CTA might also relate to meiosis.


Follow-up of coiled intracranial aneurysms: comparison of 3D time-of-flight MR angiography at 3T and 1.5T in a large prospective series.
Our aim was to compare 3D TOF-MRA sequences at 3T and 1.5T in the follow-up of coiled aneurysms. The follow-up of coiled intracranial aneurysms is mandatory to depict potential recanalization. 3D-TOF MRA is an appropriate tool for this purpose. DSA and 3D TOF-MRA at 1.5T and 3T were performed in a prospective series of 126 aneurysms in 96 patients (58 women, 38 men; age, 25-75 years; mean, 51.3 ± 11.3 years). DSA was the reference standard to which the accuracy of 3D TOF-MRA was compared. The quality of aneurysm occlusion was assessed independently and anonymously by a core lab by using a 3-grade scale (total occlusion, neck remnant, and aneurysm remnant). Adequate occlusion was defined as total occlusion or neck remnant and used in a 2-grade scale: adequate occlusion/aneurysm remnant. With DSA, total occlusion was depicted in 58 aneurysms (46.0%); neck remnant, in 33 aneurysms (26.2%); and aneurysm remnant, in 35 aneurysms (27.8%). Adequate occlusion was seen in 91 cases (72.2%). A remnant (aneurysm or neck) was depicted in 68 cases (54.0%). For the 3 imaging techniques and regardless of scale used, the interobserver agreement was always greater at 3T than at 1.5T. SE and NPV for the prediction of aneurysm remnant versus adequate occlusion were higher at 3T than at 1.5T (SE 3T, 0.74; SE 1.5T, 0.54; NPV 3T, 0.90; NPV 1.5T, 0.85). In this large prospective series of patients, 3D TOF-MRA was superior at 3T to 1.5T for the evaluation of coiled intracranial aneurysms.


-----Comparison of T1-Post and FLAIR-Post MRI for identification of traumatic meningeal enhancement in traumatic brain injury patients.
Traumatic meningeal enhancement (TME) is a novel biomarker observed on post-contrast fluid-attenuated inversion recovery (FLAIR) in patients who undergo contrast-enhanced magnetic resonance imaging (MRI) after suspected traumatic brain injury (TBI). TME may be seen on acute MRI despite the absence of other trauma-related intracranial findings. In this study we compare conspicuity of TME on FLAIR post-contrast and T1 weighted imaging (T1WI) post-contrast, and investigate if TME is best detected by FLAIR post-contrast or T1WI post-contrast sequences. Subjects selected for analysis enrolled in the parent study (NCT01132937) in 2016 and underwent contrast-enhanced MRI within 48 hours of suspected TBI. Two blinded readers reviewed pairs of pre- and post-contrast T1WI and FLAIR images for presence or absence of TME. Discordant pairs between the two blinded readers were reviewed by a third reader. Cohen's kappa coefficient was used to calculate agreement. Twenty-five subjects (15 males, 10 females; median age 48 (Q1:35-Q3:62; IQR: 27)) were included. The blinded readers had high agreement for presence of TME on FLAIR (Kappa of 0.90), but had no agreement for presence of TME on T1WI (Kappa of -0.24). The FLAIR and T1WI scans were compared among all three readers and 62% of the cases positive on FLAIR could be seen on T1WI. However, 38% of the cases who were read positive on FLAIR for TME were read negative for TME on T1WI. Conspicuity of TME is higher on post-contrast FLAIR MRI than on post-contrast T1WI. TME as seen on post-contrast FLAIR MRI can aid in the identification of patients with TBI.


Anti-apoptotic effect of a static magnetic field in human cells that had been treated with sodium fluoride.
Static magnetic field (SMF) is widely used in industry, in consumer devices and diagnostic medical equipment, hence the widespread exposure to SMF in the natural environment and in people occupationally exposed to it. In environment and in some workplaces, there is a risk of exposure also to various chemicals. Environmental factors can affect the cellular processes which can be the cause of the development of various pathological conditions. Therefore, the aim of this study was to assess the effect of SMF on the expression of the apoptosis-related genes in human fibroblast cultures that had been co-treated with fluoride ions. The control and NaF-treated cells were subjected to the influence of SMF with a moderate induction. The flow-cytometric analysis showed that the fluoride ions reduced the number of viable cells and induced early apoptosis. However, exposure to the SMF reduced the number of dead cells that had been treated with fluoride ions. Moreover, specific genes that were involved in apoptosis exhibited a differential expression in the NaF-treated cells and exposure to the SMF yielded a modulation of their transcriptional activity. Our results suggest some beneficial properties of using a moderate-intensity static magnetic field to reduce the adverse effects of fluoride.


Effects of Baduanjin exercise on oxidative stress and antioxidant status and improving quality of life among middle-aged women.
The purpose of this study was to evaluate the effects of Baduanjin exercise on oxidative stress, antioxidant status and quality of life in middle-aged women. A quasi-experimental design was adopted. Subjects were 31 middle-aged women. Subjects completed a supervised and standardized Baduanjin exercise program 3 times a week for 12 weeks. Malondialdehyde (MDA) level was measured and determined by using a spectrophotometer for oxidative stress. The superoxide dismutase (SOD) was measured for the antioxidant status. A 36-item Short Form Health Survey (SF-36) was used to evaluate changes in quality of life. All outcome measures were collected before intervention and at the end of a 12-week intervention. The results suggest that there are significant differences in serum SOD level with Baduanjin exercise. SOD level was significantly increased after exercise (p < 0.05). Baduanjin exercise contributed significantly to antioxidant status on these samples. However, a reduction in MDA level was observed. The t-test value was 2.03 with a p-value of 0.052. The changes may be meaningful at a 5% level. There are significant improvements in quality of life after the exercise program. Subjects had greater improvements in 4 dimensions of SF-36, namely physical function, body pain, social function and general mental health (p < 0.05). In conclusion, Baduanjin exercise has beneficial effects on improving quality of life, increasing antioxidant enzymes and reducing oxidative stress in middle-aged women. Reduction of MDA level may be more attributable to the increase in the antioxidant enzyme SOD.