Management of advanced endodermal sinus tumor of the ovary with preservation of reproductive function.
Endodermal sinus tumor of the ovary occurs primarily in children and young adults. This tumor is classified as a germ cell tumor which comprises approximately 5% of all ovarian tumors. In the past, patients with this highly malignant tumor had low survival. However, with the evolution of effective adjunctive chemotherapeutic regimens, specifically vincristine, actinomycin D, and cyclophosphamide, survival rates have improved. In an attempt to continuously improve survival rates, other combination chemotherapeutic regimens are currently under investigation. Unlike epithelial ovarian malignancies, endodermal sinus tumor can be monitored by a specific tumor marker, alpha-fetoprotein (AFP). Serum levels of AFP can be followed from the preoperative period through the course of chemotherapy. When elevated, AFP has excellent predictability that persistent disease is present. Because this disease presents primarily in young females, preservation of reproductive function is of utmost importance. We report a case of advanced endodermal sinus tumor which was managed with conservative surgery only, followed by radical combination chemotherapy, resulting in preservation of normal reproductive function and total resolution of disease documented by second-look laparotomy.


Distal truncation of KCC3 in non-French Canadian HMSN/ACC families.
Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a severe and progressive autosomal recessive polyneuropathy. Mutations in the potassium-chloride cotransporter 3 gene (KCC3) were identified as responsible for HMSN/ACC in the French Canadian (FC) population. In the present study, the authors were interested in finding new mutations in non-FC populations, assessing the activity of mutant proteins and refining genotype-phenotype correlations. The authors screened KCC3 for mutations using direct sequencing in six non-FC HMSN/ACC families. They then assessed the functionality of the most common mutant protein using a flux assay in Xenopus laevis oocytes. The authors identified mutations in exon 22 of KCC3: a novel mutation (del + 2994-3003; E1015X) in one family, as well as a known mutation (3031C-->T; R1011X) found in five unrelated families and associated with two different haplotypes. The function of the cotransporter was abolished, although a limited amount of mutant proteins were correctly localized at the membrane. KCC3 mutations in exon 22 constitute a recurrent mutation site for hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), regardless of ethnic origin, and are the most common cause of HMSN/ACC in the non-French Canadian (FC) families analyzed so far. Therefore, for genetic analysis, exon 22 screening should be prioritized in non-FC populations. Finally, the R1011X mutation leads to the abrogation of KCC3's function in Xenopus laevis oocytes, likely due to impaired transit of the cotransporter.


Tobacco Control Policies in Turkey in Terms of MPOWER.
Tobacco consumption is a worldwide health problem threatening all, making no differentiation between gender, age, race, and cultural or educational background. Tobacco is responsible for 7 million deaths each year. Over 6 million deaths are directly related to tobacco consumption, and over 890.000 deaths involve non-smokers exposed to tobacco smoke. Although the harmful effects of cigarettes on human health have been confirmed repeatedly, still over 1 billion people worldwide are tobacco consumers, and according the World Health Organization (WHO), unless a strict action plan is implemented, tobacco-related deaths will rise to more than 8 million per year by 2030. The WHO published the Framework Convention on Tobacco Control in 2003, which could form a common policy to guide countries in the struggle against tobacco. Tobacco control in the Convention is defined as "a range of supply, demand and harm reduction strategies that aim to improve the health of a population by eliminating or reducing their consumption of tobacco products and exposure to tobacco smoke." This agreement was adopted by Turkey in 2004 with the Law No. 5261. In 2008, the WHO published the MPOWER package, containing the following six basic strategies, which are parallel with the Tobacco Framework Convention measures and practices: Monitor tobacco use.Protect people from tobacco smoke.Offer help to quit tobacco use.Warn about the dangers of tobacco.Enforce bans on tobacco advertising and promotion.Raise taxes on tobacco products. In the 2013 Global Tobacco Control Report by the WHO, Turkey was announced as the first country achieving a high level of success in the six MPOWER strategies, and other countries were advised to adopt the Turkish policies. Here we review Turkey's MPOWER tobacco control strategies one by one.


Normal Human Lung Epithelial Cells Inhibit Transforming Growth Factor-β Induced Myofibroblast Differentiation via Prostaglandin E2.
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with very few effective treatments. The key effector cells in fibrosis are believed to be fibroblasts, which differentiate to a contractile myofibroblast phenotype with enhanced capacity to proliferate and produce extracellular matrix. The role of the lung epithelium in fibrosis is unclear. While there is evidence that the epithelium is disrupted in IPF, it is not known whether this is a cause or a result of the fibroblast pathology. We hypothesized that healthy epithelial cells are required to maintain normal lung homeostasis and can inhibit the activation and differentiation of lung fibroblasts to the myofibroblast phenotype. To investigate this hypothesis, we employed a novel co-culture model with primary human lung epithelial cells and fibroblasts to investigate whether epithelial cells inhibit myofibroblast differentiation. In the presence of transforming growth factor (TGF)-β, fibroblasts co-cultured with epithelial cells expressed significantly less α-smooth muscle actin and collagen and showed marked reduction in cell migration, collagen gel contraction, and cell proliferation compared to fibroblasts grown without epithelial cells. Epithelial cells from non-matching tissue origins were capable of inhibiting TGF-β induced myofibroblast differentiation in lung, keloid and Graves' orbital fibroblasts. TGF-β promoted production of prostaglandin (PG) E2 in lung epithelial cells, and a PGE2 neutralizing antibody blocked the protective effect of epithelial cell co-culture. We provide the first direct experimental evidence that lung epithelial cells inhibit TGF-β induced myofibroblast differentiation and pro-fibrotic phenotypes in fibroblasts. This effect is not restricted by tissue origin, and is mediated, at least in part, by PGE2. Our data support the hypothesis that the epithelium plays a crucial role in maintaining lung homeostasis, and that damaged and/ or dysfunctional epithelium contributes to the development of fibrosis.


Lactobacillus reuteri protects epidermal keratinocytes from Staphylococcus aureus-induced cell death by competitive exclusion.
Recent studies have suggested that the topical application of probiotic bacteria can improve skin health or combat disease. We have utilized a primary human keratinocyte culture model to investigate whether probiotic bacteria can inhibit Staphylococcus aureus infection. Evaluation of the candidate probiotics Lactobacillus reuteri ATCC 55730, Lactobacillus rhamnosus AC413, and Lactobacillus salivarius UCC118 demonstrated that both L. reuteri and L. rhamnosus, but not L. salivarius, reduced S. aureus-induced keratinocyte cell death in both undifferentiated and differentiated keratinocytes. Keratinocyte survival was significantly higher if the probiotic was applied prior to (P < 0.01) or simultaneously with (P < 0.01) infection with S. aureus but not when added after infection had commenced (P > 0.05). The protective effect of L. reuteri was not dependent on the elaboration of inhibitory substances such as lactic acid. L. reuteri inhibited adherence of S. aureus to keratinocytes by competitive exclusion (P = 0.026). L. salivarius UCC118, however, did not inhibit S. aureus from adhering to keratinocytes (P > 0.05) and did not protect keratinocyte viability. S. aureus utilizes the α5β1 integrin to adhere to keratinocytes, and blocking of this integrin resulted in a protective effect similar to that observed with probiotics (P = 0.03). This suggests that the protective mechanism for L. reuteri-mediated protection of keratinocytes was by competitive exclusion of the pathogen from its binding sites on the cells. Our results suggest that use of a topical probiotic prophylactically could inhibit the colonization of skin by S. aureus and thus aid in the prevention of infection.


Trafficking defects and loss of ligand binding are the underlying causes of all reported DDR2 missense mutations found in SMED-SL patients.
Spondylo-meta-epiphyseal dysplasia (SMED) with short limbs and abnormal calcifications (SMED-SL) is a rare, autosomal recessive human growth disorder, characterized by disproportionate short stature, short limbs, short broad fingers, abnormal metaphyses and epiphyses, platyspondyly and premature calcifications. Recently, three missense mutations and one splice-site mutation in the DDR2 gene were identified as causative genetic defects for SMED-SL, but the underlying cellular and biochemical mechanisms were not explored. Here we report a novel DDR2 missense mutation, c.337G>A (p.E113K), that causes SMED-SL in two siblings in the United Arab Emirates. Another DDR2 missense mutation, c.2254C>T (p.R752C), matching one of the previously reported SMED-SL mutations, was found in a second affected family. DDR2 is a plasma membrane receptor tyrosine kinase that functions as a collagen receptor. We expressed DDR2 constructs with the identified point mutations in human cell lines and evaluated their localization and functional properties. We found that all SMED-SL missense mutants were defective in collagen-induced receptor activation and that the three previously reported mutants (p.T713I, p.I726R and p.R752C) were retained in the endoplasmic reticulum. The novel mutant (p.E113K), in contrast, trafficked normally, like wild-type DDR2, but failed to bind collagen. This finding is in agreement with our recent structural data identifying Glu113 as an important amino acid in the DDR2 ligand-binding site. Our data thus demonstrate that SMED-SL can result from at least two different loss-of-function mechanisms: namely defects in DDR2 targeting to the plasma membrane or the loss of its ligand-binding activity.


Subcellular distribution of di-(2-ethylhexyl)phthalate in rat testis.
Subcellular distribution of di-(2-ethylhexyl)phthalate (DEHP) in the testis was studied by single oral administration of [3,4,5,6-(3)H]-phthalic acid di-(2-ethylhexyl) ester (DEHP-3H) or phthalic acid di-(2-ethyl[1-(3)H]hexyl) ester (3H-DEHP) to 8-week-old male rats. Autoradiographs and electron microscopic autoradiographs were prepared from the testis, liver and kidney at 6 and 24 hr after administration and distribution of radioactive materials in the tissues were observed. In the autoradiographic specimen at 6 hr after administration of DEHP 3H-labeled at phthalic acid moiety (DEHP-3H), many grains were observed in the testis, mainly at the basal area of seminiferous tubules at the stages IX to I of the spermatogenic cycle. Electron microscopic autoradiographs taken at the same time revealed that localization of grains were in the smooth-surfaced endoplasmic reticulum and mitochondria of Sertoli cells. A few grains were also present at the Golgi apparatus and lysosome of Sertoli cells, and at the interfaces between the Sertoli cells or between Sertoli cells and spermatocytes, and in the cytoplasm of spermatocytes. Autoradiographs of the liver revealed grains in the centrilobular hepatocytes, localized at mitochondria, rough-surfaced endoplasmic reticulum and peroxisomes. In the kidney, the radioactivity was localized at the brush border of the tubular cells in the pars recta of proximal tubules. In the 24-hr specimen, the grain density in the seminiferous tubules obviously decreased. On the other hand, by autoradiography with DEHP 3H-labeled at the alcohol (3H-DEHP), only a few grains were observed in autoradiographs of the testes at 6 hr after administration. No grains were noted in autoradiographs of the liver and kidney with 3H-DEHP. The results showed that the phthalic acid ester was splitted rapidly in the body and only the phthalic acid moiety distributed into the cells.


Cancer biomarker discovery and translation: proteomics and beyond.
Cancer is often diagnosed at late stages when the chance of cure is relatively low and although research initiatives in oncology discover many potential cancer biomarkers, few transition to clinical applications. This review addresses the current landscape of cancer biomarker discovery and translation with a focus on proteomics and beyond. Areas covered: The review examines proteomic and genomic techniques for cancer biomarker detection and outlines advantages and challenges of integrating multiple omics approaches to achieve optimal sensitivity and address tumor heterogeneity. This discussion is based on a systematic literature review and direct participation in translational studies. Expert commentary: Identifying aggressive cancers early on requires improved sensitivity and implementation of biomarkers representative of tumor heterogeneity. During the last decade of genomic and proteomic research, significant advancements have been made in next generation sequencing and mass spectrometry techniques. This in turn has led to a dramatic increase in identification of potential genomic and proteomic cancer biomarkers. However, limited successes have been shown with translation of these discoveries into clinical practice. We believe that the integration of these omics approaches is the most promising molecular tool for comprehensive cancer evaluation, early detection and transition to Precision Medicine in oncology.


Investigating an in silico approach for prioritizing antidepressant drug prescription based on drug-induced expression profiles and predicted gene expression.
In clinical practice, an antidepressant prescription is a trial and error approach, which is time consuming and discomforting for patients. This study investigated an in silico approach for ranking antidepressants based on their hypothetical likelihood of efficacy. We predicted the transcriptomic profile of citalopram remitters by performing an in silico transcriptomic-wide association study on STAR*D GWAS data (N = 1163). The transcriptional profile of remitters was compared with 21 antidepressant-induced gene expression profiles in five human cell lines available in the connectivity-map database. Spearman correlation, Pearson correlation, and the Kolmogorov-Smirnov test were used to determine the similarity between antidepressant-induced profiles and remitter profiles, subsequently calculating the average rank of antidepressants across the three methods and a p value for each rank by using a permutation procedure. The drugs with the top ranks were those having a high positive correlation with the expression profiles of remitters and that may have higher chances of efficacy in the tested patients. In MCF7 (breast cancer cell line), escitalopram had the highest average rank, with an average rank higher than expected by chance (p = 0.0014). In A375 (human melanoma) and PC3 (prostate cancer) cell lines, escitalopram and citalopram emerged as the second-highest ranked antidepressants, respectively (p = 0.0310 and 0.0276, respectively). In HA1E (kidney) and HT29 (colon cancer) cell types, citalopram and escitalopram did not fall among top antidepressants. The correlation between citalopram remitters' and (es)citalopram-induced expression profiles in three cell lines suggests that our approach may be useful and with future improvements, it can be applicable at the individual level to tailor treatment prescription.


Noise, multisensory integration, and previous response in perceptual disambiguation.
Sensory information about the state of the world is generally ambiguous. Understanding how the nervous system resolves such ambiguities to infer the actual state of the world is a central quest for sensory neuroscience. However, the computational principles of perceptual disambiguation are still poorly understood: What drives perceptual decision-making between multiple equally valid solutions? Here we investigate how humans gather and combine sensory information-within and across modalities-to disambiguate motion perception in an ambiguous audiovisual display, where two moving stimuli could appear as either streaming through, or bouncing off each other. By combining psychophysical classification tasks with reverse correlation analyses, we identified the particular spatiotemporal stimulus patterns that elicit a stream or a bounce percept, respectively. From that, we developed and tested a computational model for uni- and multi-sensory perceptual disambiguation that tightly replicates human performance. Specifically, disambiguation relies on knowledge of prototypical bouncing events that contain characteristic patterns of motion energy in the dynamic visual display. Next, the visual information is linearly integrated with auditory cues and prior knowledge about the history of recent perceptual interpretations. What is more, we demonstrate that perceptual decision-making with ambiguous displays is systematically driven by noise, whose random patterns not only promote alternation, but also provide signal-like information that biases perception in highly predictable fashion.


Too much or too little? A short-term longitudinal study of youth's own economic resources and risk behaviour.
This study examined socioeconomic differences in risk behaviours according to youth-oriented measures of economic resources. Using a representative sample of Swedish adolescents (n = 3,939, 51% females), the associations that youth's own economy shared with smoking, drinking and conduct problems were examined. Data was based on population register and self-report information when participants were in grades 8 (T1 aged 14-15) and 9 (T2 aged 15-16). Missing activities due to financial constraints and having a cash margin were each positively associated with concurrent risk behaviours. However, longitudinal analyses showed that missing activities only increased the likelihood of conduct problems and having a cash margin only increased the likelihood of drinking one-year later. The results demonstrate that youth-oriented conceptualisations of economic resources identify gradients in drinking, smoking and conduct problems that are distinct from family socioeconomic status. However, adolescents' absolute and relative economic resources are associated with risk behaviours in opposite directions.


Cell type-specific transcriptome of Brassicaceae stigmatic papilla cells from a combination of laser microdissection and RNA sequencing.
Pollination is an early and critical step in plant reproduction, leading to successful fertilization. It consists of many sequential processes, including adhesion of pollen grains onto the surface of stigmatic papilla cells, foot formation to strengthen pollen-stigma interaction, pollen hydration and germination, and pollen tube elongation and penetration. We have focused on an examination of the expressed genes in papilla cells, to increase understanding of the molecular systems of pollination. From three representative species of Brassicaceae (Arabidopsis thaliana, A. halleri and Brassica rapa), stigmatic papilla cells were isolated precisely by laser microdissection, and cell type-specific gene expression in papilla cells was determined by RNA sequencing. As a result, 17,240, 19,260 and 21,026 unigenes were defined in papilla cells of A. thaliana, A. halleri and B. rapa, respectively, and, among these, 12,311 genes were common to all three species. Among the17,240 genes predicted in A. thaliana, one-third were papilla specific while approximately half of the genes were detected in all tissues examined. Bioinformatics analysis revealed that genes related to a wide range of reproduction and development functions are expressed in papilla cells, particularly metabolism, transcription and membrane-mediated information exchange. These results reflect the conserved features of general cellular function and also the specific reproductive role of papilla cells, highlighting a complex cellular system regulated by a diverse range of molecules in these cells. This study provides fundamental biological knowledge to dissect the molecular mechanisms of pollination in papilla cells and will shed light on our understanding of plant reproduction mechanisms.


[Risk factors for cervico-uterine cancer in women in Zacatecas].
To determine the sociodemographic characteristics and the reproductive and sexual behavior of participants in the Cervical Cancer Prevention and Control Program and to identify the risk factors for this neoplasm. A case control study was performed among participants in the Cervical Cancer Prevention and Control Program in the state of Zacatecas. The cases consisted of all patients diagnosed and corroborated by histopathology with CIN III and invasive carcinoma of the uterine cervix (251) who were referred to the Dysplasia Clinic (within the same program), during 1993-1995. Controls were women randomly selected from the population which participates in this program, who had negative cervical cytology. One control was selected for each case and paired by age and date, simultaneous to the cervical cytology. Risk of cervical cancer was higher in women with greater number of pregnancies (more than 12 pregnancies) than in women with less than 3 (OR 5.2, CI 95% 2.6-10.5). This is also true of women with greater number of births (12 or more) who have a risk five times higher than women with less than 3. Beginning sexual activity at an early age was associated to the risk of cervical cancer; women who began their sexual activity after the age of 19 had a risk two times lower than those who started before the age of 15. The use of oral contraceptives increased the risk of cervical cancer in relation to the use of non-hormonal contraceptives (OR 1.9, CI 95% 1.3-3.4). In the present study, the risk factors for cervical cancer in the population participating in the prevention and control program were higher in women with high parity, who began sexual activity at an early age and/or who consumed oral contraceptives.


The impact of spike-frequency adaptation on balanced network dynamics.
A dynamic balance between strong excitatory and inhibitory neuronal inputs is hypothesized to play a pivotal role in information processing in the brain. While there is evidence of the existence of a balanced operating regime in several cortical areas and idealized neuronal network models, it is important for the theory of balanced networks to be reconciled with more physiological neuronal modeling assumptions. In this work, we examine the impact of spike-frequency adaptation, observed widely across neurons in the brain, on balanced dynamics. We incorporate adaptation into binary and integrate-and-fire neuronal network models, analyzing the theoretical effect of adaptation in the large network limit and performing an extensive numerical investigation of the model adaptation parameter space. Our analysis demonstrates that balance is well preserved for moderate adaptation strength even if the entire network exhibits adaptation. In the common physiological case in which only excitatory neurons undergo adaptation, we show that the balanced operating regime in fact widens relative to the non-adaptive case. We hypothesize that spike-frequency adaptation may have been selected through evolution to robustly facilitate balanced dynamics across diverse cognitive operating states.


CcNav: Understanding Compiler Optimizations in Binary Code.
Program developers spend significant time on optimizing and tuning programs. During this iterative process, they apply optimizations, analyze the resulting code, and modify the compilation until they are satisfied. Understanding what the compiler did with the code is crucial to this process but is very time-consuming and labor-intensive. Users need to navigate through thousands of lines of binary code and correlate it to source code concepts to understand the results of the compilation and to identify optimizations. We present a design study in collaboration with program developers and performance analysts. Our collaborators work with various artifacts related to the program such as binary code, source code, control flow graphs, and call graphs. Through interviews, feedback, and pair-analytics sessions, we analyzed their tasks and workflow. Based on this task analysis and through a human-centric design process, we designed a visual analytics system Compilation Navigator (CcNav) to aid exploration of the effects of compiler optimizations on the program. CcNav provides a streamlined workflow and a unified context that integrates disparate artifacts. CcNav supports consistent interactions across all the artifacts making it easy to correlate binary code with source code concepts. CcNav enables users to navigate and filter large binary code to identify and summarize optimizations such as inlining, vectorization, loop unrolling, and code hoisting. We evaluate CcNav through guided sessions and semi-structured interviews. We reflect on our design process, particularly the immersive elements, and on the transferability of design studies through our experience with a previous design study on program analysis.


A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia.
Intratumoral heterogeneity is a common feature of many myeloid leukemias and a significant reason for treatment failure and relapse. Thus, identifying the cells responsible for residual disease and leukemia re-growth is critical to better understanding how they are regulated. Here, we show that a knock-in reporter mouse for the stem cell gene Musashi 2 (Msi2) allows identification of leukemia stem cells in aggressive myeloid malignancies, and provides a strategy for defining their core dependencies. Specifically, we carry out a high throughput screen using Msi2-reporter blast crisis chronic myeloid leukemia (bcCML) and identify several adhesion molecules that are preferentially expressed in therapy resistant bcCML cells and play a key role in bcCML. In particular, we focus on syndecan-1, whose deletion triggers defects in bcCML growth and propagation and markedly improves survival of transplanted mice. Further, live imaging reveals that the spatiotemporal dynamics of leukemia cells are critically dependent on syndecan signaling, as loss of this signal impairs their localization, migration and dissemination to distant sites. Finally, at a molecular level, syndecan loss directly impairs integrin β7 function, suggesting that syndecan exerts its influence, at least in part, by coordinating integrin activity in bcCML. These data present a platform for delineating the biological underpinnings of leukemia stem cell function, and highlight the Sdc1-Itgβ7 signaling axis as a key regulatory control point for bcCML growth and dissemination.


Pituitary adenylate cyclase-activating peptide (PACAP): assessment of dipeptidyl peptidase IV degradation, insulin-releasing activity and antidiabetic potential.
Pituitary adenylate cyclase-activating peptide (PACAP) is a member of the glucagon family of peptides. Like other members, most notably glucagon-like peptide-1 (GLP-1), PACAP is rapidly degraded by dipeptidylpeptidase IV (DPP IV). This study investigated how degradation by DPP IV affected the insulinotropic activity of PACAP, and whether PACAP exerted acute antihyperglycemic properties in normal or ob/ob mice. DPP IV degradation of PACAP(1-27) over 18 h led to the formation of PACAP(3-27), PACAP(5-27) and ultimately PACAP(6-27). In contrast to 1.4-1.8-fold concentration-dependent stimulation of insulin secretion by PACAP(1-27), these peptide fragments lacked insulinotropic activity. While PACAP(1-27) and PACAP(1-38) generated significant insulin responses when given alone or together with glucose in ob/ob and normal mice, they also elevated plasma glucose. These actions were eliminated following degradation of the peptide by incubation with DPP IV. The hyperglycemic effects may be explained at least partly by a potent glucagon-releasing action in ob/ob and normal mice. In conclusion, PACAP is inactivated by DPP IV and despite insulin-releasing effects, its actions on glucagon secretion and glucose homeostasis do not make it a good therapeutic tool for the treatment of type 2 diabetes.


Embryological aspects of inducible morphological defenses in Daphnia.
Many cases of predator-induced morphological plasticity in daphnids are well studied examples of inducible defenses. However, little is known about the early development of these sometimes conspicuous traits. We compared for the first time in five different Daphnia species the embryonic development of predator-induced and noninduced animals using scanning electron microscopy (SEM). We observed significant morphological changes in the last embryonic stage in helmet formation in Daphnia cucullata and in neck-pedestal development in Daphnia pulex. In contrast, no morphological changes could be found during embryogenesis between induced and noninduced Daphnia lumholtzi, D. longicephala, and D. ambigua. Strategies for initiating the defensive traits differ among Daphnia species because of trade-offs between environmental requirements and developmental constraints. Some general features of Daphnia embryonic development are described using SEM. All Daphnia embryos have to shed at least three different membranes before leaving the brood pouch of the mother. After the embryos shed the third membrane, chemosensillae that are likely able to detect predator-released chemicals are exposed to the olfactory environment.


Perceived climate in physical activity settings.
This study focused on the perceived climate for LGBT youth and other minority groups in physical activity settings. A large sample of undergraduates and a selected sample including student teachers/interns and a campus Pride group completed a school climate survey and rated the climate in three physical activity settings (physical education, organized sport, exercise). Overall, school climate survey results paralleled the results with national samples revealing high levels of homophobic remarks and low levels of intervention. Physical activity climate ratings were mid-range, but multivariate analysis of variation test (MANOVA) revealed clear differences with all settings rated more inclusive for racial/ethnic minorities and most exclusive for gays/lesbians and people with disabilities. The results are in line with national surveys and research suggesting sexual orientation and physical characteristics are often the basis for harassment and exclusion in sport and physical activity. The current results also indicate that future physical activity professionals recognize exclusion, suggesting they could benefit from programs that move beyond awareness to skills and strategies for creating more inclusive programs.


Adenosine analogs and sleep in rats.
The effects of N6-L-(phenylisopropyl)adenosine, cyclohexyladenosine and adenosine-5'-N-ethylcarboxamide on sleep were examined in rats. These effects consist of 1) increased slow-wave sleep2 from 6.6 to 45.7%, in all doses used for cyclohexyladenosine and adenosine-5'-N-ethylcarboxamide and for 0.1 and 0.3 mumol/kg of N6-L-(phenylisopropyl)adenosine and 2) increased values for rapid-eye-movement-sleep, amounting to 56.2 and 51.6% for 0.1 mumol/kg of cyclohexyl-adenosine and 0.3 mumol/kg of N6-L-(phenylisopropyl)adenosine, respectively. Slow-wave sleep1 decreased but values for wakefulness and total sleep were unchanged for 0.03, 0.1 and 0.3-mumol/kg doses of the drugs. Only 0.9-mumol/kg dose of cyclohexyladenosine and N6-L-(phenylisopropyl)adenosine increased wakefulness and decreased total sleep, whereas the same dose of adenosine-5'-N-ethylcarboxamide increased total sleep during the 0- to 3-hr time interval. All three agents reduced rapid-eye-movement sleep at the 0.9-mumol/kg dose. The results indicate that the effect on sleep of all three adenosine analogs was obtained with nanomolar doses of the drugs and that it diminished or disappeared when the drug dose reached micromolar range (0.9 mumol/kg). It appears, therefore, that activation of A1 rather than A2 receptors contributed to the sleep effects of the drugs because adenosine and adenosine analogs activate A1 receptors in nanomolar quantities whereas activation of A2 receptors requires micromolar concentration of these compounds.(ABSTRACT TRUNCATED AT 250 WORDS)


Accessory cell function of human eosinophils. HLA-DR-dependent, MHC-restricted antigen-presentation and IL-1 alpha expression.
Although peripheral blood eosinophils express little of the class II MHC protein, HLA-DR, eosinophils could be induced to express HLA-DR by exposures to cytokines, including granulocyte-macrophage-CSF, IL-4, and IFN-gamma, with granulocyte-macrophage-CSF eliciting the greatest level of HLA-DR expression as assessed by flow cytometry. The capacity of HLA-DR+ eosinophils to function as APC was evaluated with blood eosinophils isolated free of mononuclear cells, cultured with granulocyte-macrophage-CSF to induce HLA-DR expression and then exposed to the Ag tetanus toxoid. HLA-DR+ eosinophils fixed with paraformaldehyde after Ag exposure stimulated T cell proliferation, whereas HLA-DR+ eosinophils fixed with paraformaldehyde before Ag exposure failed to stimulate lymphocyte proliferation. The lymphocyte proliferative responses elicited by Ag-pulsed HLA-DR+ eosinophils were inhibited by anti-HLA-DR mAb and were restricted to HLA-DR compatible lymphocytes. Moreover, eosinophils from a hypereosinophilic donor, both before and more prominently after stimulation with PMA, contained transcripts for IL-1-alpha mRNA detectable by Northern blot hybridization and in situ hybridization and expressed IL-1-alpha protein detectable by immunohistochemistry. These findings indicate that human eosinophils can process Ag, express the costimulatory cytokine IL-1-alpha, and after cytokine-elicited induction of HLA-DR expression can function as HLA-DR-dependent, MHC-restricted APC in stimulating T lymphocyte responses.


Malignant struma ovarii: surgical, histopathological and survival outcomes for thyroid-type carcinoma of struma ovarii with recommendations for standardising multi-modal management. A retrospective case series sharing the experience of a single institution over 10 years.
Struma ovarii is rare, accounting for 0.3-1% of ovarian tumours. Malignant transformation may occur, most often into papillary thyroid carcinoma. There is a paucity of data pertaining to malignant struma ovarii. This paper shares a decade of experience of a single institution in the management of this rare ovarian cancer, exploring the characteristics of this tumour and suggesting a standardised approach to treatment and follow-up. All patients treated for malignant struma ovarii within a large cancer centre over one decade were identified and data collected retrospectively on presentation, diagnosis, management, follow-up and survival outcomes. A literature review was also undertaken. Eleven cases of malignant struma ovarii were managed in the Oxford Cancer Centre between 2010 and 2019, 6 of which were of papillary thyroid carcinoma sub-type. No cases were correctly diagnosed pre-operatively. All patients had stage I disease and were managed surgically-but with variation in radicality. Patients identified as high-risk based on final histopathology underwent additional thyroidectomy and radio-active iodine ablation therapy. One case of synchronous malignancy of the thyroid gland proper was identified. No disease recurrence occurred. Malignant struma ovarii present a diagnostic challenge. Multi-disciplinary team (MDT) input is essential. Unilateral salpingo-oophrectomy may be adequate if stage I; reserving more radical surgery for advanced disease. Histopathological risk-stratification should be used to identify those most likely to benefit from adjuvant thyroid-targeting therapies. Patients require follow-up, anticipating an overall good prognosis.


Microbial nitrogen dynamics in organic and mineral soil horizons along a latitudinal transect in western Siberia.
Soil N availability is constrained by the breakdown of N-containing polymers such as proteins to oligopeptides and amino acids that can be taken up by plants and microorganisms. Excess N is released from microbial cells as ammonium (N mineralization), which in turn can serve as substrate for nitrification. According to stoichiometric theory, N mineralization and nitrification are expected to increase in relation to protein depolymerization with decreasing N limitation, and thus from higher to lower latitudes and from topsoils to subsoils. To test these hypotheses, we compared gross rates of protein depolymerization, N mineralization and nitrification (determined using 15N pool dilution assays) in organic topsoil, mineral topsoil, and mineral subsoil of seven ecosystems along a latitudinal transect in western Siberia, from tundra (67°N) to steppe (54°N). The investigated ecosystems differed strongly in N transformation rates, with highest protein depolymerization and N mineralization rates in middle and southern taiga. All N transformation rates decreased with soil depth following the decrease in organic matter content. Related to protein depolymerization, N mineralization and nitrification were significantly higher in mineral than in organic horizons, supporting a decrease in microbial N limitation with depth. In contrast, we did not find indications for a decrease in microbial N limitation from arctic to temperate ecosystems along the transect. Our findings thus challenge the perception of ubiquitous N limitation at high latitudes, but suggest a transition from N to C limitation of microorganisms with soil depth, even in high-latitude systems such as tundra and boreal forest. We compared soil N dynamics of seven ecosystems along a latitudinal transectShifts in N dynamics suggest a decrease in microbial N limitation with depthWe found no decrease in microbial N limitation from arctic to temperate zones.


HESX1- and TCF3-mediated repression of Wnt/β-catenin targets is required for normal development of the anterior forebrain.
The Wnt/β-catenin pathway plays an essential role during regionalisation of the vertebrate neural plate and its inhibition in the most anterior neural ectoderm is required for normal forebrain development. Hesx1 is a conserved vertebrate-specific transcription factor that is required for forebrain development in Xenopus, mice and humans. Mouse embryos deficient for Hesx1 exhibit a variable degree of forebrain defects, but the molecular mechanisms underlying these defects are not fully understood. Here, we show that injection of a hesx1 morpholino into a 'sensitised' zygotic headless (tcf3) mutant background leads to severe forebrain and eye defects, suggesting an interaction between Hesx1 and the Wnt pathway during zebrafish forebrain development. Consistent with a requirement for Wnt signalling repression, we highlight a synergistic gene dosage-dependent interaction between Hesx1 and Tcf3, a transcriptional repressor of Wnt target genes, to maintain anterior forebrain identity during mouse embryogenesis. In addition, we reveal that Tcf3 is essential within the neural ectoderm to maintain anterior character and that its interaction with Hesx1 ensures the repression of Wnt targets in the developing forebrain. By employing a conditional loss-of-function approach in mouse, we demonstrate that deletion of β-catenin, and concomitant reduction of Wnt signalling in the developing anterior forebrain of Hesx1-deficient embryos, leads to a significant rescue of the forebrain defects. Finally, transcriptional profiling of anterior forebrain precursors from mouse embryos expressing eGFP from the Hesx1 locus provides molecular evidence supporting a novel function of Hesx1 in mediating repression of Wnt/β-catenin target activation in the developing forebrain.


Evaluating changeability to improve fruit and vegetable intake among school aged children.
The purposes of this paper are two fold. First, to describe an approach used to identify fruits and vegetables to target for a child focused dietary change intervention. Second, to evaluate the concept of fruit and vegetable changeability and feasibility of applying it in a community setting. Steps for identifying changeable fruits and vegetables include (1) identifying a dietary database (2) defining geographic and (3) personal demographics that characterize the food environment and (4) determining which fruits and vegetables are likely to improve during an intervention. The validity of these methods are evaluated for credibility using data collected from quasi-experimental, controlled design among 7-9 year old children (n = 304) participating in a tutoring or mentoring program in St. Louis, MO. Using a 28-item food frequency questionnaire, parents were asked to recall for their child how often foods were eaten the past 7 days. This questionnaire was repeated eight months later (response rate 84%). T-test analyses are used to determine mean serving differences from baseline to post test. The mean serving differences from baseline to post test were significant for moderately eaten fruits (p < .001), however, not for vegetables (p = .312). Among the intervention group, significantly more children ate grapes (p < .001), peaches (p = .022), cantaloupe (p < .001), and spinach (p = .044) at post testing - all identified as changeable with information tailored to participants. Data driven, food focused interventions directed at a priority population are feasible and practical. An empirical evaluation of the assumptions associated with these methods supports this novel approach. However, results may indicate that these methods may be more relevant to fruits than vegetables. This process can be applied to diverse populations for many dietary outcomes. Intervention strategies that target only those changeable fruits and vegetables are innovative and warrant further study.


Once fat was fat and that was that: our changing perspectives on adipose tissue.
Past civilisations saw excess body fat as a symbol of wealth and prosperity as the general population struggled with food shortages and famine. Nowadays it is recognised that obesity is associated with co-morbidities such as cardiovascular disease and diabetes. Our views on the roll of adipose tissue have also changed, from being solely a passive energy store, to an important endocrine organ that modulates metabolism, immunity and satiety. The relationship between increased visceral adiposity and obesity-related co-morbidities has lead to the recognition that variation in fat distribution contributes to ethnic differences in the prevalence of obesity-related diseases. Our current negative view of adipose tissue may change with the use of pluripotent adipose-derived stromal cells, which may lead to future autologous stem cell therapies for bone, muscle, cardiac and cartilage disorders. Here, we briefly review the concepts that adipose tissue is an endocrine organ, that differences in body fat distribution underline the aetiology of obesity-related co-morbidities, and the use of adipose-derived stem cells for future therapies.


3dLOGO: a web server for the identification, analysis and use of conserved protein substructures.
3dLOGO is a web server for the identification and analysis of conserved protein 3D substructures. Given a set of residues in a PDB (Protein Data Bank) chain, the server detects the matching substructure(s) in a set of user-provided protein structures, generates a multiple structure alignment centered on the input substructures and highlights other residues whose structural conservation becomes evident after the defined superposition. Conserved residues are proposed to the user for highlighting functional areas, deriving refined structural motifs or building sequence patterns. Residue structural conservation can be visualized through an expressly designed Java application, 3dProLogo, which is a 3D implementation of a sequence logo. The 3dLOGO server, with related documentation, is available at http://3dlogo.uniroma2.it/


Parathyroid-responsive modifications in the nuclear matrix of ROS 17/2.8 rat osteosarcoma cells.
PTH is a mediator of skeletal development and remodeling that influences gene expression in osteoblastic cells. It is well established that PTH modulates the activity of membrane-associated second messenger signal transduction pathways. In these studies we have addressed the potential contribution of components of cell structure to the integration of PTH-related regulatory signals that influence the expression of bone cell genes. Chronic treatment of ROS 17/2.8 rat osteosarcoma cells with PTH is accompanied by changes in gene expression that are at least in part transcriptionally controlled. To explore the involvement of nuclear architecture in PTH-responsive modifications in gene expression, we investigated changes in the nuclear matrix after PTH treatment. Consistent with a role for the nuclear matrix in determining spatial organization and topology of chromatin as well as in the localization and targeting of transcription factors, we observed PTH-associated changes in a 200-kilodalton nuclear matrix protein in response to PTH. A significant down-regulation of synthesis was observed when nuclear matrix proteins were resolved electrophoretically in two-dimensional gels. This protein was restricted to the nuclear matrix and was not detected in the chromatin or cytoskeletal cellular fractions. These alterations in nuclear matrix proteins that occur after PTH treatment in osteosarcoma cells were phenotype related. They did not occur in UMR-106 POL or H4 hepatoma cells. Our findings support a role for the nuclear matrix in transducing PTH-mediated regulatory signals to facilitate the extent to which genes in osteoblasts are transcribed.


Anomalous left main coronary artery origin from the right sinus of Valsalva: a novel echocardiographic screening method.
Anomalous origin of the left main coronary artery from the right sinus (ALMCA) is a rare entity associated with an increased risk for sudden cardiac death. Although transthoracic echocardiography often is the primary screening tool for the diagnosis, its accuracy remains undefined, resulting in the use of more expensive methods such as cardiac catheterization and magnetic resonance imaging when clinical suspicion exists. This report aims to describe a novel echocardiographic screening method for detecting ALMCA and to apply it retrospectively for patients with confirmed findings intraoperatively and/or on autopsy. All patients with a confirmed diagnosis of ALMCA who presented to our institution from 2004 to 2012 were included in the study. Eight patients had adequate images, including two patients with an initial diagnosis of normal coronary origins. A control group consisted of 35 patients with normal coronaries shown by echocardiogram. Five of these patients had normal coronary artery origins confirmed by magnetic resonance imaging (MRI). Echocardiographic images were reviewed, and the left main coronary was identified in the parasternal long-axis view between the aorta and pulmonary trunk. The angle of the left main coronary course was measured. In patients with ALMCA, the proximal course of the vessel was steeper as it coursed posteriorly. In contrast, the course was almost horizontal in patients with normal coronary origins. Based on these findings, a cutoff angle of 28° is proposed. In the parasternal long-axis view, ALMCA can be identified by its anomalous proximal course. This screening method is reliable and increases the accuracy of transthoracic echocardiograms.


Biofouling community composition across a range of environmental conditions and geographical locations suitable for floating marine renewable energy generation.
Knowledge of biofouling typical of marine structures is essential for engineers to define appropriate loading criteria in addition to informing other stakeholders about the ecological implications of creating novel artificial environments. There is a lack of information regarding biofouling community composition (including weight and density characteristics) on floating structures associated with future marine renewable energy generation technologies. A network of navigation buoys were identified across a range of geographical areas, environmental conditions (tidal flow speed, temperature and salinity), and deployment durations suitable for future developments. Despite the perceived importance of environmental and temporal factors, geographical location explained the greatest proportion of the observed variation in community composition, emphasising the importance of considering geography when assessing the impact of biofouling on device functioning and associated ecology. The principal taxa associated with variation in biofouling community composition were mussels (Mytilus edulis), which were also important when determining loading criteria.


The challenge of measuring quality of care at health centre level in Africa: the example of Tsholotsho health district in Matabeleland North, Zimbabwe.
This study is on the evaluation of quality of health care within first line health services in rural Zimbabwe. It took place between 2001 and 2002, and consisted of a cross-sectional survey designed to compare the quality of health care on offer at a newly created health centre with that provided by the district hospital's outpatient department. The hypothesis to be tested was that the health centre offered better quality of care. A comprehensive quality of care evaluation framework was designed. The concept of patient enablement was incorporated into the study's assessment of health care delivery outcomes. The results did not provide conclusive evidence that the care offered at the health centre was better than the care on offer at the hospital OPD. The reasons for these unexpected findings are discussed in depth. They are related to the limited understanding amongst local health workers of the organisational changes introduced by the District Health Executive (DHE), together with a (European) cultural bias in the quality of care model under test. An important lesson of this study is that the notion of enablement, notwithstanding the need to put into context the tools used to measure it, was considered by the DHE as relevant in the organisation and evaluation of health care.


Correlation between circulating osteopontin level in systemic lupus erythematosus and disease activity and associations between osteopontin polymorphisms and disease susceptibility: A meta-analysis.
Objective This study aimed to systemically review the evidence regarding the relationship between circulating blood osteopontin (OPN) level and systemic lupus erythematosus (SLE), correlation between serum OPN levels and SLE activity, and association between OPN polymorphisms and SLE susceptibility. Methods We conducted a meta-analysis on the serum/plasma OPN levels in SLE patients and healthy controls, correlation coefficients between the circulating OPN level and SLE Disease Activity Index (SLEDAI) in SLE patients, and the association between OPN polymorphisms and SLE risk. Results Nine studies with 1938 SLE patients and 3037 controls were included. Meta-analysis revealed that, compared with the control group, the OPN level was significantly higher in the SLE group (SMD = 0.965, 95% CI = 0.337-1.393, p = 0.001) and in the SLE group with renal disease (SMD = 2.219, 95% CI = 0.681-3.757, p = 0.005). Meta-analysis of correlation coefficients showed a trend of positive correlation between the circulating OPN level and SLEDAI (correlation coefficient = 0.590, 95% CI = -0.025 to 0.881, p = 0.059). While no association was found between SLE and the OPN 707 T/C and 1083 G/A polymorphisms, a significant association was identified between the OPN 1239 C allele and SLE (OR = 1.192, 95% CI = 1.008-1.410, p = 0.040), and between the OPN 9250 C allele and SLE in Asians (OR = 2.070, 95% CI = 1.570-2.730, p = 2.5 × 10-7). Conclusions Our meta-analysis revealed a significantly higher circulating OPN level in SLE patients, a trend of positive correlation between OPN levels and SLE activity, and a significant association between OPN 1239 C/A and 9250 C/T polymorphisms, and SLE development.


Participative development of packages in the food industry--evaluation of ergonomics and productivity by objective measurements.
Rationalizations generally have a negative effect on health and known risk factors for musculoskeletal disorders. These effects may be reduced by paying attention to modifiers as worker participation and a resonant management style. In this study a participatory approach was used in the food industry in order to improve ergonomics and productivity. The food industry shows a high prevalence of musculoskeletal disorders, and repetitive manual work occurs extensively. Prototypes of new packaging solutions were developed in three cases, and compared in a simulated production to the existing production system through direct measurements of working postures and muscle activity, ratings of physical load, and general productivity data. Measured and rated ergonomic exposures showed that workload was significantly lower for the prototypes, in all three cases. In two cases, the number of handling operations included in the packaging operations were greatly reduced with the prototype package, as were production costs. The impact on disorders of the obtained load reductions is difficult to assess, but we believe that in "critical" situations like this, even small improvements may have an effect. This study shows that workloads during manual handling of packages as well as production costs can be reduced by applying participative development of packages.


Barriers and Facilitators Associated with the Adoption of and Adherence to a Mediterranean Style Diet in Adults: A Systematic Review of Published Observational and Qualitative Studies.
The Mediterranean diet (MedDiet) has been linked with physical and mental health benefits. Previous research, however, suggests that adoption and adherence to a Mediterranean diet might be difficult for people who live outside of the Mediterranean region. The aim of this systematic review was to investigate the factors that influence adoption and adherence to a Mediterranean style diet in adults aged 18 years old and over, as identified in published observational and qualitative studies. Following registration of our protocol on PROSPERO (ID: CRD42018116515), observational and qualitative studies of adults' perceptions and experiences relevant to following a Mediterranean style diet were identified using systematic searches of databases: MEDLINE, the Cochane Library, CINAHL, Web of Science and Scopus, over all years of records until February 2022. A narrative synthesis was then undertaken. Of 4559 retrieved articles, 18 studies fulfilled our inclusion criteria and were included. Factors influencing adoption and adherence to a MedDiet were identified and categorized as: financial, cognitive, socio-cultural, motivational, lifestyle, accessibility & availability, sensory & hedonic and demographic. Similar barriers and facilitators are often reported in relation to healthy eating or the consumption of specific healthy foods, with a few exceptions. These exceptions detailed concerns with specific components of the MedDiet; considerations due to culture and traditions, and concerns over a cooler climate. Suggestions for overcoming these barriers and facilitators specific to adoption and adherence to the Mediterranean diet are offered. These data will inform the development of future studies of robust methodology in eating behaviour change which offer pragmatic approaches for people to consume and maintain healthy diets.


Explaining income-related inequalities in doctor utilisation in Europe.
This paper presents new international comparative evidence on the factors driving inequalities in the use of GP and specialist services in 12 EU member states. The data are taken from the 1996 wave of the European Community Household Panel (ECHP). We examine two types of utilisation (the probability of a visit and the conditional number of positive visits) for two types of medical care: general practitioner and medical specialist visits using probit, truncated Negbin and generalised Negbin models. We find little or no evidence of income-related inequity in the probability of a GP visit in these countries. Conditional upon at least one visit, there is even evidence of a somewhat pro-poor distribution. By contrast, substantial pro-rich inequity emerges in virtually every country with respect to the probability of contacting a medical specialist. Despite their lower needs for such care, wealthier and higher educated individuals appear to be much more likely to see a specialist than the less well-off. This phenomenon is universal in Europe, but stronger in countries where either private insurance cover or private practice options are offered to purchase quicker and/or preferential access. Pro-rich inequity in subsequent visits adds to this access inequity but appears more related to regional disparities in utilisation than to other factors. Despite decades of universal and fairly comprehensive coverage in European countries, utilisation patterns suggest that rich and poor are not treated equally.


A dynamic warm-up model increases quadriceps strength and hamstring flexibility.
Research suggests that static stretching can negatively influence muscle strength and power and may result in decreased functional performance. The dynamic warm-up (DWU) is a common alternative to static stretching before physical activity, but there is limited research investigating the effects of a DWU. The purpose of this study was to compare the acute effects of a DWU and static stretching warm-up (SWU) on muscle flexibility, strength, and vertical jump using a randomized controlled trial design. Forty-five volunteers were randomly assigned into a control (CON), SWU, or DWU group. All participants rode a stationary bicycle for 5 minutes and completed a 10-minute warm-up protocol. During this protocol, the DWU group performed dynamic stretching and running, the SWU group performed static stretching, and the CON group rested. Dependent variables were measured immediately before and after the warm-up protocol. A digital inclinometer measured flexibility (degrees) for the hamstrings, quadriceps, and hip flexor muscles. An isokinetic dynamometer measured concentric and eccentric peak torque (N·m/kg) for the hamstrings and quadriceps. A force plate was used to measure vertical jump height (meters) and power (watts). In the DWU group, there was a significant increase in hamstring flexibility (pretest: 26.4 ± 13.5°, posttest: 16.9 ± 9.4°; p < .0001) and eccentric quadriceps peak torque (pretest: 2.49 ± 0.83 N·m/kg, posttest: 2.78 ± 0.69 N·m/kg; p = 0.04). The CON and SWU did not significantly affect any flexibility, strength, or vertical jump measures (p > 0.05). The DWU significantly improved eccentric quadriceps strength and hamstrings flexibility, whereas the SWU did not facilitate any positive or negative changes in muscle flexibility, strength, power, or vertical jump. Therefore, the DWU may be a better preactivity warm-up choice than an SWU.


Metabolic fingerprinting to understand therapeutic effects and mechanisms of silybin on acute liver damage in rat.
Metabolic fingerprinting is a rapid and noninvasive analysis, representing a powerful approach for the characterization of phenotypes and the distinction of specific metabolic states due to environmental alterations. It has become a valuable analytical approach for the characterization of phenotypes and is the rapidly evolving field of the comprehensive measurement of ideally all endogenous metabolites in bio-samples. Silybin has displayed bright prospects in the prevention and therapy of liver injury, and we had conducted a preliminary exploration on the molecular mechanism of the hepatoprotective effects of silybin. Because the knowledge on the metabolic responses of an acute liver damage rat to the silybin is still scarce, metabolic fingerprinting can provide relevant information on the intrinsic metabolic adjustments. Here, the physiological and metabolic changes in the acute liver damage rat were investigated by performing a metabolic analysis. The phenotypic response was assessed by liquid chromatography/mass spectrometry (LC/MS) combined with pattern recognition approaches such as principal components analysis and partial least squares projection to supervised latent structures and discriminant analysis. Multivariate analysis of the data showed trends in scores plots that were related to the concentration of the silybin. Results indicate 10 ions (7 upregulated and 3 downregulated) as differentiating metabolites. Key observations include perturbations of metabolic pathways linked to glutathione metabolism, tryptophan metabolism, cysteine and methionine metabolism, etc., Overall, this investigation illustrates the power of the LC/MS combined with the pattern recognition methods that can engender new insights into silybin affecting on metabolism pathways of an acute liver damage rat. The present study demonstrates that the combination of metabolic fingerprinting with appropriate chemometric analysis is a valuable approach for studying cellular responses to silybin drug and can provide additional insight into the mechanisms.


[Costs of interventions for patients with chronic renal disease].
The results of a study which identified the cost of health interventions in the management of patients with chronic renal disease are presented. The costing method was based on a consensus technique and the instrumentation of case management through the identification of the materials used and functions of production for the demand of each service solicited. The interventions included: peritoneal dialysis, hemodialysis, and renal transplant. The cost per event in U.S. dollars was $3.71, $57.95, and $8,778.32, respectively. The annual cost of case management was: Peritoneal Dialysis $5,643.07, Hemodialysis $9,631.60 and renal transplant $3,021.67. The information generated from the costs of the events differed considerably from the information that was generated by the annual cost of case management. These differences are significant for the design and evaluation of patterns for allocating resources.


Astragaloside IV attenuates free fatty acid-induced ER stress and lipid accumulation in hepatocytes via AMPK activation.
Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) is not completely understood, the increased influx of free fatty acids (FFAs) into the liver and the FFA-induced hepatic endoplasmic reticulum (ER) stress are two crucial pathogenic processes in the initiation and development of NAFLD. In this study we investigated the effects of astragaloside IV (AS-IV), a bioactive compound purified from Astragali Radix, on FFA-induced lipid accumulation in hepatocytes and elucidated the underlying mechanisms. Human HepG2 cells and primary murine hepatocytes were exposed to FFAs (1 mmol/L, oleate/palmitate, 2:1 ratio) with or without AS-IV for 24 h. Exposure to FFAs induced marked lipid accumulation in hepatocytes, whereas co-treatment with AS-IV (100 μg/mL) significantly attenuated this phenomenon. Notably, AS-IV (50-200 μg/mL) concentration-dependently enhanced the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC) and SREBP-1c, inhibited the accumulation and nuclear translocation of mature SREBP-1 and subsequently decreased the mRNA levels of lipogenic genes including acc1, fas and scd1. AS-IV treatment also concentration-dependently attenuated FFA-induced hepatic ER stress evidenced by the reduction of the key markers, GRP78, CHOP and p-PERK. Pretreated the cells with the AMPK inhibitor compound C (20 μmol/L) greatly diminished these beneficial effects of AS-IV. Our results demonstrate that AS-IV attenuates FFA-induced ER stress and lipid accumulation in an AMPK-dependent manner in hepatocytes, which supports its use as promising therapeutics for hepatic steatosis.


Functional interaction of VEGF-C and VEGF-D with neuropilin receptors.
Lymphatic vascular development is regulated by vascular endothelial growth factor receptor-3 (VEGFR-3), which is activated by its ligands VEGF-C and VEGF-D. Neuropilin-2 (NP2), known to be involved in neuronal development, has also been implicated to play a role in lymphangiogenesis. We aimed to elucidate the mechanism by which NP2 is involved in lymphatic endothelial cell signaling. By in vitro binding studies we found that both VEGF-C and VEGF-D interact with NP2, VEGF-C in a heparin-independent and VEGF-D in a heparin-dependent manner. We also mapped the domains of VEGF-C and NP2 required for their binding. The functional importance of the interaction of NP2 with the lymphangiogenic growth factors was demonstrated by cointernalization of NP2 along with VEGFR-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with VEGF-C or VEGF-D. NP2 also interacted with VEGFR-3 in coprecipitation studies. Our results show that NP2 is directly involved in an active signaling complex with the key regulators of lymphangiogenesis and thus suggest a mechanism by which NP2 functions in the development of the lymphatic vasculature.


East-West cranial differentiation in pre-Columbian human populations of South America.
South Amerindians are frequently thought of as a rather biologically homogeneous megapopulation. However, when native South Americans are assessed by information coming from DNA variability analysis, they resolve into two, major distinct entities of Eastern and Western zones. The purpose of this study is to investigate if the same dual pattern emerges from craniometric data. We approached this question by means of functional craniometric variables. We found strong evidence that Westerners and Easterners constitute two distinct and independent microevolutionary universes when cranial morphology is assessed. The existence of a third universe, Northwest, cannot be completely ruled out, but needs further investigation. We also discovered that Westerners and Easterners present similar degrees of internal variation, contrary to the findings of geneticists and molecular biologists. Palaeoamericans seem to be more similar to Easterners than to Westerners and North-Westerners. Our results suggest that this East-West cranial differentiation is more probably the result of differential rates of genetic drift and gene flow acting on each side of the Cordillera. However, different intensities of gene flow between Palaeoamericans and Amerindians in the highlands and in the lowlands cannot be completely dismissed as a possible explanation for the differentiation found.


The global burden of injury: incidence, mortality, disability-adjusted life years and time trends from the Global Burden of Disease study 2013.
The Global Burden of Diseases (GBD), Injuries, and Risk Factors study used the disability-adjusted life year (DALY) to quantify the burden of diseases, injuries, and risk factors. This paper provides an overview of injury estimates from the 2013 update of GBD, with detailed information on incidence, mortality, DALYs and rates of change from 1990 to 2013 for 26 causes of injury, globally, by region and by country. Injury mortality was estimated using the extensive GBD mortality database, corrections for ill-defined cause of death and the cause of death ensemble modelling tool. Morbidity estimation was based on inpatient and outpatient data sets, 26 cause-of-injury and 47 nature-of-injury categories, and seven follow-up studies with patient-reported long-term outcome measures. In 2013, 973 million (uncertainty interval (UI) 942 to 993) people sustained injuries that warranted some type of healthcare and 4.8 million (UI 4.5 to 5.1) people died from injuries. Between 1990 and 2013 the global age-standardised injury DALY rate decreased by 31% (UI 26% to 35%). The rate of decline in DALY rates was significant for 22 cause-of-injury categories, including all the major injuries. Injuries continue to be an important cause of morbidity and mortality in the developed and developing world. The decline in rates for almost all injuries is so prominent that it warrants a general statement that the world is becoming a safer place to live in. However, the patterns vary widely by cause, age, sex, region and time and there are still large improvements that need to be made.


Evaluation of efficacy of combination of methotrexate and hydroxychloroquine with leflunomide in active rheumatoid arthritis.
Several new drugs for rheumatoid arthritis are available including leflunomide. Comparative studies of treatment with leflunomide (against methotrexate) report a better quality of life. This study was designed to evaluate the efficacy of combination of methotrexate and hydroxychloroquine with leflunomide, a new disease modifying antirheumatoid drug. Analysis was of intent to treat group. This was an open labeled, randomized, comparative clinical trial in the department of rheumatology and immunology, at a tertiary care center in Bangalore. Patients who have diagnosed with rheumatoid arthritis as per American College of Rheumatology aged between 18 and 60 years were recruited and randomized to receive leflunomide (10 mg/day p.o.) or a combination of methotrexate and hydroxychloroquine (7.5 mg/week p.o. and 200 mg/day p.o., respectively) along with folate supplementation for 12 weeks. The European League Against Rheumatism criteria of improvement according to disease activity score 28 was considered as the primary efficacy variable. Baseline and end of study values were evaluated. The duration of the study period was 1 year. Analysis of variance (ANOVA) and Wilcoxon Signed rank test were used for statistical analysis. After 12 weeks, improvement noted in patients treated with leflunomide was similar to those treated with a combination of methotrexate and hydroxychloroquine. There was no statistical significance in improvement in disease activity between the two groups (P = 0.377). Combination of methotrexate and hydroxychloroquine is equivalent to leflunomide in terms of efficacy in reducing disease activity in the initial treatment of severe rheumatoid arthritis.


The history and future of cross-cultural psychiatric services.
With cultural issues prominent in the United States today and with ongoing rapid changes in health care management and delivery, this paper discusses the shift from a genetic-type psychiatry (i.e., assuming that humans the world over are no different, and will react to given stressors in life in the same manner) to one recognizing that cultural beliefs, mores, peer pressure, family expectations, and other ingredients operate in unique combinations in various cultures and ethnic groups. These social and cultural factors can and will impact treatment modalities and outcomes. Literature reviewed herein illustrates the progressive stages of awareness and incorporation of cultural differences and the many ways they impact treatment. Unfortunately, the rise in managed, rationed health care threatens the future of this progression. It is essential that culturally-based managed care programs be developed and funded to ensure the availability of cost-effective treatment, through an integrated system of services, to patients of all cultural and economic backgrounds.


A cell-based model of endothelial cell migration, proliferation and maturation during corneal angiogenesis.
The motivation of this work stems from two critical experimental observations associated with corneal angiogenesis: (1) angiogenesis will not succeed without endothelial cell proliferation, and (2) proliferation mainly occurs at the leading edge of developing sprouts (Sholley et al., Lab. Invest. 51:624-634, 1984). To discover the underlying mechanisms of these phenomena, we develop a cell-based mathematical model that integrates a mechanical model of elongation with a biochemical model of cell phenotype variation regulated by angiopoietins within a developing sprout. This model allows for a detailed study of the relative roles of endothelial cell migration, proliferation, and maturation. The model is validated by quantitatively comparing its predictions with data derived from corneal angiogenesis experiments. We conclude that cell elasticity and cell-to-cell adhesion allow only limited sprout extension in the absence of proliferation, and the maturation process combined with bioavailability of VEGF can explain the localization of proliferation to the leading edge. We also use this model to investigate the effects of X-ray irradiation, Ang-2 inhibition, and extracellular matrix anisotropy on sprout morphology and extension.


Multi-institutional survey on imaging practice patterns in pancreatic ductal adenocarcinoma.
To study the practice patterns for performance and interpretation of CT/MRI imaging studies in patients with pancreatic ductal adenocarcinoma (PDAC) at multiple institutions using a survey-based assessment. In this study, abdominal radiologists/body imagers on the Society of Abdominal Radiology disease-focused panel for PDAC and from multiple institutions participated in an online survey. The survey was designed to investigate the imaging and reporting practice patterns for PDAC. The survey questionnaire addressed the experience of referring providers, choice of imaging modality for diagnosis and follow-up of PDAC, structured imaging templates utilization for PDAC, and experiences with the use of structured reports. The response rate was 89.6% (43/48), with majority of the respondents working in a teaching hospital or academic research center (95.4%). While 86% of radiologists reported use of structured reporting templates in their practice, only 60.5% used standardized templates specific to PDAC. This lower percentage was despite most of them (77%) being aware of existence of PDAC-specific templates and recognizing their benefits, such as preference by referring providers (83%), improved uniformity (100%), and higher accuracy of reports (76.2%). The common impediments to the use of PDAC-specific templates were interference with efficient workflow (67.5%), lack of interest (52.5%), and complexity of existing templates (47.5%). With regards to imaging practice, 92.7% (n = 40/43) of respondents reported performing dynamic multiphasic pancreatic protocol CT for evaluation of patients with initial suspicion or staging of PDAC. Structured reporting templates for PDAC are not universally utilized in subspecialty abdominal/body imaging practices due to concerns of interference with efficient workflow and complexity of templates. Multiphasic pancreatic protocol CT is most frequently performed for evaluation of PDAC.


Redox regulation of cellular stress response in aging and neurodegenerative disorders: role of vitagenes.
Reduced expression and/or activity of antioxidant proteins lead to oxidative stress, accelerated aging and neurodegeneration. However, while excess reactive oxygen species (ROS) are toxic, regulated ROS play an important role in cell signaling. Perturbation of redox status, mutations favoring protein misfolding, altered glyc(osyl)ation, overloading of the product of polyunsaturated fatty acid peroxidation (hydroxynonenals, HNE) or cholesterol oxidation, can disrupt redox homeostasis. Collectively or individually these effects may impose stress and lead to accumulation of unfolded or misfolded proteins in brain cells. Alzheimer's (AD), Parkinson's and Huntington's disease, amyotrophic lateral sclerosis and Friedreich's ataxia are major neurological disorders associated with production of abnormally aggregated proteins and, as such, belong to the so-called "protein conformational diseases". The pathogenic aggregation of proteins in non-native conformation is generally associated with metabolic derangements and excessive production of ROS. The "unfolded protein response" has evolved to prevent accumulation of unfolded or misfolded proteins. Recent discoveries of the mechanisms of cellular stress signaling have led to new insights into the diverse processes that are regulated by cellular stress responses. The brain detects and overcomes oxidative stress by a complex network of "longevity assurance processes" integrated to the expression of genes termed vitagenes. Heat-shock proteins are highly conserved and facilitate correct protein folding. Heme oxygenase-1, an inducible and redox-regulated enzyme, has having an important role in cellular antioxidant defense. An emerging concept is neuroprotection afforded by heme oxygenase by its heme degrading activity and tissue-specific antioxidant effects, due to its products carbon monoxide and biliverdin, which is then reduced by biliverdin reductase in bilirubin. There is increasing interest in dietary compounds that can inhibit, retard or reverse the steps leading to neurodegeneration in AD. Specifically any dietary components that inhibit inappropriate inflammation, AbetaP oligomerization and consequent increased apoptosis are of particular interest, with respect to a chronic inflammatory response, brain injury and beta-amyloid associated pathology. Curcumin and ferulic acid, the first from the curry spice turmeric and the second a major constituent of fruit and vegetables, are candidates in this regard. Not only do these compounds serve as antioxidants but, in addition, they are strong inducers of the heat-shock response. Food supplementation with curcumin and ferulic acid are therefore being considered as a novel nutritional approach to reduce oxidative damage and amyloid pathology in AD. We review here some of the emerging concepts of pathways to neurodegeneration and how these may be overcome by a nutritional approach.


Randomized clinical trial to evaluate mental practice in enhancing advanced laparoscopic surgical performance.
Mental practice, the cognitive rehearsal of a task without physical movement, is known to enhance performance in sports and music. Investigation of this technique in surgery has been limited to basic operations. The purpose of this study was to develop mental practice scripts, and to assess their effect on advanced laparoscopic skills and surgeon stress levels in a crisis scenario. Twenty senior surgical trainees were randomized to either conventional training or mental practice groups, the latter being trained by an expert performance psychologist. Participants' skills were assessed while performing a porcine laparoscopic jejunojejunostomy as part of a crisis scenario in a simulated operating room, using the Objective Structured Assessment of Technical Skill (OSATS) and bariatric OSATS (BOSATS) instruments. Objective and subjective stress parameters were measured, as well as non-technical skills using the Non-Technical Skills for Surgeons rating tool. An improvement in OSATS (P = 0.003) and BOSATS (P = 0.003) scores was seen in the mental practice group compared with the conventional training group. Seven of ten trainees improved their technical performance during the crisis scenario, whereas four of the ten conventionally trained participants deteriorated. Mental imagery ability improved significantly following mental practice training (P = 0.011), but not in the conventional group (P = 0.083). No differences in objective or subjective stress levels or non-technical skills were evident. Mental practice improves technical performance for advanced laparoscopic tasks in the simulated operating room, and allows trainees to maintain or improve their performance despite added stress.


Optimum swimming pathways of fish spawning migrations in rivers.
Fishes that swim upstream in rivers to spawn must navigate complex fluvial velocity fields to arrive at their ultimate locations. One hypothesis with substantial implications is that fish traverse pathways that minimize their energy expenditure during migration. Here we present the methodological and theoretical developments necessary to test this and similar hypotheses. First, a cost function is derived for upstream migration that relates work done by a fish to swimming drag. The energetic cost scales with the cube of a fish's relative velocity integrated along its path. By normalizing to the energy requirements of holding a position in the slowest waters at the path's origin, a cost function is derived that depends only on the physical environment and not on specifics of individual fish. Then, as an example, we demonstrate the analysis of a migration pathway of a telemetrically tracked pallid sturgeon (Scaphirhynchus albus) in the Missouri River (USA). The actual pathway cost is lower than 10(5) random paths through the surveyed reach and is consistent with the optimization hypothesis. The implication--subject to more extensive validation--is that reproductive success in managed rivers could be increased through manipulation of reservoir releases or channel morphology to increase abundance of lower-cost migration pathways.


Monoclonal antibodies that distinguish non-small cell from small cell lung cancer.
Two murine IgG2Ak monoclonal antibodies (703D4, 704A 1) were produced and characterized after immunization with a human large cell lung cancer line (NCI-H 157). These antibodies detect different epitopes on 31 kilodalton [35S]methionine incorporating protein(s). Radiobinding and immunohistochemical studies show these antibodies bind to most (11/13) human non-small cell lung cancer (adenocarcinoma, epidermoid, and large cell), but not to small cell lung cancer (0/11) tumors tested. The epitopes these antibodies recognized are also expressed on human melanomas (7/8), two other tumors (osteogenic sarcoma, renal cell carcinoma), but not on many other human tumors (breast, colon, neuroblastoma, lymphoid), and not on a panel of normal adult human tissues. Because the antigen(s) are preserved after fixation and because of their ability to distinguish lung cancer types from each other and normal tissues, they should be of clinical, as well as of biologic interest.


Canine malignant melanoma alpha-3 integrin binding peptides.
There is a need to develop novel targeted imaging and therapeutic agents that can aid in early diagnosis, detection of metastasis and treatment of melanoma. Alpha-3 integrin is overexpressed in 82% of metastatic melanomas in humans and may be a potential target for peptide ligands carrying therapeutic agents. Five melanoma cell lines were generated from canine primary oral and metastatic canine tumors, grown in mice, and validated with melanoma markers Melan A, S-100, Micropthalmia transcription factor (MITF), Tyrosinase, and MART-1. The melanoma cell lines were tested for binding affinity to previously published alpha-3 integrin-binding peptides containing the cdGXGXXc motif. Fluorescent conjugates of the alpha-3 integrin binding OA02 peptide were used to quantify receptor affinity in the cell lines, a specimen of canine primary oral melanoma, and melanoma xenografts. Alpha-3 integrin was expressed by all 5 canine melanoma cell lines. Four of the 5 lines as well as the primary canine tumor showed affinity to alpha-3 integrin binding peptides with the cdGXGXXc motif. Optical imaging of canine melanoma xenografts in nude mice indicates rapid, strong uptake of the optical tracer in the tumor with an average persistence of approximately 48 h. Ex vivo images showed high tumor-to-background ratio, with tumor signals more than twice that of the kidney and other vital organs. We propose that integrin alpha-3 integrin binding ligands could potentially become useful probes for imaging and delivery of cytotoxic agents for the treatment of melanoma.


Influence of motion picture rating on adolescent response to movie smoking.
To examine the association between movie smoking exposure (MSE) and adolescent smoking according to rating category. A total of 6522 US adolescents were enrolled in a longitudinal survey conducted at 8-month intervals; 5503 subjects were followed up at 8 months, 5019 subjects at 16 months, and 4575 subjects at 24 months. MSE was estimated from 532 recent box-office hits, blocked into 3 Motion Picture Association of America rating categories: G/PG, PG-13, and R. A survival model evaluated time to smoking onset. Median MSE in PG-13-rated movies was ∼3 times higher than median MSE from R-rated movies, but their relation with smoking was essentially the same, with adjusted hazard ratios of 1.49 (95% confidence interval [CI]: 1.23-1.81) and 1.33 (95% CI: 1.23-1.81) for each additional 500 occurrences of MSE respectively. MSE from G/PG-rated movies was small and had no significant relationship with adolescent smoking. Attributable risk estimates showed that adolescent smoking would be reduced by 18% (95% CI: 14-21) if smoking in PG-13-rated movies was reduced to the fifth percentile. In comparison, making all parents maximally authoritative in their parenting would reduce adolescent smoking by 16% (95% CI: 12-19). The equivalent effect of PG-13-rated and R-rated MSE suggests it is the movie smoking that prompts adolescents to smoke, not other characteristics of R-rated movies or adolescents drawn to them. An R rating for movie smoking could substantially reduce adolescent smoking by eliminating smoking from PG-13 movies.


Somatostatin: hypothalamic inhibitor of the endocrine pancreas.
Somatostatin, a hypothalamic peptide that inhibits the secretion of pituitary growth hormone, inhibits basal insulin secretion in fasted cats and rats. In fasted baboons both basal and arginine-stimulated secretion of insulin and glucagon are inhibited. Somatostatin appears to act directly on the endocrine pancreas. The action is dose-related, rapid in onset, and readily reversed.


Uncovering the polymerase-induced cytotoxicity of an oxidized nucleotide.
Oxidative stress promotes genomic instability and human diseases. A common oxidized nucleoside is 8-oxo-7,8-dihydro-2'-deoxyguanosine, which is found both in DNA (8-oxo-G) and as a free nucleotide (8-oxo-dGTP). Nucleotide pools are especially vulnerable to oxidative damage. Therefore cells encode an enzyme (MutT/MTH1) that removes free oxidized nucleotides. This cleansing function is required for cancer cell survival and to modulate Escherichia coli antibiotic sensitivity in a DNA polymerase (pol)-dependent manner. How polymerases discriminate between damaged and non-damaged nucleotides is not well understood. This analysis is essential given the role of oxidized nucleotides in mutagenesis, cancer therapeutics, and bacterial antibiotics. Even with cellular sanitizing activities, nucleotide pools contain enough 8-oxo-dGTP to promote mutagenesis. This arises from the dual coding potential where 8-oxo-dGTP(anti) base pairs with cytosine and 8-oxo-dGTP(syn) uses its Hoogsteen edge to base pair with adenine. Here we use time-lapse crystallography to follow 8-oxo-dGTP insertion opposite adenine or cytosine with human pol β, to reveal that insertion is accommodated in either the syn- or anti-conformation, respectively. For 8-oxo-dGTP(anti) insertion, a novel divalent metal relieves repulsive interactions between the adducted guanine base and the triphosphate of the oxidized nucleotide. With either templating base, hydrogen-bonding interactions between the bases are lost as the enzyme reopens after catalysis, leading to a cytotoxic nicked DNA repair intermediate. Combining structural snapshots with kinetic and computational analysis reveals how 8-oxo-dGTP uses charge modulation during insertion that can lead to a blocked DNA repair intermediate.


[Early diagnosis and management of acute pulmonary embolism: clinical evaluation those of 225 cases].
To contribute for making early diagnosis and treatment of acute pulmonary embolism (APE), we investigated on clinical pictures of 225 patients with APE. Common underlying factors were heart disease, prolonged bed rest, post-surgical state, thrombophlebitis, malignant tumor and post-catheterization state in this order. Dyspnea, chest pain, tachycardia and shock were frequently seen as initial symptoms and signs. Blood screening showed leukocytosis, hypoxemia, hypocapnia and elevated serum LDH. Electrocardiographic findings highly demonstrated were ST.T abnormalities, such as T inversion with ST elevation in V1-3, ST depression in V4-6 and sinus tachycardia. Chest X-rays showed diminished pulmonary vascular marking and pulmonary artery dilation. Right ventricular dilatation were frequently seen on 2-dimensional echocardiograms. Pulmonary artery pressure were elevated up to 49/20 (30) mmHg. Twenty-five percent of the patients died, and the recurrence was seen in 4%. Thus, as soon as APE is suspected by above clinical findings, definitive diagnosis should be obtained by the lung perfusion scan and pulmonary arteriography, then oxygen and thrombolytic agents should be given immediately to prevent the fatal outcome.


Involvement of different risk factors in clinically severe large joint osteoarthritis according to the presence of hand interphalangeal nodes.
To quantify the differences in risk factors influencing total hip replacement (THR) and total knee replacement (TKR) based on the presence versus absence of multiple interphalangeal nodes in 2 or more rays of the fingers of each hand in patients with large joint osteoarthritis (OA). A group of 3,800 patients with large joint OA who underwent total joint replacement (1,201 of whom had the nodal phenotype) and 1,906 control subjects from 2 case-control studies and a population-based cohort in the UK were studied. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for the risk of total joint replacement in association with age, sex, body mass index (BMI), height, and prevalence of the T allele in the GDF5 rs143383 polymorphism. ORs for total joint replacement were compared between cases of nodal OA and cases of non-nodal OA and between patients who underwent TKR and those who underwent THR. Age, sex, and BMI had significantly higher ORs for an association with total joint replacement in nodal OA cases than in non-nodal OA cases. The GDF5 polymorphism was significantly associated with THR in cases of nodal OA, but not in cases of non-nodal OA, and increased height was a risk factor for THR in non-nodal OA cases only. Female sex was a protective risk factor for TKR in non-nodal OA cases (OR 0.60, 95% CI 0.52-0.70) but was predisposing for TKR in the nodal form of OA (OR 1.83, 95% CI 1.49-2.26). The nodal phenotype was associated with a significantly higher risk of undergoing both THR and TKR (OR 1.46, 95% CI 1.09-1.94) and also a significantly higher risk of bilateral TKR (OR 1.70, 95% CI 1.37-2.11), but, paradoxically, was associated with a lower risk of bilateral THR (OR 0.72, 95% CI 0.56-0.91). Nodal and non-nodal forms of large joint OA have significantly different risk factors and outcomes, indicating a different etiology for the 2 forms of OA. With regard to the likelihood of undergoing THR, this appears to be, at least in part, genetically determined.


Testing Antonovsky's sense of coherence (SOC) scale among Swedish physically active older people.
In Antonovsky's salutogenic theory, the major concept sense of coherence (SOC) is constituted of three core components called comprehensibility, manageability, and meaningfulness. Several scales that are intended to measure SOC are available and used by researchers in health and caring sciences all over the world. When using a scale, evidence of its quality in different study groups is needed in order to get reliable and valid data. The aim of this study was to test reliability and construct validity of the Swedish version of Antonovsky's original 29-item sense of coherence (SOC) scale in a group of physically active older people. The scale was tested with a convenience sample of 140 physically active older individuals, who took part in different fitness-training groups in eastern Sweden. Reliability was assessed as item to total correlations and with the Cronbach's alpha coefficient. Construct validity was assessed with the known groups technique, confirmatory factor analysis, and with logistic regression analysis. The results showed that in the studied group of older individuals, the instrument was a very reliable tool with a Cronbach's alpha coefficient of 0.92. Construct validity of the scale was supported by the fact that the global concept sense of coherence was found to be hierarchically organized in a model that consisted of the three core components of comprehensibility, manageability, and meaningfulness. Furthermore, perceived health could be explained to some degree by sense of coherence, but even more by comprehensibility, in both cases independently of chronological age. The results clearly corroborated Antonovsky's theory.


Comparing clerkship sites in a community-based medical school by evaluating students' undergraduate and postgraduate performances.
Studies have generally found clinical training sites within the same clerkship to be comparable regarding students' performances--by using undergraduate measures in individual clerkships at medical schools with university hospitals. The present study examined performance comparability among sites within two clerkships in a community-based medical school and used both undergraduate and postgraduate measures. The participants were the 349 graduates from the classes of 1988-1991 at Wright State University School of Medicine who took an internal medicine clerkship (332 of the graduates, in five principal combinations of sites) and a general surgery clerkship (349 at six sites). The undergraduate measures were final percent scores for the clerkships and subtest and total scores on the National Board of Medical Examiners (NBME) Part II examination. The postgraduate measures were supervisors' ratings from the first year of residency (210 graduates) and total score on the NBME Part III (212). Univariate analysis of variance and Tukey's multiple-range test were used for the comparisons. The only statistically significant difference among sites was for the medicine clerkship and involved only one undergraduate measure, the clerkship score (and the differences were slight, less than four percentage points). Virtually no differences in the students' performances on the undergraduate and postgraduate measures were found among sites for the two clerkships.


Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma.
Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG self-renewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor.


Travel-associated sexually transmitted infections: an observational cross-sectional study of the GeoSentinel surveillance database.
Travel is thought to be a risk factor for the acquisition of sexually transmitted infections (STIs), but no multicentre analyses have been done. We aimed to describe the range of diseases and the demographic and geographical factors associated with the acquisition of travel-related STIs through analysis of the data gathered by GeoSentinel travel medicine clinics worldwide. We gathered data from ill travellers visiting GeoSentinel clinics worldwide between June 1, 1996, and Nov 30, 2010, and analysed them to identify STIs in three clinical settings: after travel, during travel, or immigration travel. We calculated proportionate morbidity for each of the three traveller groups and did logistic regression to assess the association between STIs and demographic, geographical, and travel variables. Our final analysis was of 112 180 ill travellers-64 335 patients seen after travel, 38 287 patients seen during travel, and 9558 immigrant patients. 974 patients (0·9%) had diagnoses of STIs, and 1001 STIs were diagnosed. The proportionate STI morbidities were 6·6, 10·2, and 16·8 per 1000 travellers in the three groups, respectively. STIs varied substantially according to the traveller category. The most common STI diagnoses were non-gonococcal or unspecified urethritis (30·2%) and acute HIV infection (27·6%) in patients seen after travel; non-gonococcal or unspecified urethritis (21·1%), epididymitis (15·2%), and cervicitis (12·3%) in patients seen during travel; and syphilis in immigrant travellers (67·8%). In ill travellers seen after travel, significant associations were noted between diagnosis of STIs and male sex, travelling to visit friends or relatives, travel duration of less than 1 month, and not having pretravel health consultations. The range of STIs varies substantially according to traveller category. STI preventive strategies should be particularly targeted at men and travellers visiting friends or relatives. Our data suggest target groups for pretravel interventions and should assist in post-travel screening and decision making. US Centers for Disease Control and Prevention, and International Society of Travel Medicine.