Drosophila Ana2 is a conserved centriole duplication factor.
In Caenorhabditis elegans, five proteins are required for centriole duplication: SPD-2, ZYG-1, SAS-5, SAS-6, and SAS-4. Functional orthologues of all but SAS-5 have been found in other species. In Drosophila melanogaster and humans, Sak/Plk4, DSas-6/hSas-6, and DSas-4/CPAP-orthologues of ZYG-1, SAS-6, and SAS-4, respectively-are required for centriole duplication. Strikingly, all three fly proteins can induce the de novo formation of centriole-like structures when overexpressed in unfertilized eggs. Here, we find that of eight candidate duplication factors identified in cultured fly cells, only two, Ana2 and Asterless (Asl), share this ability. Asl is now known to be essential for centriole duplication in flies, but no equivalent protein has been found in worms. We show that Ana2 is the likely functional orthologue of SAS-5 and that it is also related to the vertebrate STIL/SIL protein family that has been linked to microcephaly in humans. We propose that members of the SAS-5/Ana2/STIL family of proteins are key conserved components of the centriole duplication machinery.


Mutation in archain 1, a subunit of COPI coatomer complex, causes diluted coat color and Purkinje cell degeneration.
Intracellular trafficking is critical for delivering molecules and organelles to their proper destinations to carry out normal cellular functions. Disruption of intracellular trafficking has been implicated in the pathogenesis of various neurodegenerative disorders. In addition, a number of genes involved in vesicle/organelle trafficking are also essential for pigmentation, and loss of those genes is often associated with mouse coat-color dilution and human hypopigmentary disorders. Hence, we postulated that screening for mouse mutants with both neurological defects and coat-color dilution will help identify additional factors associated with intracellular trafficking in neuronal cells. In this study, we characterized a mouse mutant with a unique N-ethyl-N-nitrosourea (ENU)-induced mutation, named nur17. nur17 mutant mice exhibit both coat-color dilution and ataxia due to Purkinje cell degeneration in the cerebellum. By positional cloning, we identified that the nur17 mouse carries a T-to-C missense mutation in archain 1 (Arcn1) gene which encodes the delta subunit of the coat protein I (COPI) complex required for intracellular trafficking. Consistent with this function, we found that intracellular trafficking is disrupted in nur17 melanocytes. Moreover, the nur17 mutation leads to common characteristics of neurodegenerative disorders such as abnormal protein accumulation, ER stress, and neurofibrillary tangles. Our study documents for the first time the physiological consequences of the impairment of the ARCN1 function in the whole animal and demonstrates a direct association between ARCN1 and neurodegeneration.


Acute leukemia immunohistochemistry: a systematic diagnostic approach.
The diagnosis and classification of leukemia is becoming increasingly complex. Current classification schemes incorporate morphologic features, immunophenotype, molecular genetics, and clinical data to specifically categorize leukemias into various subtypes. Although sophisticated methodologies are frequently used to detect characteristic features conferring diagnostic, prognostic, or therapeutic implications, a thorough microscopic examination remains essential to the pathologic evaluation. Detailed blast immunophenotyping can be performed with lineage- and maturation-specific markers. Although no one marker is pathognomonic for one malignancy, a well-chosen panel of antibodies can efficiently aid the diagnosis and classification of acute leukemias. To review important developments from recent and historical literature. General immunohistochemical staining patterns of the most commonly encountered lymphoid and myeloid leukemias are emphasized. The goal is to discuss the immunostaining of acute leukemias when flow cytometry and genetic studies are not available. A comprehensive review was performed of the relevant literature indexed in PubMed (National Library of Medicine) and referenced medical texts. Additional references were identified in the reviewed manuscripts. Immunophenotyping of blasts using an immunohistochemical approach to lymphoid and myeloid malignancies is presented. Initial and subsequent additional antibody panels are suggested to confirm or exclude each possibility in the differential diagnosis and a general strategy for diagnostic evaluation is discussed. Although the use of immunohistochemistry alone is limited and evaluation by flow cytometry and genetic studies is highly recommended, unavoidable situations requiring analysis of formalin-fixed tissue specimens arise. When performed in an optimized laboratory and combined with a careful morphologic examination, the immunohistochemical approach represents a useful laboratory tool for classifying various leukemias.


ParaDB: a tool for paralogy mapping in vertebrate genomes.
We present ParaDB (http://abi.marseille.inserm.fr/paradb/), a new database for large-scale paralogy studies in vertebrate genomes. We intended to collect all information (sequence, mapping and phylogenetic data) needed to map and detect new paralogous regions, previously defined as Paralogons. The AceDB database software was used to generate graphical objects and to organize data. General data were automatically collated from public sources (Ensembl, GadFly and RefSeq). ParaDB provides access to data derived from whole genome sequences (Homo sapiens, Mus musculus and Drosophila melanogaster): cDNA and protein sequences, positional information, bibliographical links. In addition, we provide BLAST results for each protein sequence, InParanoid orthologs and 'In-Paralogs' data, previously established paralogy data, and, to compare vertebrates and Drosophila, orthology data.


Mapping the literature of health care chaplaincy.
This study examined citation patterns and indexing coverage from 2008 to 2010 to determine (1) the core literature of health care chaplaincy and (2) the resources providing optimum coverage for the literature. Citations from three source journals (2008-2010 inclusive) were collected and analyzed according to the protocol created for the Mapping the Literature of Allied Health Professions Project. An analysis of indexing coverage by five databases was conducted. A secondary analysis of self-citations by source journals was also conducted. The 3 source journals--Chaplaincy Today, the Journal of Health Care Chaplaincy, and the Journal of Pastoral Care and Counseling--ranked as the top 3 journals in Zone 1 and provided the highest number of most frequently cited articles for health care chaplaincy. Additional journals that appeared in this highly productive zone covered the disciplines of medicine, psychology, nursing, and religion, which were also represented in the Zones 2 and 3 journals. None of the databases provided complete coverage for the core journals; however, MEDLINE provided the most comprehensive coverage for journals in Zones 1 and 2, followed by Academic Search Complete, CINAHL, PsycINFO, and ATLA. Self-citations for the source journals ranged from 9% to 16%. Health care chaplaincy draws from a diverse body of inter-professional literature. Libraries wishing to provide access to journal literature to support health care chaplaincy at their institutions will be best able to do this by subscribing to databases and journals that cover medical, psychological, nursing, and religion- or spirituality-focused disciplines.


The Associations of Plant Protein Intake With All-Cause Mortality in CKD.
Plant protein intake is associated with lower production of uremic toxins and lower serum phosphorus levels. Therefore, at a given total protein intake, a higher proportion of dietary protein from plant sources might be associated with lower mortality in chronic kidney disease. Observational study. 14,866 NHANES III participants 20 years or older without missing data for plant and animal protein intake and mortality. Plant protein to total protein ratio and total plant protein intake. Patients were stratified by estimated glomerular filtration rate (eGFR)<60 or ≥60mL/min/1.73m(2). All-cause mortality. Plant and total protein intakes were estimated from 24-hour dietary recalls. Mortality was ascertained by probabilistic linkage with National Death Index records through December 31, 2000. Mean values for plant protein intake and plant protein to total protein ratio were 24.6±13.2 (SD) g/d and 33.0% ± 14.0%, respectively. The prevalence of eGFRs<60mL/min/1.73m(2) was 4.9%. There were 2,163 deaths over an average follow-up of 8.4 years. Adjusted for demographics, smoking, alcohol use, comorbid conditions, body mass index, calorie and total protein intake, and physical inactivity, each 33% increase in plant protein to total protein ratio was not associated with mortality (HR, 0.88; 95% CI, 0.74-1.04) in the eGFR≥60mL/min/1.73m(2) subpopulation, but was associated with lower mortality risk (HR, 0.77; 95% CI, 0.61-0.96) in the eGFR<60mL/min/1.73m(2) subpopulation. In sensitivity analyses, results were similar in those with eGFR<60mL/min/1.73m(2) defined by serum cystatin C level. Whether results are related to plant protein itself or to other factors associated with more plant-based diets is difficult to establish. A diet with a higher proportion of protein from plant sources is associated with lower mortality in those with eGFR<60mL/min/1.73m(2). Future studies are warranted to determine the causal role of plant protein intake in reducing mortality in those with eGFR<60mL/min/1.73m(2).


Effects of the putative lithium mimetic ebselen on pilocarpine-induced neural activity.
Lithium, commonly used to treat bipolar disorder, potentiates the ability of the muscarinic agonist pilocarpine to induce seizures in rodents. As this potentiation by lithium is reversed by the administration of myo-inositol, the potentiation may be mediated by inhibition of inositol monophosphatase (IMPase), a known target of lithium. Recently, we demonstrated that ebselen is a 'lithium mimetic' in regard to behaviours in both mice and man. Ebselen inhibits IMPase in vitro and lowers myo-inositol in vivo in the brains of mice and men, making ebselen the only known inhibitor of IMPase, other than lithium, that penetrates the blood-brain barrier. Our objective was to determine the effects of ebselen on sensitization to pilocarpine-induced seizures and neural activity. We administered ebselen at different doses and time intervals to mice, followed by injection of a sub-seizure dose of pilocarpine. We assessed seizure and neural activity by a subjective seizure rating scale, by monitoring tremors, and by induction of the immediate early gene c-fos. In contrast to lithium, ebselen did not potentiate the ability of pilocarpine to induce seizures. Unexpectedly, ebselen inhibited pilocarpine-induced tremor as well as pilocarpine-induced increases in c-fos mRNA levels. Both lithium and ebselen inhibit a common target, IMPase, but only lithium potentiates pilocarpine-induced seizures, consistent with their polypharmacology at diverse molecular targets. We conclude that ebselen does not potentiate pilocarpine-induced seizures and instead, reduces pilocarpine-mediated neural activation. This lack of potentiation of muscarinic sensitization may be one reason for the lack of side-effects observed with ebselen treatment clinically.


In vitro activity of xanthorrhizol against Candida glabrata, C. guilliermondii, and C. parapsilosis biofilms.
The formation of Candida biofilms has important clinical ramifications, because these biofilms exhibit increased resistance to conventional antifungal therapies. The aim of this study was to investigate the activity of xanthorrhizol on biofilms produced by non-C. albicans Candida (NCAC) species, including C. glabrata, C. guilliermondii, and C. parapsilosis. NCAC biofilms were generated in flat-bottom 96-well microtiter plates and quantified using the XTT (2, 3 - bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenyl amino) carbonyl]-2H-tetrazolium hydroxide) reduction assay. The NCAC biofilms at adherent, intermediate, and mature growth phases were treated with 0.5-512 μg/ml of xanthorrhizol for 24 h. The ranges of sessile minimum inhibitory concentrations (SMICs) of xanthorrhizol against C. glabrata, C. guilliermondii, and C. parapsilosis biofilms were 8-32 μg/ml, 8-16 μg/ml, and 8-64 μg/ml, respectively. Xanthorrhizol affected cell density that had an indirect effect on the biofilm OD(490). The compound eradicated the viable cells of the C. glabrata and C. parapsilosis biofilms at the adherent growth phase at 16 μg/ml and that of C. guilliermondii at 8 μg/ml. Treatment with 128 μg/ml of xanthorrhizol reduced the OD(490) of C. glabrata, C. guilliermondii, and C. parapsilosis biofilms at the mature growth phase by 77.8%, 88.5%, and 64.5%, respectively. These results indicate that xanthorrhizol exhibits potent activity against NCAC biofilms in vitro. Therefore, xanthorrhizol has potential therapeutic value in treating biofilm-associated NCAC infections and should be further evaluated in vivo.


Relationship between Fecal Content of Fatty Acids and Cyclooxygenase mRNA Expression and Fatty Acid Composition in Duodenal Biopsies, Serum Lipoproteins, and Dietary Fat in Colectomized Familial Adenomatous Polyposis Patients.
A few familial adenomatous polyposis studies have focused upon faecal sterols and bile acids but none has analysed the fecal content of fatty acids. We report here findings of an observational study on 29 colectomized familial adenomatous polyposis patients that describe the fecal content of fatty acids, and relate this to the proportions of fatty acids and levels of cyclooxygenase mRNA expression in duodenal biopsies, levels of serum lipoproteins, and diet. In the ileostomy group separately (n = 12), the fecal content of arachidonic acid was correlated negatively to the proportions of eicosapentaenoic acid and docosahexaenoic acid in duodenal biopsies. Total serum-cholesterol was negatively correlated to the fecal content of saturates and monounsaturates. The fecal palmitoleic acid/palmitic acid ratio was positively correlated to the levels of cyclooxygease-2 expression in duodenal biopsies.In the ileal-pouch-anal anastomosis group separately (n = 17), significant correlations were found between the fecal contents of oleic acid, linoleic acid, and alpha-linolenic acid, and the proportions of myristic acid, oleic acid and eicosaenoic acid in duodenal biopsies. Dietary monounsaturates were positively correlated to different fecal fatty acids. Future studies should focus on molecular mechanisms relevant to fatty acid metabolism, inflammation, and angiogenesis, in addition to nutrition.


Advances on EGFR mutation for lung cancer.
Patients with advanced non-small-cell lung cancer (NSCLC) and somatic activating mutations of the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR) gene represent a biologically distinct disease entity that shows exquisite sensitivity to the reversible EGFR-TK inhibitors (-TKIs) gefitinib or erlotinib. Phase III randomized studies have clearly demonstrated that a reversible EGFR-TKI is significantly superior in terms of response rate, progression-free survival and quality of life to platinum-based chemotherapy in advanced NSCLC patients who carry an activating EGFR mutation, thus resulting into a new standard of care for this biologically selected group of patients. Unfortunately, approximately one third of EGFR-mutated patients show primary resistance to gefitinib or erlotinib, whereas virtually all patients who initially benefit from treatment will eventually develop acquired resistance. Importantly, revealing the molecular mechanisms that underlie resistance to reversible EGFR-TKIs is key to the development of EGFR-targeting strategies with the potential to prevent, delay or overcome such resistance. Early results of clinical trials with irreversible EGFR-TKIs or dual combination strategies aiming to block EGFR-mediated signaling at different levels have shown encouraging results in EGFR-mutated patients pretreated or not with a reversible EGFR-TKI. Therefore, in the near future it is reasonable to hypothesize that EGFR-mutated NSCLCs could be treated with multiple lines of EGFR-targeting therapies beyond disease progression, limiting chemotherapy to selected cases of resistant disease. This evolving treatment scenario highlights once again how important is the identification of a single oncogenic "addiction" that functions as unique determinant of progression and survival of NSCLC.


Genome-wide RAD sequence data provide unprecedented resolution of species boundaries and relationships in the Lake Victoria cichlid adaptive radiation.
Although population genomic studies using next generation sequencing (NGS) data are becoming increasingly common, studies focusing on phylogenetic inference using these data are in their infancy. Here, we use NGS data generated from reduced representation genomic libraries of restriction-site-associated DNA (RAD) markers to infer phylogenetic relationships among 16 species of cichlid fishes from a single rocky island community within Lake Victoria's cichlid adaptive radiation. Previous attempts at sequence-based phylogenetic analyses in Victoria cichlids have shown extensive sharing of genetic variation among species and no resolution of species or higher-level relationships. These patterns have generally been attributed to the very recent origin (<15,000 years) of the radiation, and ongoing hybridization between species. We show that as we increase the amount of sequence data used in phylogenetic analyses, we produce phylogenetic trees with unprecedented resolution for this group. In trees derived from our largest data supermatrices (3 to >5.8 million base pairs in width), species are reciprocally monophyletic with high bootstrap support, and the majority of internal branches on the tree have high support. Given the difficulty of the phylogenetic problem that the Lake Victoria cichlid adaptive radiation represents, these results are striking. The strict interpretation of the topologies we present here warrants caution because many questions remain about phylogenetic inference with very large genomic data set and because we can with the current analysis not distinguish between effects of shared ancestry and post-speciation gene flow. However, these results provide the first conclusive evidence for the monophyly of species in the Lake Victoria cichlid radiation and demonstrate the power that NGS data sets hold to resolve even the most difficult of phylogenetic challenges.


Mesoscale eddies drive increased silica export in the subtropical Pacific Ocean.
Mesoscale eddies may play a critical role in ocean biogeochemistry by increasing nutrient supply, primary production, and efficiency of the biological pump, that is, the ratio of carbon export to primary production in otherwise nutrient-deficient waters. We examined a diatom bloom within a cold-core cyclonic eddy off Hawaii. Eddy primary production, community biomass, and size composition were markedly enhanced but had little effect on the carbon export ratio. Instead, the system functioned as a selective silica pump. Strong trophic coupling and inefficient organic export may be general characteristics of community perturbation responses in the warm waters of the Pacific Ocean.


Effect of pulsed electromagnetic fields on maturation of regenerate bone in a rabbit limb lengthening model.
To study the effect of applying pulsed electromagnetic fields (PEMF) during the consolidation phase of limb lengthening, a mid-tibial osteotomy was performed in 18 adult New Zealand White rabbits and an external fixator was applied anteromedially. Animals were randomly assigned to treatment and control groups. After a 7-day latency period, the tibiae were distracted 0.5 mm every 12 h for 10 days. The treatment group received a 20-day course of PEMF for 60 min daily, coinciding with initiation of the consolidation phase. The control group received sham PEMF. Radiographs were performed weekly after distraction. Animals were euthanized 3 weeks after the end of distraction. Radiographic analysis revealed no significant difference in regenerate callus area between treatment and control tibiae immediately after distraction, at 1 week, 2 weeks, or 3 weeks after distraction ( p = 0.71, 0.22, 0.44, and 0.50, respectively). There was also no significant difference in percent callus mineralization ( p = 0.96, 0.69, 0.99, and 0.99, respectively). There was no significant difference between groups with respect to structural stiffness ( p = 0.80) or maximal torque to failure ( p = 0.62). However, there was a significant positive difference in mineral apposition rate between groups during the interval 1-2 weeks post-distraction ( p < 0.05). This difference was no longer evident by the interval 2-3 weeks post-distraction. While PEMF applied during the consolidation phase of limb lengthening did not appear to have a positive effect on bone regenerate, it increased osteoblastic activity in the cortical bone adjacent to the distraction site. Since the same PEMF signal was reported to be beneficial in the rabbit distraction osteogenesis when applied during distraction phase and consolidation phase, application of PEMF in the early phase may be more effective. Further work is necessary to determine optimal timing of the PEMF stimulation during distraction osteogenesis.


Efficacy of Daflon in the treatment of hemorrhoids.
To demonstrate the value of Daflon in the management of hemorrhoidal symptoms in Saudi patients attending the Surgical clinic. This is a prospective clinical study of 105 consecutive patients suffering from hemorrhoidal problems including thrombosed piles. Detailed history and proctoscopic examination to determine position, size, and degree of hemorrhoids was conducted in all patients attending the Surgical Clinic at Dammam Central Hospital, Dammam, Kingdom of Saudi Arabia (KSA). The study was conducted over a 6-months period (December 2000 to May 2001). All were started on Daflon; 2 tablets twice daily for 4 weeks and were followed up weekly during the study period and proctoscopic examination was conducted at each consultation. The mean age was 35 (range 19-70) years. The majority (77%) suffered congested hemorrhoidal disease and only 8% had thrombosed piles. Previous surgery for piles was noted in 11%. Concomitant medical diseases were present in 10%. The degrees of piles were first degree (23 patients), 2nd degree (73), 3rd degree (9) and 4th degree (0). There was a statistically significant (p<0.001) improvement in pain, heaviness, bleeding, pruritus, and mucosal discharge from baseline to last visit. There was also a significant (p<0.001) improvement on the proctoscopic appearance. Five patients failed to improve on Daflon; therefore, they underwent surgery. The side effects of Daflon (mainly gastrointestinal symptoms) were encountered in 5 patients but did not force interruption of the medication. Daflon is a very safe and effective drug in the treatment of all hemorrhoidal symptoms in the population of Eastern KSA.


A novel diagnostic method for malaria using loop-mediated isothermal amplification (LAMP) and MinION™ nanopore sequencer.
A simple and accurate molecular diagnostic method for malaria is urgently needed due to the limitations of conventional microscopic examination. In this study, we demonstrate a new diagnostic procedure for human malaria using loop mediated isothermal amplification (LAMP) and the MinION™ nanopore sequencer. We generated specific LAMP primers targeting the 18S-rRNA gene of all five human Plasmodium species including two P. ovale subspecies (P. falciparum, P. vivax, P. ovale wallikeri, P. ovale curtisi, P. knowlesi and P. malariae) and examined human blood samples collected from 63 malaria patients in Indonesia. Additionally, we performed amplicon sequencing of our LAMP products using MinION™ nanopore sequencer to identify each Plasmodium species. Our LAMP method allowed amplification of all targeted 18S-rRNA genes of the reference plasmids with detection limits of 10-100 copies per reaction. Among the 63 clinical samples, 54 and 55 samples were positive by nested PCR and our LAMP method, respectively. Identification of the Plasmodium species by LAMP amplicon sequencing analysis using the MinION™ was consistent with the reference plasmid sequences and the results of nested PCR. Our diagnostic method combined with LAMP and MinION™ could become a simple and accurate tool for the identification of human Plasmodium species, even in resource-limited situations.


An alternative mechanical parameter for assessing the viability of articular cartilage.
This paper is a sequel to previously published findings showing that mechanical indentation alone cannot clearly discriminate between normal and degraded articular cartilage. Consequently, the structural elasticity potential Rc = epsilon r/sigma i, which combines indentation stress sigma i with near-instantaneous rebound epsilon r following unloading, is hypothesized as a potential cartilage assessment parameter, which arguably measures the integrity of the collagen fibre-proteoglycan entrapment system. To establish the validity of our hypothesis, samples of normal intact, artificially degraded, and osteoarthritic bovine cartilage were subjected to quasi-static compression at 0.1 s(-1) and 0.025 s(-1) to 30 per cent strain and then unloaded. A significant reduction in recovery was observed for artificially and naturally degraded samples in the first 5s following unloading (p < 0.01). The structural elasticity potential provided a considerable improvement over the results obtained using the individual indentation and rebound parameters to distinguish between paired normal and artificially degraded samples and indicated a high statistical significance of p < 0.005 when applied to the differentiation of normal and osteoarthritic samples.


Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development.
Chondrocyte hypertrophy followed by cartilage matrix degradation and vascular invasion, characterized by expression of type X collagen (COL10A1), matrix metalloproteinase-13 (MMP-13) and vascular endothelial growth factor (VEGF), respectively, are central steps of endochondral ossification during normal skeletal growth and osteoarthritis development. A COL10A1 promoter assay identified hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) as the most potent transactivator of COL10A1. HIF-2alpha enhanced promoter activities of COL10A1, MMP13 and VEGFA through specific binding to the respective hypoxia-responsive elements. HIF-2alpha, independently of oxygen-dependent hydroxylation, was essential for endochondral ossification of cultured chondrocytes and embryonic skeletal growth in mice. HIF-2alpha expression was higher in osteoarthritic cartilages versus nondiseased cartilages of mice and humans. Epas1-heterozygous deficient mice showed resistance to osteoarthritis development, and a functional single nucleotide polymorphism (SNP) in the human EPAS1 gene was associated with knee osteoarthritis in a Japanese population. The EPAS1 promoter assay identified RELA, a nuclear factor-kappaB (NF-kappaB) family member, as a potent inducer of HIF-2alpha expression. Hence, HIF-2alpha is a central transactivator that targets several crucial genes for endochondral ossification and may represent a therapeutic target for osteoarthritis.


Knowledge-based biomedical word sense disambiguation: comparison of approaches.
Word sense disambiguation (WSD) algorithms attempt to select the proper sense of ambiguous terms in text. Resources like the UMLS provide a reference thesaurus to be used to annotate the biomedical literature. Statistical learning approaches have produced good results, but the size of the UMLS makes the production of training data infeasible to cover all the domain. We present research on existing WSD approaches based on knowledge bases, which complement the studies performed on statistical learning. We compare four approaches which rely on the UMLS Metathesaurus as the source of knowledge. The first approach compares the overlap of the context of the ambiguous word to the candidate senses based on a representation built out of the definitions, synonyms and related terms. The second approach collects training data for each of the candidate senses to perform WSD based on queries built using monosemous synonyms and related terms. These queries are used to retrieve MEDLINE citations. Then, a machine learning approach is trained on this corpus. The third approach is a graph-based method which exploits the structure of the Metathesaurus network of relations to perform unsupervised WSD. This approach ranks nodes in the graph according to their relative structural importance. The last approach uses the semantic types assigned to the concepts in the Metathesaurus to perform WSD. The context of the ambiguous word and semantic types of the candidate concepts are mapped to Journal Descriptors. These mappings are compared to decide among the candidate concepts. Results are provided estimating accuracy of the different methods on the WSD test collection available from the NLM. We have found that the last approach achieves better results compared to the other methods. The graph-based approach, using the structure of the Metathesaurus network to estimate the relevance of the Metathesaurus concepts, does not perform well compared to the first two methods. In addition, the combination of methods improves the performance over the individual approaches. On the other hand, the performance is still below statistical learning trained on manually produced data and below the maximum frequency sense baseline. Finally, we propose several directions to improve the existing methods and to improve the Metathesaurus to be more effective in WSD.


Expanding the role for psychology in addressing environmental challenges.
Environmental challenges, though daunting, present an important area for psychologists to apply their knowledge. Psychological theories, research methods, and interventions are essential for examining the questions about human impacts, tendencies, and capacities that are integral to constructing effective responses to these challenges. Although a great deal of relevant research has been done, there is scope for psychologists to be more extensively involved. Following a brief review of existing research, we outline some important new directions. We also highlight 2 key divergences, arguing that psychological research needs to expand beyond a traditional, theory-based and decontextualized approach to environmental issues to incorporate a contextualized or "place-based" approach and a willingness to collaborate in interdisciplinary research teams that focus on specific environmental problems. Suggestions for promoting such interdisciplinary collaborations are reviewed. We encourage psychologists to expand their engagement with important environmental issues through multiple research approaches in order to further their understanding of human behavior, contributions to human well-being, and relevance to other disciplines and to society.


Placental first trimester's measurements in relation to maternal plasma adiponectin, leptin and insulin concentrations.
The dysregulation of adiponectin and leptin is found in insulin resistance. There is evidence that both cytokines and insulin might contribute to the placental development and the fetal growth. The objective of this study was to evaluate the relationship of maternal plasma cytokine and insulin concentrations with the placental dimension in the first trimester of pregnancy. 34 women with singleton pregnancy, between 11th and 14th weeks, were included to the study. Plasma levels of adiponectin, leptin, insulin and glucose were quantified with ultrasound measurements of the placenta. HOMA-IR were calculated to assess the insulin sensitivity. Mean concentrations of adiponectin, leptin and insulin were 18,39±13.99 µg/ml; 6.99±5.67 ng/ml and 43.98±23.89 pmol/l respectively. The placenta thickness was positively associated with the maternal adiponectin plasma concentration (r=0.36; p=0.037). There were no associations between placental measurements and leptin, fasting insulin, fasting glucose and HOMA-IR. There was not significant correlation between placental measurements and the fetal Crown Rump Length (CRL). The results of this study imply that maternal adiponectin plasma concentration may have a role in placental growth.


Update on major reconstruction of the head and neck.
Reconstruction of soft-tissue defects in the head and neck is best accomplished using similar composite tissue. In the head and neck, this tissue is usually available in the form of adjacent tissue transfer. The local adjacent tissue resembles the resected tissue in color and composition. In some circumstances, the local tissue is not suitable for transfer. This may be due to previous surgery, exposure to radiation, or a defect that is too large for local tissue transfer. In these cases, free tissue transfer may be needed. Free tissue transfer allows for the replacement of similar composite tissue that has not seen previous treatment. The diversity of sites that may be harvested allows a relatively similar tissue match. This article discusses recent advances in the reconstruction of 3 areas that in the past have presented many problems to the reconstructive surgeon. Total nasal and lip reconstruction have been problematic. In heavily pretreated patients, the reconstruction often results in suboptimal outcomes. Large scalp defects in the setting of previous excisions or irradiation are difficult to reconstruct and rehabilitate. In all of these cases, the ability to transfer composite tissue has improved the functional and cosmetic outcomes.


Sodium bicarbonate ingestion augments the increase in PGC-1α mRNA expression during recovery from intense interval exercise in human skeletal muscle.
We tested the hypothesis that ingestion of sodium bicarbonate (NaHCO3) prior to an acute session of high-intensity interval training (HIIT) would augment signaling cascades and gene expression linked to mitochondrial biogenesis in human skeletal muscle. On two occasions separated by ∼1 wk, nine men (mean ± SD: age 22 ± 2 yr, weight 78 ± 13 kg, V̇O(2 peak) 48 ± 8 ml·kg(-1)·min(-1)) performed 10 × 60-s cycling efforts at an intensity eliciting ∼90% of maximal heart rate (263 ± 40 W), interspersed with 60 s of recovery. In a double-blind, crossover manner, subjects ingested a total of 0.4 g/kg body weight NaHCO3 before exercise (BICARB) or an equimolar amount of a placebo, sodium chloride (PLAC). Venous blood bicarbonate and pH were elevated at all time points after ingestion (P < 0.05) in BICARB vs. PLAC. During exercise, muscle glycogen utilization (126 ± 47 vs. 53 ± 38 mmol/kg dry weight, P < 0.05) and blood lactate accumulation (12.8 ± 2.6 vs. 10.5 ± 2.8 mmol/liter, P < 0.05) were greater in BICARB vs. PLAC. The acute exercise-induced increase in the phosphorylation of acetyl-CoA carboxylase, a downstream marker of AMP-activated protein kinase activity, and p38 mitogen-activated protein kinase were similar between treatments (P > 0.05). However, the increase in PGC-1α mRNA expression after 3 h of recovery was higher in BICARB vs. PLAC (approximately sevenfold vs. fivefold compared with rest, P < 0.05). We conclude that NaHCO3 before HIIT alters the mRNA expression of this key regulatory protein associated with mitochondrial biogenesis. The elevated PGC-1α mRNA response provides a putative mechanism to explain the enhanced mitochondrial adaptation observed after chronic HIIT supplemented with NaHCO3 in rats.


Variability of FP-CIT PET Patterns Associated With Clinical Features of Multiple System Atrophy.
To validate the role of the dopamine transporter (DAT) imaging as a biomarker in multiple system atrophy (MSA), we analyzed the association between spatial patterns of [18F]fluoro-propyl-carbomethoxy-iodophenyl-tropane ([18F]FP-CIT) PET and the clinical characteristics of MSA. Sixty-five patients with MSA who underwent [18F]FP-CIT PET between 2009 and 2018 were retrospectively enrolled. To identify spatial patterns of [18F]FP-CIT PET, principal component (PC) analysis was used and correlated with the clinical presentation. Of the 65 patients, 42 presented with parkinsonian subtype of MSA, and 23 presented with cerebellar subtype of MSA (mean age 63.7 ± 9.3 years; disease duration, 1.8 ± 1.8 years). Each PC represents a specific pattern of degeneration: PC1 and PC2 were associated with the DAT binding of the entire putamen and the posterior putamen, respectively. PC3 was associated with increased [18F]FP-CIT uptake of the caudate and decreased uptake of the dorsal pons. PC2 was significantly correlated with the presence of parkinsonism (p = 5.34 × 10-5) and a positive levodopa response (p = 0.044), with age as a cofactor. PC3 was correlated with the presence of urinary incontinence (p = 0.036). Onset age was significantly correlated with both PC2 (R = 0.48, p = 5.0 × 10-5) and PC3 (R = -0.39, p = 0.0013). The spatial pattern of DAT binding can reflect distinct clinical features of MSA and provides insight into the underlying pathophysiology of a broad spectrum of clinical features in MSA.


Use of Sedatives, Antidepressants and Antipsychotic Medicine among Seventh-day Adventists and Baptists in Denmark.
Earlier it has been found that female Seventh-day Adventists (SDA) and Baptists have an increased incidence of psychiatric affective disorders, in contrast to findings that religious practice is associated with better health. In this study, we examined whether the increase in incidence is due to less use of prescribed antidepressants, sedatives and antipsychotics by members of these religious societies than by the general population. In a cohort study, we examined records of all drugs redeemed by 3121 SDA and 2888 Baptists and 29,817 age- and gender-matched members of the general population between 1995 and 2010 in the Danish Prescription Register and compared the prevalence and incidence of use of antidepressants, sedatives and antipsychotics. The prevalence of antidepressant use by women was lower in 1998 but no different from that in controls in 2003 and 2008; the prevalence of antidepressant use by men was higher in both 1998 and 2008 than in the Danish population. The incidence of antidepressant use was lower for female members in 1996-2000, but no difference was observed in the other periods. The prevalence and incidence of use of sedatives and antipsychotics did not consistently differ from those of the general population. The prevalence and incidence of use of antidepressants, sedatives and antipsychotics by female SDA and Baptists were not consistently lower than in the general Danish population. Our findings hence do not explain the increased incidence of psychiatric disorders among female members of these Danish religious societies.


Advanced tools for tissue engineering: scaffolds, bioreactors, and signaling.
This article contains the collective views expressed at the second session of the workshop "Tissue Engineering--The Next Generation,'' which was devoted to the tools of tissue engineering: scaffolds, bioreactors, and molecular and physical signaling. Lisa E. Freed and Farshid Guilak discussed the integrated use of scaffolds and bioreactors as tools to accelerate and control tissue regeneration, in the context of engineering mechanically functional cartilage and cardiac muscle. Edward Guo focused on the opportunities that tissue engineering generates for studies of mechanobiology and on the need for tissue engineers to learn about mechanical forces during tissue and organ genesis. Martha L. Gray focused on the potential of biomedical imaging for noninvasive monitoring of engineered tissues and on the opportunities biomedical imaging can generate for the development of new markers. Robert Tranquillo reviewed the approach to tissue engineering of a spectrum of avascular habitually loaded tissues- blood vessels, heart valves, ligaments, tendons, cartilage, and skin. Jeffrey W. Holmes offered the perspective of a "reverse paradigm''--the use of tissue constructs in quantitative studies of cell-matrix interactions, cell mechanics, matrix mechanics, and mechanobiology. Milica Radisic discussed biomimetic design of tissue-engineering systems, on the example of synchronously contractile cardiac muscle. Michael V. Sefton proposed a new, simple approach to the vascularization of engineered tissues. This session stressed the need for advanced scaffolds, bioreactors, and imaging technologies and offered many enlightening examples on how these advanced tools can be utilized for functional tissue engineering and basic research in medicine and biology.


Identifying nonalcoholic fatty liver disease patients with active fibrosis by measuring extracellular matrix remodeling rates in tissue and blood.
Excess collagen synthesis (fibrogenesis) in the liver plays a causal role in the progression of nonalcoholic fatty liver disease (NAFLD). Methods are needed to identify patients with more rapidly progressing disease and to demonstrate early response to treatment. We describe here a novel method to quantify hepatic fibrogenesis flux rates both directly in liver tissue and noninvasively in blood. Twenty-one patients with suspected NAFLD ingested heavy water (2 H2 O, 50-mL aliquots) two to three times daily for 3-5 weeks prior to a clinically indicated liver biopsy. Liver collagen fractional synthesis rate (FSR) and plasma lumican FSR were measured based on 2 H labeling using tandem mass spectrometry. Patients were classified by histology for fibrosis stage (F0-F4) and as having nonalcoholic fatty liver or nonalcoholic steatohepatitis (NASH). Magnetic resonance elastography measurements of liver stiffness were also performed. Hepatic collagen FSR in NAFLD increased with advancing disease stage (e.g., higher in NASH than nonalcoholic fatty liver, positive correlation with fibrosis score and liver stiffness) and correlated with hemoglobin A1C. In addition, plasma lumican FSR demonstrated a significant correlation with hepatic collagen FSR. Using a well-characterized cohort of patients with biopsy-proven NAFLD, this study demonstrates that hepatic scar in NASH is actively remodeled even in advanced fibrosis, a disease that is generally regarded as static and slowly progressive. Moreover, hepatic collagen FSR correlates with established risks for fibrotic disease progression in NASH, and plasma lumican FSR correlates with hepatic collagen FSR, suggesting applications as direct or surrogate markers, respectively, of hepatic fibrogenesis in humans. (Hepatology 2017;65:78-88).


Optimal 10-Aminoartemisinins With Potent Transmission-Blocking Capabilities for New Artemisinin Combination Therapies-Activities Against Blood Stage P. falciparum Including PfKI3 C580Y Mutants and Liver Stage P. berghei Parasites.
We have demonstrated previously that amino-artemisinins including artemiside and artemisone in which an amino group replaces the oxygen-bearing substituents attached to C-10 of the current clinical artemisinin derivatives dihydroartemisinin (DHA), artemether and artesunate, display potent activities in vitro against the asexual blood stages of Plasmodium falciparum (Pf). In particular, the compounds are active against late blood stage Pf gametocytes, and are strongly synergistic in combination with the redox active drug methylene blue. In order to fortify the eventual selection of optimum amino-artemisinins for development into new triple combination therapies also active against artemisinin-resistant Pf mutants, we have prepared new amino-artemisinins based on the easily accessible and inexpensive DHA-piperazine. The latter was converted into alkyl- and aryl sulfonamides, ureas and amides. These derivatives were screened together with the comparator drugs DHA and the hitherto most active amino-artemisinins artemiside and artemisone against asexual and sexual blood stages of Pf and liver stage P. berghei (Pb) sporozoites. Several of the new amino-artemisinins bearing aryl-urea and -amide groups are potently active against both asexual, and late blood stage gametocytes (IC50 0.4-1.0 nM). Although the activities are superior to those of artemiside (IC50 1.5 nM) and artemisone (IC50 42.4 nM), the latter are more active against the liver stage Pb sporozoites (IC50 artemisone 28 nM). In addition, early results indicate these compounds tend not to display reduced susceptibility against parasites bearing the Pf Kelch 13 propeller domain C580Y mutation characteristic of artemisinin-resistant Pf. Thus, the advent of the amino-artemisinins including artemiside and artemisone will enable the development of new combination therapies that by virtue of the amino-artemisinin component itself will possess intrinsic transmission-blocking capabilities and may be effective against artemisinin resistant falciparum malaria.


Quality of Cancer Surveillance Clinical Practice Guidelines: Specificity and Consistency of Recommendations.
Primary care clinicians, who are increasingly responsible for caring for the growing population of cancer survivors, may be unfamiliar with appropriate cancer surveillance strategies. Clinical practice guidelines can inform cancer follow-up care and surveillance testing. Vague recommendations and inconsistencies among guidelines can lead to overuse and underuse of health care resources and have a negative impact on cost and quality of survivorship care. To examine the specificity and consistency of recommendations for surveillance after active treatment across cancer guidelines. Retrospective cross-sectional analysis of national cancer guidelines from North America and Europe published since 2010 addressing posttreatment care for survivors of the 9 most common cancers. We categorized surveillance modalities into history and physical examinations, tumor markers, diagnostic procedures (eg, colonoscopy), and imaging. Within each guideline, we classified individual recommendations into 5 categories: (1) risk-based recommendation, (2) recommendation for surveillance, (3) addressed but no clear recommendation, (4) recommendation against surveillance, or (5) cases in which surveillance was not addressed. We reviewed each surveillance recommendation for frequency and a stop date, evaluated consistency among guidelines, and analyzed associations between the organizations proposing the guidelines and recommendation characteristics. Description of guideline recommendations for cancer surveillance. We identified 41 guidelines published between January 1, 2010, and March 1, 2016. Eighty-five percent of guidelines (35) were from professional organizations. Ambiguous recommendations (ie, modality not discussed or discussed without a clear recommendation) were present in 83% of guidelines (34), and 44% (18) recommended against at least 1 test. European guidelines were more likely than North American guidelines to contain ambiguous recommendations (100% vs 68%; P < .01). Recommendations commonly specified testing frequency (from 88% [14 of 16] for tumor markers to 92% [24 of 26] for procedures and/or imaging) but infrequently provided a definitive stop time. Cross-sectional imaging recommendations varied among guidelines for each cancer. For example, among breast cancer guidelines, surveillance computed tomographic scans were recommended against in 2, discussed without a clear recommendation in 1, and not addressed in 3 guidelines. Guidelines addressing the care of cancer survivors have low specificity and consistency. As guidelines continue to be revised, developers should clarify recommendations with simple, nonambiguous, definitive language for or against the use of specific tests to optimize care quality and resource utilization.


Influence of caffeine on metabolic and cardiovascular functions during sustained light intensity cycling and at rest.
This study assessed the influence of caffeine on metabolic and cardiovascular functions during sustained, light intensity cycling and at rest. Eight healthy, recreationally active adults participated in four randomly assigned, double-blind experimental trials of 60 min upright seated cycle exercise (30% VO2 max) or equivalent rest with caffeine (5 mg.kg-1) or placebo consumed 60 min prior to data collection. Gas exchange was measured by open-circuit spirometry indirect calorimetry. Global blood flow was evaluated by thoracic impedance cardiography and arterial blood pressure by auscultation. A repeated measures ANOVA indicated that pretrial caffeine increased oxygen uptake and energy expenditure rate (p < 0.05) but did not change respiratory exchange ratio. Systolic, diastolic, and mean arterial blood pressure were elevated following caffeine intake (p < 0.05). Cardiac output, heart rate, stroke volume, and systemic vascular resistance were not significantly different between caffeine and placebo sessions. For each of the metabolic and hemodynamic variables examined, the effects of caffeine were similar during constant-load, light intensity cycling and at rest. These data illustrate that caffeine's mild thermogenic influence can be mediated without a major shift in substrate oxidation mixture. Caffeine at this dosage level alters cardiovascular dynamics by augmenting arterial blood pressure.


Origins of Life Research: a Bibliometric Approach.
This study explores the collaborative nature and interdisciplinarity of the origin(s) of life (OoL) research community. Although OoL research is one of the oldest topics in philosophy, religion, and science; to date there has been no review of the field utilizing bibliometric measures. A dataset of 5647 publications that are tagged as OoL, astrobiology, exobiology, and prebiotic chemistry is analyzed. The most prolific authors (Raulin, Ehrenfreund, McKay, Cleaves, Cockell, Lazcano, etc.), most cited scholars and their articles (Miller 1953, Gilbert 1986, Chyba & Sagan 1992, Wȁchtershȁuser 1988, etc.), and popular journals (Origins of Life and Evolution of Biospheres and Astrobiology) for OoL research are identified. Moreover, interdisciplinary research conducted through research networks, institutions (NASA, Caltech, University of Arizona, University of Washington, CNRS, etc.), and keywords & concepts (astrobiology, life, Mars, amino acid, prebiotic chemistry, evolution, RNA) are explored.


Monitoring deep brain stimulation by measuring regional brain oxygen responses in freely moving mice.
Translational studies investigating the effects of deep brain stimulation (DBS) on brain function up to now mainly relied on BOLD responses measured with fMRI. However, fMRI studies in rodents face technical and practical limitations (e.g., immobilization, sedation or anesthesia, spatial and temporal resolution of data). Direct measurement of oxygen concentration in the brain using electrochemical sensors is a promising alternative to the use of fMRI. Here, we tested for the first time if such measurements can be combined with DBS. We combined bilateral DBS in the internal capsule (IC-DBS) with simultaneous amperometric measurements of oxygen in the medial prefrontal cortex (prelimbic area) and striatum of freely moving mice. Using a two-day within-animal experimental design, we tested the effects of DBS on baseline oxygen concentrations, and on novelty- and restraint-induced increases in oxygen concentration. Basal oxygen levels were stable across the daily sampling periods. Exposure to novelty and immobilization reproducibly increased oxygen concentrations in both areas. IC-DBS did not significantly alter basal oxygen, but reduced the novelty-induced increase in the striatum. Amperometric detection of brain oxygen concentration with high temporal and spatial resolution can be performed in a number of key brain areas to study the effects of DBS in animal models of disease. The method is easily implemented and does not require expensive equipment or complicated data analysis processes. Direct and simultaneous measurement of brain oxygen concentration in multiple brain areas can be used to study the effects of bilateral DBS neuromodulation on brain activity in freely moving mice.


Analysis of cyclitols in different Quercus species by gas chromatography-mass spectrometry.
The carbohydrate profile of some woods used for aging wines and spirits has been recently studied using a pressurized liquid extraction method, the main differences found being related to cyclitol content. The aim of this study was to perform a detailed study of these compounds in woods of different Quercus species in order to identify two unknown compounds which appeared in the extracts and to verify whether the obtained profile was homogeneous for other Quercus species. Besides the known monosaccharides and five cyclitols previously described, three deoxy-inositols (epi-, vibo- and scyllo-quercitol) were identified. The presence of these eight cyclitols was confirmed in all subgenera and species of Quercus analyzed, allowing a characteristic cyclitol profile. Three deoxy-inositols (quercitols) have been identified in the carbohydrate profile of oak wood. All examined Quercus species displayed a common profile consisting of four inositols and four quercitols, which represent a good dataset for characterization of this genus.


Systematic analysis of YFP traps reveals common mRNA/protein discordance in neural tissues.
While post-transcriptional control is thought to be required at the periphery of neurons and glia, its extent is unclear. Here, we investigate systematically the spatial distribution and expression of mRNA at single molecule sensitivity and their corresponding proteins of 200 YFP trap lines across the intact Drosophila nervous system. 97.5% of the genes studied showed discordance between the distribution of mRNA and the proteins they encode in at least one region of the nervous system. These data suggest that post-transcriptional regulation is very common, helping to explain the complexity of the nervous system. We also discovered that 68.5% of these genes have transcripts present at the periphery of neurons, with 9.5% at the glial periphery. Peripheral transcripts include many potential new regulators of neurons, glia, and their interactions. Our approach is applicable to most genes and tissues and includes powerful novel data annotation and visualization tools for post-transcriptional regulation.


The Presence of Scarring and Associated Morbidity in the Burn Model System National Database.
Postburn scarring is common, but the risk factors, natural history, and consequences of such scars are still poorly understood. This study aims to describe the frequency of scar-related morbidity for up to 2 years after injury and to analyze the impact of burn scars on long-term functional, psychosocial, and reintegration outcomes. Analysis was conducted on data collected between January 2006 and May 2014 from 960 patients (2440 anatomic burn sites) using the Burn Model System (BMS) database. Study population demographics were analyzed and odds ratios for the development of raised or thick scarring were determined. Regression analyses were used to evaluate the impact of hypertrophic scarring (HTS) on psychosocial outcomes, including the Community Integration Questionnaire, Satisfaction with Life Scale, Distress, and the Short Form 12. Symptoms associated with scarring were analyzed at discharge and 6, 12, and 24 months after burn using a set of questions on scarring developed by the BMS. Mixed-effect modeling was used to determine linear change over time and the significance of symptoms. The study population was primarily white (65.0%) and male (71.8%), with a mean (SD) age of 44.0 (15.2) years and mean total body surface area burned of 19.6% (17.9%). The incidence of raised or thick scars increased from 65% to 80% (P < 0.0001) for the 2-year follow-up period. The presence of scarring was not associated with Community Integration Questionnaire, Satisfaction with Life Scale, or Short Form 12 scores. Most patients reported symptoms associated with scarring at 2 years after burn, including dry or fragile skin, scars that restrict range of motion at a joint, issues with hand function, and scar pain and itch. In this large, longitudinal, multicenter cohort of burn survivors, nearly all patients noted the presence of scarring, and a majority noted additional symptoms and morbidity related to their scars even at 2 years after injury. This study demonstrates a need for the continued support of burn survivors to address scar-related morbidity. Furthermore, future studies examining the impact of novel treatments for scarring should use similar scar problem questionnaires and distress scores.


Historical changes in northeastern US bee pollinators related to shared ecological traits.
Pollinators such as bees are essential to the functioning of terrestrial ecosystems. However, despite concerns about a global pollinator crisis, long-term data on the status of bee species are limited. We present a long-term study of relative rates of change for an entire regional bee fauna in the northeastern United States, based on >30,000 museum records representing 438 species. Over a 140-y period, aggregate native species richness weakly decreased, but richness declines were significant only for the genus Bombus. Of 187 native species analyzed individually, only three declined steeply, all of these in the genus Bombus. However, there were large shifts in community composition, as indicated by 56% of species showing significant changes in relative abundance over time. Traits associated with a declining relative abundance include small dietary and phenological breadth and large body size. In addition, species with lower latitudinal range boundaries are increasing in relative abundance, a finding that may represent a response to climate change. We show that despite marked increases in human population density and large changes in anthropogenic land use, aggregate native species richness declines were modest outside of the genus Bombus. At the same time, we find that certain ecological traits are associated with declines in relative abundance. These results should help target conservation efforts focused on maintaining native bee abundance and diversity and therefore the important ecosystems services that they provide.


Chimeric hERG channels containing a tetramerization domain are functional and stable.
Biochemical and detailed structural information of human ether-a-go-go-related gene (hERG) potassium channels are scarce but are a prerequisite to understand the unwanted interactions of hERG with drugs and the effect of mutations that lead to long QT syndrome. Despite the huge interest in hERG, to our knowledge, procedures that provide a purified, functional, and tetrameric hERG channel are not available. Here, we describe hybrid hERG molecules, termed chimeric hERG channels, in which the N-terminal Per-Arnt-Sim (PAS) domain is deleted and the C-terminal C-linker as well as the cyclic nucleotide binding domain (CNBD) portion is replaced by an artificial tetramerization domain. These chimeric hERG channels can be overexpressed in HEK cells, solubilized in detergent, and purified as tetramers. When expressed in Xenopus laevis oocytes, the chimeric channels exhibit efficient trafficking to the cell surface, whereas a hERG construct lacking the PAS and C-linker/CNBD domains is retained in the cytoplasm. The chimeric hERG channels retain essential hERG functions such as voltage-dependent gating and inhibition by astemizole and the scorpion toxin BeKm-1. The chimeric channels are thus powerful tools for helping to understand the contribution of the cytoplasmic hERG domains to the gating process and are suitable for in vitro biochemical and structural studies.


Insulin like activity in (-) epicatechin.
Water extract of the bark of plant of Pterocarpus marsupium Roxb is used as an antidiabetic drug in indigenous medicine in India. (-) Epicatechin, its active principle, has been found to be insulinogenic. The present in vitro study reports some insulin like activities of (-) epicatechin. Like insulin, (-) epicatechin stimulates oxygen uptake in fat cells and tissue slices of various organs, increases glycogen content of rat diaphragm in dose-dependent manner with corresponding increase in U14-C glucose uptake, and inhibits theophylline induced lipolysis in isolated fat pads in dose-dependent manner. Experiments on competitive binding of 125I-insulin and (-) epicatechin to liver cell plasma membrane indicate that insulin does not share binding site with (-) epicatechin. (-) Epicatechin at a concentration of up to 1 mM does not effect the release of glucagon from the islets in vitro. Thus, (-) epicatechin has insulinogenic as well as insulin like properties.


Diagnostic accuracy of manual office blood pressure measurement in ambulatory hypertensive patients in Korea.
Currently, office blood pressure (OBP) is the most widely used method of measuring blood pressure (BP) in daily clinical practice. However, data on the diagnostic accuracy of OBP in reference to ambulatory blood pressure (ABP) are scarce in Korea. In retrospective and prospective cohorts, manual OBP and ABP measurements were compared among ambulatory hypertensive patients. Hypertension was defined as systolic OBP ≥ 140 mmHg and/or diastolic OBP ≥ 90 mmHg, and systolic ABP ≥ 130 mmHg and/or diastolic ABP ≥ 80 mmHg. In the retrospective cohort (n = 903), the mean OBP1 (before ABP measurement) was higher than ABP in both systolic (138 ± 17 mmHg vs. 123 ± 13 mmHg, p < 0.001) and diastolic (84 ± 12 mmHg vs. 78 ± 11 mmHg, p < 0.001) measurements. Interestingly, there was only a weak correlation between OBP and ABP (r2 = 0.038, p < 0.001). The overall discordance rate of OBP compared to ABP, which is the reference method for measuring BP, was 43.9%. The prospective cohort (n = 57) showed similar results. In a subgroup analysis, male patients had higher false negative results (masked or under-treated hypertension) than did female patients (26.1% vs. 17.8%, p = 0.003), whereas female patients had a higher false positive rate (white-coat or over-treated hypertension) than did male patients (28.7% vs. 15.2%, p < 0.001). The diagnostic accuracy of manual OBP is low in reference to ABP. Men and women have different patterns of discordance. These findings indicate that management of hypertensive patients with manual OBP measurements may be suboptimal and encourages the use of ABP in ambulatory hypertensive patients.


[Preparing For the COVID-19 Pandemic: The Perspective of a Department of Anesthesiology in a Tertiary Hospital in Portugal].
Since the detection of the first cases of COVID-19, reported by the People's Republic of China on the 31st December 2019, up to the confirmation of the first cases in Portugal, on the 2nd March, countries like Italy and Spain faced the collapse of their healthcare systems. Anticipating this possibility, the Portuguese National Health Service carried out measures to prepare for this reality. This paper describes the changes implemented in the Anesthesiology department of a tertiary hospital center in Portugal, aiming to ensure the safety of both patients and healthcare professionals. The measures implemented had to do mostly with scientific preparation and team reorganization; management of personal protective equipment; redesigning the department's clinical common areas, separation of patient circuits with creation of a designated COVID Operating Room, Post-Anesthetic Care Unit; rescheduling of elective surgery and testing all patients before anesthesia procedures and consulting other hospital departments. The reported data covers the period between the 2nd March and the 30th April of 2020. In this period, 64 cases with COVID-19 or with high clinical suspicion were approached. To date, there have been no cases of in-hospital spread to other patients or to professionals in this department. With this paper we intend to start a reflection that will end up with the optimization of strategies that allows health systems to deal better with COVID-19, keeping patients and health providers safe.


Preoperative cardiac risk assessment for patients having peripheral vascular surgery.
To review the methods used for preoperative cardiac risk stratification of patients having peripheral vascular surgery. Relevant studies published before August 1991 were identified using a MEDLINE search of the English-language literature, followed by a manual search of the references of all identified articles. All clinical studies evaluating methods used for preoperative cardiac risk stratification of patients having peripheral vascular surgery. The key data extracted from each article included the inclusion and exclusion criteria of the study patients, the techniques used for testing and the corresponding definitions of positive test results, and the clinical outcomes of the tested patients. Data were analyzed using a Bayesian conceptual framework, and pretest probabilities were converted to post-test probabilities using calculation of likelihood ratios. Patients with high scores on clinical cardiac risk indexes (Goldman index greater than 12 or Detsky index greater than 15), or more than three of the criteria identified by Eagle (age greater than 70 years, diabetes, angina, Q waves on electrocardiogram, or ventricular arrhythmias) are likely to be at higher risk for cardiac death and myocardial infarction after vascular surgery. Those with both low scores and none of Eagle's criteria may be at lower risk, but this result has not been reproduced by independent studies. Neither group of patients would benefit from further investigation for cardiac risk stratification. Patients with one or two of these criteria may be at intermediate risk and would benefit most from further testing for the purposes of risk stratification. Most of the published evidence shows that the absence of redistribution on dipyridamole-thallium scanning identifies a low risk for postoperative cardiac complications, whereas the presence of redistribution predicts a high risk. Preliminary reports suggest that preoperative monitoring for silent myocardial ischemia may also be useful in identifying a high-risk subset of patients. Patients identified clinically to be at either very low or high risk for cardiac complications after peripheral vascular surgery are unlikely to benefit from further risk stratification. Dipyridamole-thallium scanning is the test of choice for further evaluation of patients at intermediate clinical risk because studies have shown that it is sensitive enough to rule out a high-risk status for patients who do not have redistribution.


CD44 Regulates Formation of Spheroids and Controls Organ-Specific Metastatic Colonization in Epithelial Ovarian Carcinoma.
Disseminating epithelial ovarian cancer cells often become assembled into spheroids prior to their arrival at metastatic sites within the peritoneal cavity. Although epithelial ovarian carcinoma (EOC) is the deadliest gynecologic malignancy, the mechanisms regulating formation and metastatic potential of spheroids are poorly understood. We show that expression of a cell surface glycoprotein CD44 is an important contributing factor for spheroid formation and spheroid adhesion to mesothelial cells, and its loss impairs mesenteric metastasis. In contrast, loss of CD44 resulted in significant increase of tumor burden at several locoregional sites, including liver, and unleashed distant metastases to the thoracic cavity. Altogether our studies suggest that CD44 regulates metastatic progression of EOC in an organ-specific manner. IMPLICATIONS: Expression of CD44 promotes spheroid formation, mesothelial adhesion, and formation of mesenteric metastasis, but it suppresses development of metastasis to several peritoneal sites, including liver, and the thoracic cavity.


Optimization of Current Injection in AlGaInP Core-Shell Nanowire Light-Emitting Diodes.
Core-shell nanowires offer great potential to enhance the efficiency of light-emitting diodes (LEDs) and expand the attainable wavelength range of LEDs over the whole visible spectrum. Additionally, nanowire (NW) LEDs can offer both improved light extraction and emission enhancement if the diameter of the wires is not larger than half the emission wavelength (λ/2). However, AlGaInP nanowire LEDs have so far failed to match the high efficiencies of traditional planar technologies, and the parameters limiting the efficiency remain unidentified. In this work, we show by experimental and theoretical studies that the small nanowire dimensions required for efficient light extraction and emission enhancement facilitate significant loss currents, which result in a low efficiency in radial NW LEDs in particular. To this end, we fabricate AlGaInP core-shell nanowire LEDs where the nanowire diameter is roughly equal to λ/2, and we find that both a large loss current and a large contact resistance are present in the samples. To investigate the significant loss current observed in the experiments in more detail, we carry out device simulations accounting for the full 3D nanowire geometry. According to the simulations, the low efficiency of radial AlGaInP nanowire LEDs can be explained by a substantial hole leakage to the outer barrier layer due to the small layer thicknesses and the close proximity of the shell contact. Using further simulations, we propose modifications to the epitaxial structure to eliminate such leakage currents and to increase the efficiency to near unity without sacrificing the λ/2 upper limit of the nanowire diameter. To gain a better insight of the device physics, we introduce an optical output measurement technique to estimate an ideality factor that is only dependent on the quasi-Fermi level separation in the LED. The results show ideality factors in the range of 1-2 around the maximum LED efficiency even in the presence of a very large voltage loss, indicating that the technique is especially attractive for measuring nanowire LEDs at an early stage of development before electrical contacts have been optimized. The presented results and characterization techniques form a basis of how to simultaneously optimize the electrical and optical efficiency of core-shell nanowire LEDs, paving the way to nanowire light emitters that make true use of larger-than-unity Purcell factors and the consequently enhanced spontaneous emission.


Modeling the transformation of atmospheric CO2 into microalgal biomass.
Marine phytoplankton acts as a considerable sink of atmospheric CO2 as it sequesters large quantities of this greenhouse gas for biomass production. To assess microalgae's counterbalancing of global warming, the quantities of CO2 they fix need to be determined. For this task, it is mandatory to understand which environmental and physiological parameters govern this transformation from atmospheric CO2 to microalgal biomass. However, experimental analyses are challenging as it has been found that the chemical environment has a major impact on the physiological properties of the microalgae cells (diameter typ. 5-20 μm). Moreover, the cells can only chemically interact with their immediate vicinity and thus compound sequestration needs to be studied on a microscopic spatial scale. Due to these reasons, computer simulations are a more promising approach than the experimental studies. Modeling software has been developed that describes the dissolution of atmospheric CO2 into oceans followed by the formation of HCO3- which is then transported to individual microalgae cells. The second portion of this model describes the competition of different cell species for this HCO3-, a nutrient, as well as its uptake and utilization for cell production. Two microalgae species, i.e. Dunaliella salina and Nannochloropsis oculata, were cultured individually and in a competition situation under different atmospheric CO2 conditions. It is shown that this novel model's predictions of biomass production are in very good agreement with the experimental flow cytometry results. After model validation, it has been applied to long-term prediction of phytoplankton generation. These investigations were motivated by the question whether or not cell production slows down as cultures grow. This is of relevance as a reduced cell production rate means that the increase in a culture's CO2-sinking capacity slows down as well. One implication resulting from this is that an increase in anthropogenic CO2 may not be counterbalanced by an increase in phytoplankton production. Modeling studies have found that for several different atmospheric CO2 levels provided to single-species cultures as well as to species in competing scenarios the cell production rate does slow down over time.


LabDisk with complete reagent prestorage for sample-to-answer nucleic acid based detection of respiratory pathogens verified with influenza A H3N2 virus.
Portable point-of-care devices for pathogen detection require easy, minimal and user-friendly handling steps and need to have the same diagnostic performance compared to centralized laboratories. In this work we present a fully automated sample-to-answer detection of influenza A H3N2 virus in a centrifugal LabDisk with complete prestorage of reagents. Thus, the initial supply of the sample remains the only manual handling step. The self-contained LabDisk automates by centrifugal microfluidics all necessary process chains for PCR-based pathogen detection: pathogen lysis, magnetic bead based nucleic acid extraction, aliquoting of the eluate into 8 reaction cavities, and real-time reverse transcription polymerase chain reaction (RT-PCR). Prestored reagents comprise air dried specific primers and fluorescence probes, lyophilized RT-PCR mastermix and stick-packaged liquid reagents for nucleic acid extraction. Employing two different release frequencies for the stick-packaged liquid reagents enables on-demand release of highly wetting extraction buffers, such as sequential release of lysis and binding buffer. Microfluidic process-flow was successful in 54 out of 55 tested LabDisks. We demonstrate successful detection of the respiratory pathogen influenza A H3N2 virus in a total of 18 LabDisks with sample concentrations down to 2.39 × 10(4) viral RNA copies per ml, which is in the range of clinical relevance. Furthermore, we detected RNA bacteriophage MS2 acting as internal control in 3 LabDisks with a sample concentration down to 75 plaque forming units (pfu) per ml. All experiments were applied in a 2 kg portable, laptop controlled point-of-care device. The turnaround time of the complete analysis from sample-to-answer was less than 3.5 hours.


Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia.
The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.


Cystic lung disease in birt-hogg-dubé syndrome: a case series of three patients.
Birt-Hogg-Dubé syndrome is characterized by clinical manifestations such as hamartomas of the skin, renal tumors and lung cysts with spontaneous pneumothoraces. Patients with Birt-Hogg-Dubé syndrome may present with only multiple lung cysts. We report the chest computerized tomography (CT) features of three patients with Birt-Hogg-Dubé syndrome. Each patient had multiple lung cysts of various sizes according to chest CT evaluation, most of which were located in lower lobes and related to pleura. The identification of unique characteristics in the chest CT of patients with Birt-Hogg-Dubé syndrome may provide an efficient mechanism for diagnosis.


Folic acid administration inhibits amyloid β-peptide accumulation in APP/PS1 transgenic mice.
Alzheimer's disease (AD) is associated with malnutrition, altered one-carbon metabolism and increased hippocampal amyloid-β peptide (Aβ) accumulation. Aberrant DNA methylation may be an epigenetic mechanism that underlies AD pathogenesis. We hypothesized that folic acid acts through an epigenetic gene silencing mechanism to lower Aβ levels in the APP/PS1 transgenic mouse model of AD. APP/PS1 mice were fed either folate-deficient or control diets and gavaged daily with 120 μg/kg folic acid, 13.3mg/kg S-adenosylmethionine (SAM) or both. Examination of the mice after 60 days of treatment showed that serum folate concentration increased with intake of folic acid but not SAM. Folate deficiency lowered endogenous SAM concentration, whereas neither intervention altered S-adenosylhomocysteine concentration. DNA methyltransferase (DNMT) activity increased with intake of folic acid raised DNMT activity in folate-deficient mice. DNA methylation rate was stimulated by folic acid in the amyloid precursor protein (APP) promoter and in the presenilin 1 (PS1) promoter. Folate deficiency elevated hippocampal APP, PS1 and Aβ protein levels, and these rises were prevented by folic acid. In conclusion, these findings are consistent with a mechanism in which folic acid increases methylation potential and DNMT activity, modifies DNA methylation and ultimately decreases APP, PS1 and Aβ protein levels.


RADSeq: next-generation population genetics.
Next-generation sequencing technologies are making a substantial impact on many areas of biology, including the analysis of genetic diversity in populations. However, genome-scale population genetic studies have been accessible only to well-funded model systems. Restriction-site associated DNA sequencing, a method that samples at reduced complexity across target genomes, promises to deliver high resolution population genomic data-thousands of sequenced markers across many individuals-for any organism at reasonable costs. It has found application in wild populations and non-traditional study species, and promises to become an important technology for ecological population genomics.


A palliative intervention allows discovery of a rare tumor: lymphoepithelioma-like carcinoma of the skin.
An 85-year-old man is presented, suffering end-stage metastasizing hepatocellular carcinoma with a disabling tumor mass of 5 cm in diameter on his forehead. The tumor emitted an extremely foul odor, very disconcerting to the patient and family. The tumor was excised under local anaesthesia. Histopathologic examination disclosed the astonishing diagnosis of an extremely rare lymphoepithelioma-like carcinoma of the skin.


Entropy, entropy rate, and pattern classification as tools to typify complexity in short heart period variability series.
An integrated approach to the complexity analysis of short heart period variability series (approximately 300 cardiac beats) is proposed and applied to healthy subjects during the sympathetic activation induced by head-up tilt and during the driving action produced by controlled respiration (10, 15, and 20 breaths/min, CR10, CR15, and CR20 respectively). The approach relies on: 1) the calculation of Shannon entropy (SE) of the distribution of patterns lasting three beats; 2) the calculation of a regularity index based on an entropy rate (i.e., the conditional entropy); 3) the classification of frequent deterministic patterns (FDPs) lasting three beats. A redundancy reduction criterion is proposed to group FDPs in four categories according to the number and type or of heart period changes: a) no variation (0V); b) one variation (1V); and c) two like variations (2LV); 4) two unlike variations (2UV). We found that: 1) the SE decreased during tilt due to the increased percentage of missing patterns; 2) the regularity index increased during tilt and CR10 as patterns followed each other according to a more repetitive scheme; and 3) during CR10, SE and regularity index were not redundant as the regularity index significantly decreased while SE remained unchanged. Concerning pattern analysis we found that: a) at rest mainly three classes (0V, 1V, and 2LV) were detected; b) 0V patterns were more likely during tilt; c) 1V and 2LV patterns were more frequent during CR10; and d) 2UV patterns were more likely during CR20. The proposed approach based on quantification of complexity allows a full characterization of heart period dynamics and the identification of experimental conditions known to differently perturb cardiovascular regulation.


Role of Enteric Supplementation of Probiotics on Late-onset Sepsis by Candida species in Preterm Low Birth Weight Neonates: A Randomized, Double Blind, Placebo-controlled Trial.
The increase in invasive fungal infections (IFIs) in neonatal intensive care unit (NICU) is jeopardizing the survival of preterm neonates. Probiotics modulating the intestinal microflora of preterm neonates may minimize enteral fungal colonization. This study was to examine whether probiotic supplementation in neonates reduced fungal septicemia. This prospective, randomized, double blind trial investigating the supplementation of preterm infants with a probiotic was done from May 2012 to April 2013, with 112 subjects randomized into two groups. Decreased fungal colonization in gastrointestinal tract. Others: Incidence of late onset septicemia; duration of the primary hospital admission; number of days until full enteral feeds established. Full feed establishment was earlier in probiotics group compared to placebo group (P = 0.016). The duration of hospitalization was less in the probiotic group (P = 0.002). Stool fungal colonization, an important outcome parameter was 3.03 ± 2.33 × 10(5) colony formation units (CFU) in the probiotics group compared to 3 ± 1.5 × 10(5) CFU in the placebo group (P = 0.03). Fungal infection is less in the study group (P = 0.001). The key features of our study were reduced enteral fungal colonization, reduce invasive fungal sepsis, earlier establishment of full enteral feeds, and reduced duration of hospital stay in the probiotics group.


Inhibition of Bmp signaling affects growth and differentiation in the anagen hair follicle.
Growth and differentiation of postnatal hair follicles are controlled by reciprocal interactions between the dermal papilla and the surrounding epidermal hair precursors. The molecular nature of these interactions is largely unknown, but they are likely to involve several families of signaling molecules, including Fgfs, Wnts and Bmps. To analyze the function of Bmp signaling in postnatal hair development, we have generated transgenic mice expressing the Bmp inhibitor, Noggin, under the control of the proximal Msx2 promoter, which drives expression in proliferating hair matrix cells and differentiating hair precursor cells. Differentiation of the hair shaft but not the inner root sheath is severely impaired in Msx2-Noggin transgenic mice. In addition to hair keratins, the expression of several transcription factors implicated in hair development, including Foxn1 and Hoxc13, is severely reduced in the transgenic hair follicles. Proliferating cells, which are normally restricted to the hair matrix surrounding the dermal papilla, are found in the precortex and hair shaft region. These results identify Bmps as key regulators of the genetic program controlling hair shaft differentiation in postnatal hair follicles.


Distal heme pocket conformers of carbonmonoxy derivatives of Ascaris hemoglobin: evidence of conformational trapping in porous sol-gel matrices.
We report the ligand dependence of the conformer distribution in the distal heme pocket of Ascaris suum hemoglobin (Hb) studied by resonance Raman spectroscopy. The heme-bound CO is used as a spectroscopic antenna to probe the original distribution of conformers in the dioxygen derivative of Ascaris Hb, by utilizing sol-gel encapsulation. The first step is to encapsulate the dioxygen derivative in the porous sol-gel and let the gel age, thus trapping the equilibrium conformational distribution of Ascaris dioxygen Hb. In the second step, the dioxygen ligand is replaced by CO. The sol-gel environment impedes any large scale movements, drastically slowing down the conformational relaxation triggered by the ligation change, essentially "locking in" the initial quaternary and even tertiary structure of the protein. Studying the Fe-CO frequencies of the latter sample allows evaluation of the distribution of the distal heme pocket conformers that was originally associated with the dioxygen derivative. Extending the study to the Ascaris mutants allows for examination of the effect of specific residues in the distal pocket on the conformational distribution. The choice of mutants was largely based on the anticipated variation in hydrogen bonding patterns. The results show that the sol-gel encapsulation can slow or prevent re-equilibration within the distal heme pocket of Ascaris Hb and that the distribution of distal heme pocket conformers for the CO derivative of Ascaris Hb in the sol-gel is highly dependent on the history of the sample. Additionally, we report a detailed study of the CO complex of the mutants in solution for assignment of the various heme pocket conformers, and we present a comparison of the sol-gel data with solution data. The results support a picture in which the dioxygen derivative biases the population strongly toward a tightly packed configuration that favors the network of strong hydrogen bonding interactions, and suggest that Ascaris Hb is uniquely designed for dioxygen capture.


Neglect of medical evidence of torture in Guantánamo Bay: a case series.
In the wake of the September 11, 2001 attacks on the US, the government authorized the use of "enhanced interrogation" techniques that were previously recognized as torture. While the complicity of US health professionals in the design and implementation of US torture practices has been documented, little is known about the role of health providers, assigned to the US Department of Defense (DoD) at the US Naval Station Guantánamo Bay, Cuba (GTMO), who should have been in a position to observe and document physical and psychological evidence of torture and ill treatment. We reviewed GTMO medical records and relevant case files (client affidavits, attorney-client notes and summaries, and legal affidavits of medical experts) of nine individuals for evidence of torture and ill treatment and documentation by medical personnel. In each of the nine cases, GTMO detainees alleged abusive interrogation methods that are consistent with torture as defined by the UN Convention Against Torture as well as the more restrictive US definition of torture that was operational at the time. The medical affidavits in each of the nine cases indicate that the specific allegations of torture and ill treatment are highly consistent with physical and psychological evidence documented in the medical records and evaluations by non-governmental medical experts. However, the medical personnel who treated the detainees at GTMO failed to inquire and/or document causes of the physical injuries and psychological symptoms they observed. Psychological symptoms were commonly attributed to "personality disorders" and "routine stressors of confinement." Temporary psychotic symptoms and hallucinations did not prompt consideration of abusive treatment. Psychological assessments conducted by non-governmental medical experts revealed diagnostic criteria for current major depression and/or PTSD in all nine cases. The findings in these nine cases from GTMO indicate that medical doctors and mental health personnel assigned to the DoD neglected and/or concealed medical evidence of intentional harm.


Identification of microRNAs linked to regulators of muscle protein synthesis and regeneration in young and old skeletal muscle.
Over the course of ageing there is a natural and progressive loss of skeletal muscle mass. The onset and progression of age-related muscle wasting is associated with an attenuated activation of Akt-mTOR signalling and muscle protein synthesis in response to anabolic stimuli such as resistance exercise. MicroRNAs (miRNAs) are novel and important post-transcriptional regulators of numerous cellular processes. The role of miRNAs in the regulation of muscle protein synthesis following resistance exercise is poorly understood. This study investigated the changes in skeletal muscle miRNA expression following an acute bout of resistance exercise in young and old subjects with a focus on the miRNA species predicted to target Akt-mTOR signalling. Ten young (24.2±0.9 years) and 10 old (66.6±1.1 years) males completed an acute resistance exercise bout known to maximise muscle protein synthesis, with muscle biopsies collected before and 2 hours after exercise. We screened the expression of 754 miRNAs in the muscle biopsies and found 26 miRNAs to be regulated with age, exercise or a combination of both factors. Nine of these miRNAs are highly predicted to regulate targets within the Akt-mTOR signalling pathway and 5 miRNAs have validated binding sites within the 3' UTRs of several members of the Akt-mTOR signalling pathway. The miR-99/100 family of miRNAs notably emerged as potentially important regulators of skeletal muscle mass in young and old subjects. This study has identified several miRNAs that were regulated with age or with a single bout of resistance exercise. Some of these miRNAs were predicted to influence Akt-mTOR signalling, and therefore potentially skeletal muscle mass. These miRNAs should be considered as candidate targets for in vivo modulation.


Targeting cancer stem cells in breast cancer: potential anticancer properties of 6-shogaol and pterostilbene.
Breast cancer stem cells (BCSCs) constitute a small fraction of the primary tumor that can self-renew and become a drug-resistant cell population, thus limiting the treatment effects of chemotherapeutic drugs. The present study evaluated the cytotoxic effects of five phytochemicals including 6-gingerol (6-G), 6-shogaol (6-S), 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5-HF), nobiletin (NOL), and pterostilbene (PTE) on MCF-7 breast cancer cells and BCSCs. The results showed that 6-G, 6-S, and PTE selectively killed BCSCs and had high sensitivity for BCSCs isolated from MCF-7 cells that expressed the surface antigen CD44(+)/CD24(-). 6-S and PTE induced cell necrosis phenomena such as membrane injury and bleb formation in BCSCs and inhibited mammosphere formation. In addition, 6-S and PTE increased the sensitivity of isolated BCSCs to chemotherapeutic drugs and significantly increased the anticancer activity of paclitaxel. Analysis of the underlying mechanism showed that 6-S and PTE decreased the expression of the surface antigen CD44 on BCSCs and promoted β-catenin phosphorylation through the inhibition of hedgehog/Akt/GSK3β signaling, thus decreasing the protein expression of downstream c-Myc and cyclin D1 and reducing BCSC stemness.


Simultaneous Evaluation of Diagnostic Assays for Pharyngeal and Rectal Neisseria gonorrhoeae and Chlamydia trachomatis Using a Master Protocol.
Pharyngeal and rectal Neisseria gonorrhoeae and Chlamydia trachomatis play important roles in infection and antibacterial resistance transmission, but no US Food and Drug Administration (FDA)-cleared assays for detection at these sites existed prior to this study. The objective was to estimate performance of assays to detect those infections in pharyngeal and rectal specimens to support regulatory submission. We performed a cross-sectional, single-visit study of adults seeking sexually transmitted infection testing at 9 clinics in 7 states. We collected pharyngeal and rectal swabs from participants. The primary outcome was positive and negative percent agreement for detection of N. gonorrhoeae and C. trachomatis for 3 investigational assays compared to a composite reference. Secondary outcomes included positivity as well as positive and negative predictive values and likelihood ratios. Subgroup analyses included outcomes by symptom status and sex. A total of 2598 participants (79% male) underwent testing. We observed N. gonorrhoeae positivity of 8.1% in the pharynx and 7.9% in the rectum and C. trachomatis positivity of 2.0% in the pharynx and 8.7% in the rectum. Positive percent agreement ranged from 84.8% to 96.5% for different anatomic site infection combinations, whereas negative percent agreement was 98.8% to 99.6%. This study utilized a Master Protocol to generate diagnostic performance data for multiple assays from different manufacturers in a single study population, which ultimately supported first-in-class FDA clearance for extragenital assays. We observed very good positive percent agreement when compared to a composite reference method for the detection of both pharyngeal and rectal N. gonorrhoeae and C. trachomatis. NCT02870101.


Interactive image segmentation via adaptive weighted distances.
An interactive algorithm for soft segmentation of natural images is presented in this paper. The user first roughly scribbles different regions of interest, and from them, the whole image is automatically segmented. This soft segmentation is obtained via fast, linear complexity computation of weighted distances to the user-provided scribbles. The adaptive weights are obtained from a series of Gabor filters, and are automatically computed according to the ability of each single filter to discriminate between the selected regions of interest. We present the underlying framework and examples showing the capability of the algorithm to segment diverse images.


Neurologic complications of prostate cancer.
Neurologic complications continue to pose problems in patients with metastatic prostate cancer. From 15 to 30 percent of metastases are the result of prostate cancer cells traveling through Batson's plexus to the lumbar spine. Metastatic disease in the lumbar area can cause spinal cord compression. Metastasis to the dura and adjacent parenchyma occurs in 1 to 2 percent of patients with metastatic prostate cancer and is more common in those with tumors that do not respond to hormone-deprivation therapy. Leptomeningeal carcinomatosis, the most frequent form of brain metastasis in prostate cancer, has a grim prognosis. Because neurologic complications of metastatic prostate cancer require prompt treatment, early recognition is important. Physicians should consider metastasis in the differential diagnosis of new-onset low back pain or headache in men more than 50 years of age. Spinal cord compression requires immediate treatment with intravenously administered corticosteroids and pain relievers, as well as prompt referral to an oncologist for further treatment.


The effects of a twenty-four-week aquatic training program on muscular strength performance in healthy elderly women.
The purpose of the present study was to determine the effectiveness of a 24-week aquatic training (AT) program, which included both aerobic and resistance components, on muscle strength (isometric and dynamic), flexibility, and functional mobility in healthy women over 60 years of age. Twenty-two subjects were assigned randomly to either an AT (n = 12) or a control (C, n = 10) group. Volunteers participated in a supervised shallow-water exercise program for 60 minutes a day, 3 days a week; the exercise program consisted of a 10-minute warm-up and stretching, 25 minutes of endurance-type exercise (dancing) at 80% of heart rate (HR)(max), 20 minutes of upper- and lower-body resistance exercises with specialized water-resistance equipment, and a 5-minute cool down. Maximal isometric torque of knee extensors (KEXT) and knee flexors (KFLEX) were evaluated by a Cybex Norm dynamometer, grip strength (HGR) was evaluated using a Jamar hydraulic dynamometer, and dynamic strength was evaluated via the 3 repetition maximum (3RM) test for chest press, knee extension, lat pull down, and leg press. Jumping performance was evaluated using the squat jump (SJ), functional mobility with the timed up-and-go (TUG) test, and trunk flexion with the sit-and-reach test. Body composition was measured using the bioelectrical impedance method. The AT induced significant improvements in KEXT (10.5%) and KFLEX (13.4%) peak torque, HGR strength (13%), 3RM (25.7-29.4%), SJ (24.6%), sit-and-reach (11.6%), and TUG (19.8%) performance. The AT group demonstrated a significant increase in lean body mass (3.4%). No significant changes in these variables were observed in the C group. The results indicate that AT, with both aerobic and resistance components, is an alternative training method for improving neuromuscular and functional fitness performance in healthy elderly women.