Patient satisfaction with treatment decisions for clinically localized prostate carcinoma. Results from the Prostate Cancer Outcomes Study.
Men with early-stage prostate carcinoma can choose aggressive treatment or conservative management. The authors used data from a population-based cohort of men with clinically localized prostate carcinoma to describe satisfaction with treatment decisions 24 months after diagnosis and to examine the association of demographic, socioeconomic, and clinical characteristics with treatment satisfaction. The authors evaluated 2365 men with clinically localized prostate carcinoma, diagnosed between October 1994 and October 1995, in one of six Surveillance, Epidemiology, and End Results tumor registries and who were available for 24 month follow-up. Medical record review and patient-completed surveys provided demographic, socioeconomic, and clinical data and measured treatment satisfaction. Logistic regression analyses were used to identify factors associated with satisfaction. Overall, 59.2% of subjects were delighted or very pleased with their treatment selection. The perception of being cancer free (66.4%), maintaining urinary (64.2%) and bowel (60.5%) control and normal erectile function (65.9%), having good general health (71.3%), and preserving social relationships (68.1%) were significantly associated with being satisfied (P < 0.05). Men receiving no active treatment were less satisfied (50.5%, P < 0.001) than actively treated men, and Hispanic men were less satisfied than non-Hispanic white men after undergoing radical prostatectomy (50.1% vs. 58.0%, P = 0.05) or androgen deprivation (29.7% vs. 71.8%, P < 0.02). The majority of men were satisfied with their treatment selection for clinically localized prostate carcinoma. Receiving an active treatment, believing oneself to be free of cancer, avoiding treatment complications, and having good overall health and social support were positively associated with satisfaction.


Validation of the Yale Food Addiction Scale 2.0 Among a Bariatric Surgery Population.
Addictive eating, a highly debated problematic eating behavior, may contribute to obesity and impede the success of individuals seeking bariatric surgery. The original Yale Food Addiction Scale (YFAS) was validated for use among patients who underwent bariatric surgery; however, the YFAS was revised to reflect changes in substance use criteria in the DSM-5. The purpose of this study was to validate the use of the revised measure, the YFAS 2.0, among patients pursuing bariatric surgery. A retrospective chart review was conducted of 314 patients who underwent pre-surgical psychological evaluation for bariatric surgery. Information gathered included symptoms of addictive eating (YFAS 2.0), emotional eating (Emotional Eating Scale; EES), and a history of substance use and binge eating. In this sample, 27.3% met criteria for "food addiction" according to the YFAS 2.0. Of those, more than half met criteria for severe food addiction. The YFAS 2.0 was related to all factors of the EES: anger/frustration (p < .001); anxiety (p < .001); and depression (p < .001). There was no relationship between the YFAS 2.0 and a history of substance use. The YFAS 2.0 accounted for significant variance in history of binge eating after controlling for emotional eating (p < .001; Exp(B) = 1.30). Results were similar to a prior validation of the YFAS among a bariatric population, and the updated YFAS 2.0 may be useful in assessing addictive eating among bariatric surgery candidates to further explore the concept of "food addiction."


Precision shielding for COVID-19: metrics of assessment and feasibility of deployment.
The ability to preferentially protect high-risk groups in COVID-19 is hotly debated. Here, the aim is to present simple metrics of such precision shielding of people at high risk of death after infection by SARS-CoV-2; demonstrate how they can estimated; and examine whether precision shielding was successfully achieved in the first COVID-19 wave. The shielding ratio, S, is defined as the ratio of prevalence of infection among people in a high-risk group versus among people in a low-risk group. The contrasted risk groups examined here are according to age (≥70 vs <70 years), and institutionalised (nursing home) setting. For age-related precision shielding, data were used from large seroprevalence studies with separate prevalence data for elderly versus non-elderly and with at least 1000 assessed people≥70 years old. For setting-related precision shielding, data were analysed from 10 countries where information was available on numbers of nursing home residents, proportion of nursing home residents among COVID-19 deaths and overall population infection fatality rate (IFR). Across 17 seroprevalence studies, the shielding ratio S for elderly versus non-elderly varied between 0.4 (substantial shielding) and 1.6 (substantial inverse protection, that is, low-risk people being protected more than high-risk people). Five studies in the USA all yielded S=0.4-0.8, consistent with some shielding being achieved, while two studies in China yielded S=1.5-1.6, consistent with inverse protection. Assuming 25% IFR among nursing home residents, S values for nursing home residents ranged from 0.07 to 3.1. The best shielding was seen in South Korea (S=0.07) and modest shielding was achieved in Israel, Slovenia, Germany and Denmark. No shielding was achieved in Hungary and Sweden. In Belgium (S=1.9), the UK (S=2.2) and Spain (S=3.1), nursing home residents were far more frequently infected than the rest of the population. In conclusion, the experience from the first wave of COVID-19 suggests that different locations and settings varied markedly in the extent to which they protected high-risk groups. Both effective precision shielding and detrimental inverse protection can happen in real-life circumstances. COVID-19 interventions should seek to achieve maximal precision shielding.


Sequence specificity despite intrinsic disorder: How a disease-associated Val/Met polymorphism rearranges tertiary interactions in a long disordered protein.
The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) in precursor brain-derived neurotrophic factor (BDNF) is one of the earliest SNPs to be associated with neuropsychiatric disorders, and the underlying molecular mechanism is unknown. Here we report on over 250 μs of fully-atomistic, explicit solvent, temperature replica-exchange molecular dynamics (MD) simulations of the 91 residue BDNF prodomain, for both the V66 and M66 sequence. The simulations were able to correctly reproduce the location of both local and non-local secondary structure changes due to the Val66Met mutation, when compared with NMR spectroscopy. We find that the change in local structure is mediated via entropic and sequence specific effects. We developed a hierarchical sequence-based framework for analysis and conceptualization, which first identifies "blobs" of 4-15 residues representing local globular regions or linkers. We use this framework within a novel test for enrichment of higher-order (tertiary) structure in disordered proteins; the size and shape of each blob is extracted from MD simulation of the real protein (RP), and used to parameterize a self-avoiding heterogenous polymer (SAHP). The SAHP version of the BDNF prodomain suggested a protein segmented into three regions, with a central long, highly disordered polyampholyte linker separating two globular regions. This effective segmentation was also observed in full simulations of the RP, but the Val66Met substitution significantly increased interactions across the linker, as well as the number of participating residues. The Val66Met substitution replaces β-bridging between V66 and V94 (on either side of the linker) with specific side-chain interactions between M66 and M95. The protein backbone in the vicinity of M95 is then free to form β-bridges with residues 31-41 near the N-terminus, which condenses the protein. A significant role for Met/Met interactions is consistent with previously-observed non-local effects of the Val66Met SNP, as well as established interactions between the Met66 sequence and a Met-rich receptor that initiates neuronal growth cone retraction.


Macrophages orchestrate breast cancer early dissemination and metastasis.
Cancer cell dissemination during very early stages of breast cancer proceeds through poorly understood mechanisms. Here we show, in a mouse model of HER2+ breast cancer, that a previously described sub-population of early-evolved cancer cells requires macrophages for early dissemination. Depletion of macrophages specifically during pre-malignant stages reduces early dissemination and also results in reduced metastatic burden at end stages of cancer progression. Mechanistically, we show that, in pre-malignant lesions, CCL2 produced by cancer cells and myeloid cells attracts CD206+/Tie2+ macrophages and induces Wnt-1 upregulation that in turn downregulates E-cadherin junctions in the HER2+ early cancer cells. We also observe macrophage-containing tumor microenvironments of metastasis structures in the pre-malignant lesions that can operate as portals for intravasation. These data support a causal role for macrophages in early dissemination that affects long-term metastasis development much later in cancer progression. A pilot analysis on human specimens revealed intra-epithelial macrophages and loss of E-cadherin junctions in ductal carcinoma in situ, supporting a potential clinical relevance.


Aromatase cytochrome P450 enzyme expression in prolactinomas and its relationship to tumor behavior.
The aim of the study was to evaluate the presence of aromatase cytochrome P450 enzyme (P450AROM) expression in normal pituitary tissues and tumor tissues of patients with prolactinoma and to examine the impact of the P450AROM expression on clinical outcome. Twenty-six consecutive human pituitary tissue samples were obtained from autopsies performed at the Institute of Forensic Medicine. Sixty-four patients who had an adenomectomy between 2000 and 2009 after prolactinoma diagnosis with histologically confirmed pituitary tumor tissues were retrospectively included in this study. The slices from the pituitary tissues were subjected to immunohistochemical staining for evaluation of P450AROM and estrogen receptor beta (ER beta) subunit. Immunohistochemistry results were compared according to age, gender, remission rate, resistance and invasion status of the patients. Higher than normal P450AROM expression was found in the pituitary tissues of the patients with prolactinoma (p < 0.001). P450AROM intensity had no relation to resistance or remission in patients with prolactinoma (p = 0.44, p = 0.45, respectively). The subgroup analysis showed that compared to males without invasive adenoma, males with invasive adenoma had higher P450AROM expression (p = 0.048). ER beta was found to have an impact on resistance (p = 0.049). This study shows that P450AROM expression is present in the pituitary tissues of patients with prolactinoma and that this presence could be important in development and tumor behavior of prolactinomas.


Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update.
To combine the clinical data from 3 academic institutions that serve as centers of excellence for the surgical treatment of clinically localized prostate cancer and develop a multi-institutional model combining serum prostate-specific antigen (PSA) level, clinical stage, and Gleason score to predict pathological stage for men with clinically localized prostate cancer. In this update, we have combined clinical and pathological data for a group of 4133 men treated by several surgeons from 3 major academic urologic centers within the United States. Multinomial log-linear regression was performed for the simultaneous prediction of organ-confined disease, isolated capsular penetration, seminal vesicle involvement, or pelvic lymph node involvement. Bootstrap estimates of the predicted probabilities were used to develop nomograms to predict pathological stage. Additional bootstrap analyses were then obtained to validate the performance of the nomograms. A total of 4133 men who had undergone radical retropubic prostatectomy for clinically localized prostate cancer at The Johns Hopkins Hospital (n=3116), Baylor College of Medicine (n=782), and the University of Michigan School of Medicine (n=235) were enrolled into this study. None of the patients had received preoperative hormonal or radiation therapy. Simultaneous prediction of organ-confined disease, isolated capsular penetration, seminal vesicle involvement, or pelvic lymph node involvement using updated nomograms. Prostate-specific antigen level, TNM clinical stage, and Gleason score contributed significantly to the prediction of pathological stage (P<.001). Bootstrap estimates of the median and 95% confidence interval of the predicted probabilities are presented in the nomograms. For most cells in the nomograms, there is a greater than 25% probability of qualifying for more than one of the pathological stages. In the validation analyses, 72.4% of the time the nomograms correctly predicted the probability of a pathological stage to within 10% (organ-confined disease, 67.3%; isolated capsular penetration, 59.6%; seminal vesicle involvement, 79.6%; pelvic lymph node involvement, 82.9%). The data represent a multi-institutional modeling and validation of the clinical utility of combining PSA level measurement, clinical stage, and Gleason score to predict pathological stage for a group of men with localized prostate cancer. Clinicians can use these nomograms when counseling individual patients regarding the probability of their tumor being a specific pathological stage; this will enable patients and physicians to make more informed treatment decisions based on the probability of a pathological stage, as well as risk tolerance and the values they place on various potential outcomes.


The use of kallikrein-related peptidases as adjuvant prognostic markers in colorectal cancer.
Several members of the human tissue kallikrein-related peptidase (KLK) family are emerging cancer biomarkers. The aim of this study was to analyse the expression of a panel of KLKs in colorectal cancer and to find out if the multiparametric combination of them can increase the accuracy of prediction of patients survival beyond the traditional clinical information. Nine KLKs (KLK5-8, KLK10, KLK11, KLK13-15) were measured using ELISA assays in cytosolic extracts of 122 colon cancer tissues and their nearby normal mucosa, obtained during surgery. The mean levels of almost all KLKs in tumour tissues were significantly different from their counterparts of normal tissue (P<0.0001). KLK 5, 6, 7, 13, 14 were significantly associated with overall survival in univariate analysis, but after adjusting for age, TNM and differentiation stage, only KLK5 (HR: 1.24 (95% CI: 1.05-1.47)), KLK7 (HR: 1.57 (95% CI: 1.04-2.37)) and KLK14 (HR: 1.43 (95% CI: 1.05-1.94)) remained significant. Addition of a panel of selected KLK markers to clinical parameters gave an increment in AUC of 0.86 beyond the clinical factors at year 1, showing that it can increase the accuracy of prediction of overall survival beyond the traditional clinical information, particularly the short-term (1 year) survival after surgery.


Tryptophan degradation by human placental indoleamine 2,3-dioxygenase regulates lymphocyte proliferation.
1. The physiological importance of human placental indoleamine 2,3-dioxygenase (EC 188.8.131.52), the first and rate-limiting enzyme in tryptophan metabolism, in regulating feto-maternal immunology has been studied. 2. Concentrations were measured in placental villous explant conditioned media of 14 amino acids that are known to be required for lymphocyte proliferation. In the absence of interferon-gamma only tryptophan and threonine were significantly lowered; in the presence of interferon-gamma (known to stimulate indoleamine 2,3-dioxygenase) tryptophan but not threonine depletion was much greater. 3. Peripheral blood mononuclear cell proliferation determined by measuring thymidine incorporation into DNA following culture in the medium previously conditioned by culture of villous explants was markedly reduced when placental indoleamine 2,3-dioxygenase was stimulated with interferon-gamma. Inhibition of placental indoleamine 2,3-dioxygenase by 1-methyl-tryptophan prevented inhibition of thymidine incorporation. Supplementation of the conditioned medium with tryptophan but no other amino acid completely reversed the inhibition of thymidine incorporation. 4. Flow cytometric analysis showed that CD4-positive T lymphocyte division was specifically suppressed by indoleamine 2,3-dioxygenase-mediated tryptophan depletion. This inhibition of T cell proliferation was due to arrest of cell cycle progression. 5. To study the mechanism of tryptophan sensing we examined the ability of 11 L-tryptophan analogues to support lymphocyte proliferation. Only L-tryptophan methyl and ethyl esters were able to stimulate proliferation in tryptophan-free media. Since both of these molecules are readily degraded to tryptophan by intracellular esterases this suggests that the tryptophan sensor is intracellular. 6. Our results show that mechanisms are present in the human placenta which are able to regulate cellular proliferation of the maternal immune system. This mechanism is dependent both on placental indoleamine 2,3-dioxygenase-mediated tryptophan degradation and on tryptophan sensing systems within lymphocytes.


Indicators of carbon storage in U.S. ecosystems: baseline for terrestrial carbon accounting.
Policymakers, program managers, and landowners need information about net terrestrial carbon sequestration in forests, croplands, grasslands, and shrublands to understand the cumulative effects of carbon trading programs, expanding biofuels production, and changing environmental conditions in addition to agricultural and forestry uses. Objective information systems that establish credible baselines and track changes in carbon storage can provide the accountability needed for carbon trading programs to achieve durable carbon sequestration and for biofuels initiatives to reduce net greenhouse gas emissions. A multi-sector stakeholder design process was used to produce a new indicator for the 2008 State of the Nation's Ecosystems report that presents metrics of carbon storage for major ecosystem types, specifically change in the amount of carbon gained or lost over time and the amount of carbon stored per unit area (carbon density). These metrics have been developed for national scale use, but are suitable for adaptation to multiple scales such as individual farm and forest parcels, carbon offset markets and integrated national and international assessments. To acquire the data necessary for a complete understanding of how much, and where, carbon is gained or lost by U.S. ecosystems, expansion and integration of monitoring programs will be required.


Real-world research and its importance in respiratory medicine.
To improve understanding of: The relative benefits and limitations of evidence derived from different study designs and the role that real-life asthma studies can play in addressing limitations in the classical randomised controlled trial (cRCT) evidence base.The importance of guideline recommendations being modified to fit the populations studied and the model of care provided in their reference studies. Classical randomised controlled trials (cRCTs) show results from a narrow patient group with a constrained ecology of care.Patients with "real-life" co-morbidities and lifestyle factors receiving usual care often have different responses to medication which will not be captured by cRCTs if they are excluded by strict selection criteria.Meta-analyses, used to direct guidelines, contain an inherent meta-bias based on patient selection and artificial patient care.Guideline recommendations should clarify where they related to cRCT ideals (in terms of patient populations, medical resources and care received) and could be enhanced through inclusion of evidence from studies designed to better model the populations and care approaches present in routine care. Clinical practice requires a complex interplay between experience and training, research, guidelines and judgement, and must not only draw on data from traditional or classical randomised controlled trials (cRCTs), but also from pragmatically designed studies that better reflect real-life clinical practice. To minimise extraneous variables and to optimise their internal validity, cRCTs exclude patients, clinical characteristics and variations in care that could potentially confound outcomes. The result is that respiratory cRCTs often enrol a small, non-representative subset of patients and overlook the important interplay and interactions between patients and the real world, which can effect treatment outcomes. Evidence from real-life studies (e.g. naturalistic or pragmatic clinical trials and observational studies encompassing healthcare database studies and cohort studies) can be combined with cRCT evidence to provide a fuller picture of intervention effectiveness and realistic treatment outcomes, and can provide useful insights into alternative management approaches in more challenging asthma patients. The Respiratory Effectiveness Group (REG), in collaboration with the European Academy of Allergy and Clinical Immunology (EAACI) and the European Respiratory Society (ERS), is developing quality appraisal tools and methods for integrating different sources of evidence. A REG/EAACI taskforce aims to help support future guideline developers to avoid a one-size-fits-all approach to recommendations and to tailor the conclusions of their meta-analyses to the populations under consideration.


Smart Sensing Using Electromagnetic Waves for Inspection of Defects in Rock Bolts.
The stability of tunnels and rock slopes is adversely affected by defects in rock bolts. This study investigates the suitability of the smart sensing method using electromagnetic waves for inspecting defects in rock bolts. Experiments were performed with one fully grouted and eight defective rock bolts, out of which five have non-grouted parts at the ends with different non-grouted ratios, and three have different types of voids. Electromagnetic waves were generated and detected using a time domain reflectometer by configuring two-conductor transmission lines in the rock bolts. Results show that electromagnetic waves are reflected both at defects and ends of rock bolts. The electromagnetic wave velocity increases with an increase in the non-grouted ratio and decreases when rock bolts are embedded in a concrete block simulating rock mass. The estimated locations of defects found by electromagnetic waves are in good agreement with actual defect locations. This study demonstrates that smart sensing using electromagnetic waves is an effective method for inspecting and determining defect locations and the non-grouted ratio of rock bolts.


Regional nitrogen dynamics in the TERENO Bode River catchment, Germany, as constrained by stable isotope patterns.
Interactions between hydrological characteristics and microbial activities affect the isotopic composition of dissolved nitrate in surface water. Nitrogen and oxygen isotopic signatures of riverine nitrate in 133 sampling locations distributed over the Bode River catchment in the Harz Mountains, Germany, were used to identify nitrate sources and transformation processes. An annual monitoring programme consisting of seasonal sampling campaigns in spring, summer and autumn was conducted. δ(15)N and δ(18)O of nitrate and corresponding concentrations were measured as well as δ(2)H and δ(18)O of water to determine the deuterium excess. In addition, precipitation on 25 sampling stations was sampled and considered as a potential input factor. The Bode River catchment is strongly influenced by agricultural land use which is about 70 % of the overall size of the catchment. Different nitrogen sources such as ammonia (NH4) fertilizer, soil nitrogen, organic fertilizer or nitrate in precipitation show partly clear nitrate isotopic differences. Processes such as microbial denitrification result in fractionation and lead to an increase in δ(15)N of nitrate. We observed an evident regional and partly temporal variation of nitrate isotope signatures which are clearly different between main landscape types. Spring water sections within the high mountains contain nitrate in low concentrations with low δ(15)NNO3 values of -3 ‰ and high δ(18)ONO3 values up to 13 ‰. High mountain stream water sub-catchments dominated by nearly undisturbed forest and grassland contribute nitrate with δ(15)NNO3 and δ(18)ONO3 values of -1 and -3.5 ‰, respectively. In the further flow path, which is affected by an increasing agricultural land use and urban sewage, we recognized an increase in δ(15)NNO3 and δ(18)ONO3 up to 22 and 18 ‰, respectively, with high variations during the year. A correlation seems to exist between the percentage of agricultural land use area and the corresponding δ(15)NNO3 values for sub-catchments. A shift towards heavier isotope values in stream water samples taken in July 2012 is significant (p-value = 6 · 10(-6)) compared to samples from March and October 2012. We also see a season-depending impact of microbial denitrification. Denitrification, especially evident in the lowlands, predominantly takes place in the riverbeds. In addition, mixing processes of different nitrate sources and temperature-depending biological processes such as nitrification have to be taken into consideration. Constant-tempered groundwater does not play a noticeable role in the processes of the stream water system. As constrained from oxygen isotope signatures, precipitation associated with low nitrate concentrations does not have an obvious impact on stream water nitrate in the high mountain region.


The convergence of cochlear implantation with induced pluripotent stem cell therapy.
According to 2010 estimates from The National Institute on Deafness and other Communication Disorders, approximately 17% (36 million) American adults have reported some degree of hearing loss. Currently, the only clinical treatment available for those with severe-to-profound hearing loss is a cochlear implant, which is designed to electrically stimulate the auditory nerve in the absence of hair cells. Whilst the cochlear implant has been revolutionary in terms of providing hearing to the severe-to-profoundly deaf, there are variations in cochlear implant performance which may be related to the degree of degeneration of auditory neurons following hearing loss. Hence, numerous experimental studies have focused on enhancing the efficacy of cochlear implants by using neurotrophins to preserve the auditory neurons, and more recently, attempting to replace these dying cells with new neurons derived from stem cells. As a result, several groups are now investigating the potential for both embryonic and adult stem cells to replace the degenerating sensory elements in the deaf cochlea. Recent advances in our knowledge of stem cells and the development of induced pluripotency by Takahashi and Yamanaka in 2006, have opened a new realm of science focused on the use of induced pluripotent stem (iPS) cells for therapeutic purposes. This review will provide a broad overview of the potential benefits and challenges of using iPS cells in combination with a cochlear implant for the treatment of hearing loss, including differentiation of iPS cells into an auditory neural lineage and clinically relevant transplantation approaches.


Histamine causes influx via T-type voltage-gated calcium channels in an enterochromaffin tumor cell line: potential therapeutic target in adverse food reactions.
The P-STS human ileal neuroendocrine tumor cells, as a model for gut enterochromaffin cells, are strongly and synergistically activated by histamine plus acetylcholine (ACh), presumably via histamine 4 receptors, and weakly activated by histamine alone. Sensing these signals, enterochromaffin cells could participate in intestinal intolerance or allergic reactions to food constituents associated with elevated histamine levels. In this study we aimed to analyze the underlying molecular mechanisms. Inhibition by mepyramine and mibefradil indicated that histamine alone caused a rise in intracellular calcium concentration ([Ca2+]i) via histamine 1 receptors involving T-type voltage-gated calcium channels (VGCCs). Sensitivity to histamine was enhanced by pretreatment with the inflammatory cytokine tumor necrosis factor-α (TNF-α). In accordance with the relief it offers some inflammatory bowel disease patients, otilonium bromide, a gut-impermeable inhibitor of T-type (and L-type) VGCCs and muscarinic ACh receptors, efficiently inhibited the [Ca2+]i responses induced by histamine plus ACh or by histamine alone in P-STS cells. It will take clinical studies to show whether otilonium bromide has promise for the treatment of adverse food reactions. The cells did not react to the nutrient constituents glutamate, capsaicin, cinnamaldehyde, or amylase-trypsin inhibitors and the transient receptor potential channel vanilloid 4 agonist GSK-1016790A. The bacterial product butyrate evoked a rise in [Ca2+]i only when added together with ACh. Lipopolysaccharide had no effect on [Ca2+]i despite the presence of Toll-like receptor 4 protein. Our results indicate that inflammatory conditions with elevated levels of TNF-α might enhance histamine-induced serotonin release from intestinal neuroendocrine cells. NEW & NOTEWORTHY We show that histamine synergistically enhances the intracellular calcium response to the physiological agonist acetylcholine in human ileal enterochromaffin tumor cells. This synergistic activation and cell activation by histamine alone largely depend on T-type voltage-gated calcium channels and are inhibited by the antispasmodic otilonium bromide. The cells showed no response to wheat amylase-trypsin inhibitors, suggesting that enterochromaffin cells are not directly involved in nongluten wheat sensitivity.


Microbial, chemical-physical, rheological and organoleptic characterisation of roe deer (Capreolus capreolus) salami.
Game meat and related products are important in the promotion of local economies and rural areas. Microbiological, chemical-physical, rheological and sensory characteristics of fermented meat products (salami) made by different percentages of pork and hunted roe-deer (Capreolus capreolus) meat were evaluated. The microbiological determination indicated that the products are safe to eat, as neither Listeria monocytogenes nor Salmonella spp. was isolated from the samples. The hygienic adequacy of the process was guaranteed, as there was below 3 log CFU/g of Enterobacteriaceae level in the final products. The proximal composition analyses showed lower lipid levels in comparison to pork salami. The difference in chemical composition affects the rheological and sensory traits of the final products; the products were harder and with higher gumminess when 50% of roe-deer meat was used. Game meat flavour and odour increased with the increasing percentage of roe-deer meat.


Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome.
Townes-Brocks syndrome (TBS) is characterized by a spectrum of malformations in the digits, ears, and kidneys. These anomalies overlap those seen in a growing number of ciliopathies, which are genetic syndromes linked to defects in the formation or function of the primary cilia. TBS is caused by mutations in the gene encoding the transcriptional repressor SALL1 and is associated with the presence of a truncated protein that localizes to the cytoplasm. Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity. By using proximity proteomics, we show that truncated SALL1 interacts with factors related to cilia function, including the negative regulators of ciliogenesis CCP110 and CEP97. This most likely contributes to more frequent cilia formation in TBS-derived fibroblasts, as well as in a CRISPR/Cas9-generated model cell line and in TBS-modeled mouse embryonic fibroblasts, than in wild-type controls. Furthermore, TBS-like cells show changes in cilia length and disassembly rates in combination with aberrant SHH signaling transduction. These findings support the hypothesis that aberrations in primary cilia and SHH signaling are contributing factors in TBS phenotypes, representing a paradigm shift in understanding TBS etiology. These results open possibilities for the treatment of TBS.


Basal nitric oxide production is enhanced by hydraulic pressure in cultured human trabecular cells.
Nitric oxide donors reduce intraocular pressure. Human trabecular cells in culture were examined for their nitric oxide production in response to hydraulic pressure. Human trabecular cells were cultured from trabeculum tissue fragments excised during trabeculectomy and exposed to hydraulic pressure change in a culture flask connected to a glass syringe. The pressure was exerted by automatic infusion of the piston of the syringe and monitored by a pressure gauge. The intracellular nitric oxide level was measured in real time with a nitric oxide binding fluorescent dye, diaminofluorescein-2. Intracellular nitric oxide levels in cultured trabecular cells showed spontaneous fluctuation during 400 seconds of observation. Peak levels of intracellular nitric oxide were significantly higher at hydraulic pressure of 30, 40, and 50 mm Hg, compared with 0 and 25 mm Hg (p<0.0001, one way ANOVA, and p<0.05, Tukey-Kramer test). The fluctuation was completely abolished by the presence of N-methyl-L-arginine (L-NMMA), a nitric oxide synthase inhibitor. The cultured trabecular cells were shown by immunohistochemistry to express brain nitric oxide synthase (bNOS). Higher levels of hydraulic pressure enhanced basal production of nitric oxide in human trabecular cells. Nitric oxide would be a physiological mediator in the regulation of intraocular pressure.


Fitting perception in and to cognition.
Perceptual modules adapt at evolutionary, lifelong, and moment-to-moment temporal scales to better serve the informational needs of cognizers. Perceptual learning is a powerful way for an individual to become tuned to frequently recurring patterns in its specific local environment that are pertinent to its goals without requiring costly executive control resources to be deployed. Mechanisms like predictive coding, categorical perception, and action-informed vision allow our perceptual systems to interface well with cognition by generating perceptual outputs that are systematically guided by how they will be used. In classic conceptions of perceptual modules, people have access to the modules' outputs but no ability to adjust their internal workings. However, humans routinely and strategically alter their perceptual systems via training regimes that have predictable and specific outcomes. In fact, employing a combination of strategic and automatic devices for adapting perception is one of the most promising approaches to improving cognition.


Environmental factors associated with overweight and obesity in taiwanese children.
We explored the relationship among sociodemographic, behavioural, household environmental and perinatal factors, and risks of childhood overweight and obesity in Taiwan. A total of 7930 children aged 9 to 14 years were recruited from 14 randomly selected Taiwanese communities in 2007 and 2010. Height and weight were measured using standard protocols during school visits. Questionnaires that contained children's family information, birth conditions, exercise habits and household environmental factors were answered by the parents. Associations between risk factors and childhood overweight and obesity were estimated through odds ratio and 95% confidence interval from mixed models. In this cohort, 32.3% of the children were overweight and 17.5% were obese. Male gender, high birthweight, exposure to in utero maternal smoking and current exposure to household environmental tobacco smoke (stronger effect of maternal than paternal smoking) were positively associated with childhood overweight/obesity. In contrast, higher parental education level, number of siblings, active exercise habits and taking vitamins were associated with reduced risks of childhood obesity. Birthweight revealed a J-shaped relationship with the probability of childhood overweight/obesity. This study uncovers several modifiable risk factors for childhood overweight and obesity, and parents are encouraged to provide an anti-obesity environment such as quitting smoking, controlling birthweight of child during pregnancy and building up exercise habits.


Health disparities among Latina/o adolescents in urban and rural schools: educators' perspectives.
This qualitative pilot study examined health disparities among rural and urban Latina/o adolescents from the perspective of middle and high school administrators, counselors, nurses, and teachers. Participants were asked to describe Latina/o health disparities in their schools, reasons attributed to health disparities, and school-based interventions for addressing health disparities. Focus group participants reported that common health disparities for Latina/o youth in rural and urban settings include poor vision care and high teenage pregnancy rates. However, participants reported differences in physical health and mental health disparities, as well as differences in social-cultural-economic contributors to disparities and school-based interventions.


Delayed-type hypersensitivity to fragrance materials in a select North American population.
In published reports from Europe, 3- and 4-(4-hydroxy-4-methylpentyl)cyclohexene-1-carboxaldehyde (HMPCC) (Lyral) has been described as a common cause of allergic contact dermatitis (ACD). In Europe, the rates of reaction to HMPCC among patients undergoing patch testing for suspected ACD have varied from 1.2 to 17.0%, depending on the country. Data on the incidence of sensitivity to HMPCC among North Americans with suspected ACD have not been reported. The goals of this study were (1) to assess the incidence of delayed-type hypersensitivity reactions to HMPCC among patients undergoing patch testing for evaluation of eczematous dermatitis at six centers throughout North America; (2) to determine the most appropriate concentration of HMPCC to use in performing patch tests; and (3) to compare and contrast the incidence rates for HMPCC hypersensitivity to those for other fragrance materials screened with the North American Contact Dermatitis Group (NACDG) screening tray, which includes fragrance mix, Myroxilon pereirae (balsam of Peru), cinnamic aldehyde, ylang ylang oil, jasmine absolute, and tea tree oil. This report represents the prospective multicenter data on patients tested with the fragrance-related allergens on the NACDG standard screening tray and with HMPCC at 5%, 1.5%, and 0.5% concentrations in petrolatum. Statistical analyses were performed with Student's t-test (two tailed) and the chi-square test. Data from 1,603 patients evaluated at five US sites and one Canadian site were analyzed. Most patients (87.8%) were Caucasian. The majority (67%) were women, and 26.2% had a history consistent with atopic dermatitis. The patients ranged in age from 1 to 88 years, and the mean +/- standard deviation was 46.3 +/- 16.5 years. Myroxilon pereirae (balsam of Peru) and fragrance mix were the most frequent patch-test-positive fragrance allergens (6.6% and 5.9%, respectively). Cinnamic aldehyde (1.7%), ylang ylang oil (0.6%), jasmine absolute (0.4%), HMPCC (0.4% for 5% HMPCC, 0.3% for 1.5% HMPCC, and 0.2% for 0.5% HMPCC), and tea tree oil (0.3%) less frequently yielded positive reactions. Men were more likely than women to be allergic to cinnamic aldehyde. Women were more likely than men to be allergic to jasmine absolute. Atopic patients were no more likely to react to fragrance materials than were nonatopic patients. Patients who reacted to jasmine absolute tended to be older than the general population whereas those who reacted to tea tree oil tended to be younger than the general population. There were no other demographic differences between patients who reacted to a given fragrance material and the entire population studied. Testing with fragrance mix and balsam of Peru failed to identify the majority of patients in this study who were found to be sensitized to jasmine absolute, HMPCC, or tea tree oil. HMPCC is an uncommon allergen in the North American population. We recommend testing with 5% HMPCC in petrolatum for those patients suspected of having a fragrance allergy.


Chanarin Dorfman syndrome: a case report with novel nonsense mutation.
Chanarin Dorfman syndrome (CDS) is a very rare neutral lipid metabolism disorder with multisystem involvement. It is inherited as an autosomal recessive manner. It is characterized with congenital ichthyosiform erythroderma and involvement of liver, muscle, and central nervous system. Demonstration of lipid vacuoles in neutrophils from peripheral blood smears in patients with ichthyosiform erythroderma leads to the diagnosis. We report a novel ABHD5 truncating variant in a twenty nine month old female child, who presented with icthyosiform erythroderma.


Identification and functional characterization of a novel nuclear localization signal present in the yeast Nab2 poly(A)+ RNA binding protein.
The nuclear import of proteins bearing a basic nuclear localization signal (NLS) is dependent on karyopherin alpha/importin alpha, which acts as the NLS receptor, and karyopherin beta1/importin beta, which binds karyopherin alpha and mediates the nuclear import of the resultant ternary complex. Recently, a second nuclear import pathway that allows the rapid reentry into the nucleus of proteins that participate in the nuclear export of mature mRNAs has been identified. In mammalian cells, a single NLS specific for this alternate pathway, the M9 NLS of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), has been described. The M9 NLS binds a transport factor related to karyopherin beta1, termed karyopherin beta2 or transportin, and does not require a karyopherin alpha-like adapter protein. A yeast homolog of karyopherin beta2, termed Kap104p, has also been described and proposed to play a role in the nuclear import of a yeast hnRNP-like protein termed Nab2p. Here, we define a Nab2p sequence that binds to Kap104p and that functions as an NLS in both human and yeast cells despite lacking any evident similarity to basic or M9 NLSs. Using an in vitro nuclear import assay, we demonstrate that Kap104p can direct the import into isolated human cell nuclei of a substrate containing a wild-type, but not a defective mutant, Nab2p NLS. In contrast, other NLSs, including the M9 NLS, could not function as substrates for Kap104p. Surprisingly, this in vitro assay also revealed that human karyopherin beta1, but not the Kap104p homolog karyopherin beta2, could direct the efficient nuclear import of a Nab2p NLS substrate in vitro in the absence of karyopherin alpha. These data therefore identify a novel NLS sequence, active in both yeast and mammalian cells, that is functionally distinct from both basic and M9 NLS sequences.


Long-term clinical outcomes of peritoneal dialysis patients: single center experience from Korea.
Of a large body of literature reporting clinical outcomes for patients maintained on peritoneal dialysis (PD), most publications have focused on relatively short-term results. Few reports have focused on long-term survival in PD patients. Here, we present our experience with long-term patient outcomes and further analyses of the trends in demographics and clinical outcomes of 2301 end-stage renal disease (ESRD) patients treated with continuous ambulatory PD (CAPD) during a 25-year period (1981 - 2005) at our institute. Outcomes were analyzed for 1656 patients, excluding those younger than 15 years of age at initiation of CAPD, those having less than 3 months' follow-up, or those who had been on hemodialysis or who received a kidney graft before starting CAPD. In the study patients, technique survival at 5 and 10 years was 71.9% and 48.1% respectively. Patient survival was 69.8% and 51.8%. Mean age at the start of PD (50.4 +/- 13.9 years vs. 44.2 +/- 13.9 years, p < 0.01), ESRD incidence as a result of diabetic nephropathy (30.5% vs. 19.5%, p < 0.01), and incidence of cardiovascular comorbidities (26.6% vs. 20.5%, p < 0.01) were all significantly greater in patients who started PD during the second half of the study period (1993 - 2005) as compared with the first half (1981 - 1992). A multivariate analysis adjusting for these changes in demographics and comorbid conditions revealed that PD therapy starting in 1993 - 2005 was associated with a significant reduction in technique failure [hazard ratio (HR): 0.65; p < 0.01] and mortality (HR: 0.68; p < 0.01) as compared with the earlier period. However, in subgroup analyses, technique survival was not observed to be significantly improved in patients with diabetes. In summary, technique and patient survival have significantly improved despite increases in patient age, cardiovascular comorbidity, and ESRD caused by diabetes. Although diabetes, older age, and cardiovascular comorbidities are not factors that are easily modifiable to improve PD outcomes, results at our institution are encouraging in an era of declining PD utilization.


Opportunities for exercise during pullet rearing, Part I: Effect on the musculoskeletal characteristics of pullets.
Increased load-bearing exercise improves bone quality characteristics in a variety of species, including laying hens. Providing increased opportunities for exercise during the pullet rearing phase, a period of substantial musculoskeletal growth, offers a proactive approach to reducing osteoporosis by improving bone composition. The main objective of this study was to determine whether differing opportunities for exercise during rearing influences pullet musculoskeletal characteristics. Two flock replicates of 588 Lohmann Selected Leghorn-Lite pullets were reared in either standard, conventional cages (Conv) or an aviary rearing system (Avi) from day-old chicks until 16 wk of age. The keel bone and the muscles and long bones of the wings and legs were collected at 16 wk to measure muscle growth differences between rearing treatments and quantify bone quality characteristics using quantitative computed tomography (QCT) and bone breaking strength (BBS) assessment. Keel bone characteristics and muscle weights were adjusted for BW and analyses for QCT and BBS included BW as a covariate. At 16 wk of age, rearing system had an effect on the majority of keel bone characteristics (P < 0.05). The length of the keel metasternum, caudal tip cartilage length, and the overall percentage of cartilage present on the keel at 16 wk was greater in the Avi pullets compared to the Conv pullets (P < 0.01). Wing and breast muscle weights of the Avi pullets were greater than the Conv pullets (P < 0.001), but leg muscle weights were greater in the Conv pullets (P = 0.026). Avi pullets had greater total bone density, total cross-sectional area, cortical cross-sectional area, total bone mineral content, and cortical bone mineral content than Conv pullets for the radius, humerus, and tibia (P < 0.001). Avi pullets had greater BBS compared to the Conv pullets for the radius, humerus, and tibia (P < 0.01). Increased opportunities for exercise offered by the aviary rearing system increased muscle and bone growth characteristics in pullets at 16 wk of age.


Revision of infected knee arthroplasty.
Sixteen infected knee arthroplasties were revised and followed for 5 (1-10) years. There were nine recurrences of infections, but in one of these a second revision was successfully carried out. The remaining seven revisions resulted in only four functioning prostheses. The results were poor for hinged and stabilized prostheses for which arthrodesis, after eradication of the infection, is recommended. Infected compartmental prostheses with good bone stock could be treated with a two-stage procedure using tricompartmental revision prostheses.


Safety of pasteurised Akkermansia muciniphila as a novel food pursuant to Regulation (EU) 2015/2283.
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on pasteurised Akkermansia muciniphila as a novel food (NF) pursuant to Regulation (EU) 2015/2283. A. muciniphila is a well-characterised non-toxin producing, avirulent microorganism that has been reported as part of normal gut microbiota. The NF, pasteurised A. muciniphila, is proposed by the applicant to be used as a food supplement at max. 5 × 1010 cells/day by adults excluding pregnant and lactating women, and in foods for special medical purposes. The Panel considers that the production process of the NF is sufficiently described and that the information provided on the composition of the NF is sufficient for its characterisation. Taking into account the composition of the NF and the proposed conditions of use, the consumption of the NF is not nutritionally disadvantageous. Based on literature data, and by applying an uncertainty factor of 200 to the no observed adverse effect level (NOAEL) of a 90-day repeated dose oral toxicity study in rats, the Panel concludes that the consumption of 3.4 × 1010 cells/day is safe for the target population under the provision that the number of viable cells in the NF is < 10 colony forming units (CFU)/g (i.e. limit of detection).


Identification and Management of Colletotrichum acutatum on Immature Bell Peppers.
Farmers in northwestern Ohio reported severe losses due to anthracnose in immature (green) bell pepper as early as 1998. Two fungal isolates (AN1 and AN2) were recovered from immature fruit showing severe anthracnose symptoms. The pathogen was identified as Colletotrichum acutatum based on morphological and cultural characteristics, polymerase chain reaction (PCR) assay with the C. acutatum species-specific primer (CaInt2), and nucleotide sequencing. Isolate AN1 was pathogenic on immature pepper, tomato, and strawberry. Twenty-two bell pepper cultivars evaluated in field trials were all susceptible to C. acutatum AN1 and AN2, but the degree of susceptibility varied among cultivars. 'Crusader', 'Valiant', and 'ACX229' were the most susceptible, while 'North Star' and 'Paladin' were least susceptible. The fungicides pyraclostrobin (Cabrio) alternated with manganese ethylenebisdithiocarbamate (Manex), chlorothalonil (Bravo Ultrex) alone, Manex plus copper hydroxide (Kocide 2000), and pyraclostrobin + boscalid (BAS 516 = Pristine) alternated with Manex significantly reduced anthracnose incidence and intensity in bell peppers compared with the untreated control.


Hedgehog-inspired nanostructures for hydrogel-based all-solid-state hybrid supercapacitors with excellent flexibility and electrochemical performance.
High-security deformable energy-storage devices that are mechanically robust, with considerable energy and power densities are becoming desirable for smart wearable electronics. Here, a highly flexible hydrogel-based all-solid-state hybrid supercapacitor was rationally designed and assembled, with unique NiCo2O4@NixCoyMoO4 (x : y = 3 : 1) nanostructures as the electrode, which was bio-inspired by the curling up and relaxation of hedgehogs. The hybrid supercapacitor shows no obvious decay in capacitance during bending to different states, indicating its outstanding flexibility and mechanical stability. The capacitance was still maintained at 92.0% of the initial value, even after continuous bending for 3000 cycles. The highly monodisperse NiCo2O4@NixCoyMoO4 nanostructures releasing stress during bending is responsible for the favorable stability and flexibility. Furthermore, the hybrid supercapacitor displayed outstanding electrochemical performance, with a high specific capacitance of 207 F g-1 at 1 A g-1, a high energy density of 64.7 W h kg-1 at 749.6 W kg-1, and favorable cycling stability (nearly 100% after 10 000 cycles). The flexible hybrid supercapacitor could be charged with a solar cell and served as the power source to light up LEDs. This simple and reliable hybrid supercapacitor, with extraordinary mechanical stability and electrochemical performance, is a promising power source for smart wearable electronics.


DNA/protein interaction and cytotoxic activity of imidazole terpyridine derived Cu(II)/Zn(II) metal complexes.
Two imidazole terpyridine (itpy) based complexes, [Cu(itpy)(OAc)(H2O)]NO3·H2O (1) and [Zn(itpy)(OAc)]OAc (2) have been synthesised and characterized. The crystal structure of complex 1 shows distorted octahedral geometry with an anti-parallel stacking arrangement. The interactions of the two complexes with Calf thymus DNA (ctDNA) have been studied using absorption titration and circular dichroism. Complex 1 shows coordinate binding to DNA bases, and complex 2 shows an intercalative mode of binding with DNA. Complex 1 cleaves the DNA via an oxidative pathway in the presence of additives, because of the presence of a redox active copper(II) centre. However, complex 2 cleaves DNA hydrolytically. Interactions of the two complexes with bovine serum albumin have been studied using fluorescence quenching and circular dichroism experiments. Circular dichroic analysis reveals that both the complexes strongly influence the secondary structure of the protein. Fluorescence quenching experiments indicate that there are different binding sites for complexes 1 and 2 on the protein. Furthermore, the complexes show potential cytotoxicity towards the A549 lung cancer cell line. Both the complexes have been found to induce apoptosis.


Usefulness of body mass index as a sufficient adiposity measurement for sex hormone concentration associations in postmenopausal women.
Both obesity and sex hormones are known risk factors for postmenopausal breast cancer. Although adiposity and sex hormones have been studied in the past, previous reports in postmenopausal women have not been conducted under carefully controlled dietary conditions. In this study, we investigated the usefulness of body mass index (BMI) as a sufficient adiposity measurement to assess associations with sex hormone levels. This study was conducted as a cross-sectional analysis within the control segment (0 g alcohol group) of a randomized, crossover design, in which 51 postmenopausal women consumed 0 (control), 15 (one drink), and 30 (two drinks) g alcohol (ethanol)/d for 8 weeks each as part of a controlled diet. Dual-energy X-ray absorptiometry scans were administered to the women during the control (0 g alcohol) segment, and a blood sample was drawn at the end of that diet period for hormone analysis. In multivariate analysis (adjusted for age, race, family history of breast cancer, parity, and menarche <12 years), women who were overweight or obese had significantly higher serum concentrations of estradiol, bioavailable estradiol, estrone, and estrone sulfate and lower sex hormone-binding globulin than normal weight women (all P < 0.05). In models adjusted for BMI and the covariates above, none of the dual-energy X-ray absorptiometry adiposity measures added further information (all P > 0.10) for these five analytes beyond that of BMI alone. In this population of postmenopausal women, under carefully controlled dietary conditions, we confirmed previous findings that higher levels of adiposity were associated with higher concentrations of estrogens and lower sex hormone-binding globulin, and we found that the use of the epidemiology-friendly BMI seems sufficient to assess associations with these hormone levels.


Role of xenobiotics in the induction and progression of fatty liver disease.
Non-alcoholic fatty liver disease is a major cause of chronic liver pathology in humans. Fatty liver disease involves the accumulation of hepatocellular fat in hepatocytes that can progress to hepatitis. Steatohepatitis is categorized into alcoholic (ASH) or non-alcoholic (NASH) steatohepatitis based on the etiology of the insult. Both pathologies involve an initial steatosis followed by a progressive inflammation of the liver and eventual hepatic fibrosis (steatohepatitis) and cirrhosis. The involvement of pharmaceuticals and other chemicals in the initiation and progression of fatty liver disease has received increased study. This review will examine not only how xenobiotics initiate hepatic steatosis and steatohepatitis but also how the presence of fatty liver may modify the metabolism and pathologic effects of xenobiotics. The feeding of a high fat diet results in changes in the expression of nuclear receptors that are involved in adaptive and adverse liver effects following xenobiotic exposure. High fat diets also modulate cellular and molecular pathways involved in inflammation, metabolism, oxidative phosphorylation and cell growth. Understanding the role of hepatic steatosis and steatohepatitis on the sequelae of toxic and pathologic changes seen following xenobiotic exposure has importance in defining proper and meaningful human risk characterization of the drugs and other chemical agents.


Evaluation of professional bra fitting criteria for bra selection and fitting in the UK.
A correctly fitting bra is essential for good health; this study investigates the use of professional bra fitting criteria to establish best-fit in an underwire bra commonly sold in the UK. A comparison was made between women's bra size as measured by the traditional bra fitting method with their recommended bra size based on professional bra fitting criteria. Forty-five female participants were recruited; their mode self-reported bra size was 34DD. Participants were measured in their own bra using the traditional bra-fitting method to establish their 'traditional size'. A 'best-fit' bra size was recorded for participants based on professional bra fitting criteria. Significant differences were found between traditional and best-fit cup and band sizes (p < 0.001); the traditional method of bra fitting overestimated band size and underestimated cup size. As band size increased the traditional method also became more inaccurate (p < 0.001). It is recommended that women are educated in assessing their own bra fit using professional bra fitting criteria and less emphasis placed on determining absolute bra size. Practitioner Summary: This is the first study to investigate using professional bra fitting criteria to establish best-fit in an underwired bra commonly sold in the UK. The traditional method of bra fitting was found to be inadequate, especially for larger-breasted women; the use of professional bra fitting criteria should be encouraged.


Trimetrexate in the treatment of recurrent or advanced leiomyosarcoma of the uterus: a phase II study of the Gynecologic Oncology Group.
This study was conducted to determine the objective response of trimetrexate in patients with advanced or recurrent leiomyosarcoma of the uterus. Eligibility was restricted to patients with measurable disease who had received no more than one prior chemotherapy regimen, who had adequate bone marrow, renal, and hepatic function, and who had recovered from previous therapy. Trimetrexate was begun at 5 mg/m2/day orally for 5 days every other week, with dose modifications specified by study design. Of 28 patients entered into the study, 27 were evaluable for toxicity and 23 for response. Prior therapy included radiation (7 patients) and/or chemotherapy (10 patients). Measurable disease was extrapelvic in 20 cases and confined to the pelvis in 3. The overall response rate was 4.3%; there were no complete responses and 1 partial response. Toxicities were mild to moderate with no treatment-related deaths. Hematological toxicity was most common, consisting of leukopenia (grade 1 to 2, 8 patients; grade 3 or 4, 2 patients), thrombocytopenia (grade 1 to 2, 10 patients; grade 3 or 4, 1 patient), and anemia (grade 1 to 2, 6 patients; grade 3 or 4, 4 patients. Severe (grade 3 or 4) nonhematologic toxicity was uncommon: nausea/vomiting/gastrointestinal (3 patients) and neurological (1 patient). Progression-free and overall survival, in months, was 2.2 (range: 0.9-13.4) and 7.2+ (range: 1.0-13.4+), respectively. Although toxicity is acceptable, trimetrexate at this dose and schedule is ineffective therapy for patients with recurrent leiomyosarcoma. Further development of this specific regimen for this indication is unwarranted.


Post-abscission, pre-dispersal seeds of Digitalis purpurea remain in a developmental state that is not terminated by desiccation ex planta.
Seed quality may be compromised if seeds are harvested before natural dispersal (shedding). It has been shown previously that slow or delayed drying can increase potential quality compared with immediate rapid drying. This study set out to investigate whether or not there is a critical moisture content, below which drying terminates maturation events for seeds harvested after mass maturity but before dispersal. Seeds of foxglove (Digitalis purpurea) in the post-abscission pre-dispersal phase were held at between 15 and 95 % RH for 4 or 8 d, with or without re-hydration to 95 % RH for a further 4 d, before drying to equilibrium at 15 % RH. In addition, dry seeds were primed for 48 h at -1 MPa. Subsequent seed longevity was assessed at 60 % RH and 45 degrees C. Rate of germination and longevity were improved by holding seeds at a wide range of humidities after harvest. Longevity was further improved by re-hydration at 95 % RH. Priming improved the longevity of the seeds dried immediately after harvest, but not of those first held at 95 % RH for 8 d prior to drying. Maturation continued ex planta in these post-abscission, pre-dispersal seeds of D. purpurea dried at 15-80 % RH at a rate correlated positively with RH (cf. ageing of mature seeds). Subsequent re-hydration at 95 % RH enabled a further improvement in quality. Priming seeds initially stored air-dry for 3 months also allowed maturation events to resume. However, once individual seeds within the population had reached maximum longevity, priming had a negative impact on their subsequent survival.


Reinstating object-based attention under positional certainty: the importance of subjective parsing.
Previous studies have shown that interference from flanking distractors can be modulated by the object organization of the scene. The experiments reported here test for object-based attention under conditions of positional certainty, which allow a narrow focus of attention to the target. Prior research has suggested that object-based attention does not arise in these circumstances, but the experiments presented here show that object-based attention can still appear if previous experience with the stimuli leads participants to interpret the stimulus pattern as two separate objects. Two control experiments demonstrate that the appearance of object-based attention is not due simply to a widening of the focus of spatial attention. The presence of object-based attention in such a focused-attention task argues against Shomstein and Yantis's (2002) proposed explanation of object-based attention based on priority in the order of visual search.


SGO1 but not SGO2 is required for maintenance of centromere cohesion in Arabidopsis thaliana meiosis.
Shugoshin is a protein conserved in eukaryotes and protects sister chromatid cohesion at centromeres in meiosis. In our study, we identified the homologs of SGO1 and SGO2 in Arabidopsis thaliana. We show that AtSGO1 is necessary for the maintenance of centromere cohesion in meiosis I since atsgo1 mutants display premature separation of sister chromatids starting from anaphase I. Furthermore, we show that the localization of the specific centromeric cohesin AtSYN1 is not affected in atsgo1, suggesting that SGO1 centromere cohesion maintenance is not mediated by protection of SYN1 from cleavage. Finally, we show that AtSGO2 is dispensable for both meiotic and mitotic cell progression in Arabidopsis.


The effects of magnesium on ion transport in short-circuited rabbit terminal ileum.
The effects of MgCl2 on the electrical characteristics and sodium and chloride transport in short-circuited rabbit terminal ileum in vitro were studied. Increasing the magnesium concentration from a basal concentration of 1.1 mmol/l to either 2.5 or 10.3 mmol/l (mucosal or serosal addition) resulted in increases in the unidirectional flux of chloride from serosa to mucosa (JCl sm), short-circuit current (SCC) and transmucosal potential difference (p.d.). Increasing the magnesium concentration from a low basal concentration (0.3 mmol/l) to 10.3 mmol/l (mucosal or serosal addition) abolished net sodium absorption and converted net chloride absorption into net secretion, as a result of a decrease in the unidirectional flux of sodium from mucosa to serosa (JNa ms), and increases in the unidirectional fluxes of sodium and chloride from serosa to mucosa (JNa sm and JCl sm). Increases in SCC and p.d. occurred after mucosal, but not serosal, addition of magnesium. Incubation of stripped ileal mucosa with MgCl2 (10.3 mmol/l) did not result in increased mucosal concentrations of cAMP or cGMP. These data suggest that at least part of the cathartic effect of magnesium salts is likely to result from marked changes in ileal ion transport and provide a rational explanation for the watery diarrhoea commonly seen after the oral administration of magnesium salts to hypomagnesaemic patients.


Transepithelial signaling to neutrophils by salmonellae: a novel virulence mechanism for gastroenteritis.
Salmonella serotypes which elicit human enteritis cannot be distinguished from those that do not on the basis of their in vitro interactions with eukaryotic cells. We have recently reported that an enteritis-producing strain of Salmonella typhimurium signals intact intestinal epithelium to recruit subepithelial neutrophils to migrate across the epithelial (B. A. McCormick, S. P. Colgan, C. D. Archer, S. I. Miller, and J. L. Madara, J. Cell Biol. 123:895-907, 1993). We now utilize a cell culture model of human intestinal epithelium (with T84 cells) to examine whether such transepithelial signaling to neutrophils by salmonellae is predictive of potential to elicit gastroenteritis. Various Salmonella serotypes, including S. typhimurium, S. enteritidis, S. pullorum, S. arizonae, S. typhi, and S. paratyphi, as well as invasion-defective mutants of S. typhimurium, were studied. Strains or serotypes which elicit diffuse enteritis in humans (defined histologically as transepithelial migration of neutrophils) exhibited transepithelial signaling to neutorphils across epithelial cell monolayers, while those which do not elicit diffuse enteritis in humans did not display transepithelial signaling. In contrast, the ability to enter the apical surface of T84 cells did not differentiate strains or serotypes which induce diffuse enteritis from those which do not. These results strongly suggest that the ability of salmonellae to elicit transepithelial signaling to neutrophils is a key virulence mechanism underlying Salmonella-elicited enteritis.


Sodium-ion batteries: present and future.
Energy production and storage technologies have attracted a great deal of attention for day-to-day applications. In recent decades, advances in lithium-ion battery (LIB) technology have improved living conditions around the globe. LIBs are used in most mobile electronic devices as well as in zero-emission electronic vehicles. However, there are increasing concerns regarding load leveling of renewable energy sources and the smart grid as well as the sustainability of lithium sources due to their limited availability and consequent expected price increase. Therefore, whether LIBs alone can satisfy the rising demand for small- and/or mid-to-large-format energy storage applications remains unclear. To mitigate these issues, recent research has focused on alternative energy storage systems. Sodium-ion batteries (SIBs) are considered as the best candidate power sources because sodium is widely available and exhibits similar chemistry to that of LIBs; therefore, SIBs are promising next-generation alternatives. Recently, sodiated layer transition metal oxides, phosphates and organic compounds have been introduced as cathode materials for SIBs. Simultaneously, recent developments have been facilitated by the use of select carbonaceous materials, transition metal oxides (or sulfides), and intermetallic and organic compounds as anodes for SIBs. Apart from electrode materials, suitable electrolytes, additives, and binders are equally important for the development of practical SIBs. Despite developments in electrode materials and other components, there remain several challenges, including cell design and electrode balancing, in the application of sodium ion cells. In this article, we summarize and discuss current research on materials and propose future directions for SIBs. This will provide important insights into scientific and practical issues in the development of SIBs.


Entry techniques in laparoscopic radical and partial nephrectomy: a multicenter international survey of contemporary practices.
There is no clear consensus as to the optimal method of entry in laparoscopic renal surgery and no reports have compared them in Urology. To analyze contemporary practice patterns in entry technique and port placement for laparoscopic kidney surgery. We identified 60 high volume urological laparoscopic centers. A purpose-built questionnaire was sent to surgeons. The survey included 22 questions regarding access techniques and port configuration during laparoscopic kidney surgery. Data on were collected and retrospectively analyzed. Concordance among port configurations was assessed using Cohen's Kappa statistics. The survey was sent to 60 surgeons and completed by 32 of them. Surgical procedures included were laparoscopic radical nephrectomy (1177 LRN/year) and laparoscopic partial nephrectomy (1047 LPN/year). The transperitoneal route was preferred (85%). Hasson technique was used for the access in 55% of the cases. Patient lateral recumbent position is the most frequently used during the port placement (41%). Although there is a high variability in the port positioning among the surgeons, in more than 90% of cases it was found a specific concordance in triangulation of optics and operating trocars. There were no significant differences between port configuration in LRN and LPN. Limitations include retrospective design and limited sample. A standard port configuration has not been previously reported in urological literature. Our study suggests that the transperitoneal approach, the Hasson technique and a specific triangulation of optics and operating trocars have a significant concordance in some high volume laparoscopic urologic centers.


Clinical profile of dengue infection in patients with hematological diseases.
Managing hematological disorders in a tropical country presents several unique diagnostic and management problems. Apart from the disease process, we need to be aware of infections that can exacerbate or mimic serious hematological problems. We present here a series of five patients with pre-existing hematological diseases who were infected by dengue virus. These cases highlight the need to keep a strong suspicion of common endemic diseases in tropical countries before considering extensive workup for the basic hematological disease. There was no mortality and all patients recovered without any significant impact on their pre-existing hematological condition inspite of their low baseline blood counts. There was no excessive bleeding, prolonged stay in the hospital or relapse of underlying hematological disease in these patients and the only major concern was the increased anxiety among both the patient and treating physician regarding the relapse/progression of pre-existing hematological disease.


Dynamics of the 2001 UK foot and mouth epidemic: stochastic dispersal in a heterogeneous landscape.
Foot-and-mouth is one of the world's most economically important livestock diseases. We developed an individual farm-based stochastic model of the current UK epidemic. The fine grain of the epidemiological data reveals the infection dynamics at an unusually high spatiotemporal resolution. We show that the spatial distribution, size, and species composition of farms all influence the observed pattern and regional variability of outbreaks. The other key dynamical component is long-tailed stochastic dispersal of infection, combining frequent local movements with occasional long jumps. We assess the history and possible duration of the epidemic, the performance of control strategies, and general implications for disease dynamics in space and time.


Probabilistic Contextual and Structural Dependencies Learning in Grammar-Based Genetic Programming.
Genetic Programming is a method to automatically create computer programs based on the principles of evolution. The problem of deceptiveness caused by complex dependencies among components of programs is challenging. It is important because it can misguide Genetic Programming to create suboptimal programs. Besides, a minor modification in the programs may lead to a notable change in the program behaviours and affect the final outputs. This article presents Grammar-Based Genetic Programming with Bayesian Classifiers (GBGPBC) in which the probabilistic dependencies among components of programs are captured using a set of Bayesian network classifiers. Our system was evaluated using a set of benchmark problems (the deceptive maximum problems, the royal tree problems, and the bipolar asymmetric royal tree problems). It was shown to be often more robust and more efficient in searching the best programs than other related Genetic Programming approaches in terms of the total number of fitness evaluation. We studied what factors affect the performance of GBGPBC and discovered that robust variants of GBGPBC were consistently weakly correlated with some complexity measures. Furthermore, our approach has been applied to learn a ranking program on a set of customers in direct marketing. Our suggested solutions help companies to earn significantly more when compared with other solutions produced by several well-known machine learning algorithms, such as neural networks, logistic regression, and Bayesian networks.


Porcine intestinal mast cells. Evaluation of different fixatives for histochemical staining techniques considering tissue shrinkage.
Staining of mast cells (MCs), including porcine ones, is critically dependent upon the fixation and staining technique. In the pig, mucosal and submucosal MCs do not stain or stain only faintly after formalin fixation. Some fixation methods are particularly recommended for MC staining, for example the fixation with Carnoy or lead salts. Zinc salt fixation (ZSF) has been reported to work excellently for the preservation of fixation-sensitive antigens. The aim of this study was to establish a reliable histological method for counting of MCs in the porcine intestinum. For this purpose, different tissue fixation and staining methods that also allow potential subsequent immunohistochemical investigations were evaluated in the porcine mucosa, as well as submucosa of small and large intestine. Tissues were fixed in Carnoy, lead acetate, lead nitrate, Zamboni and ZSF and stained subsequently with either polychromatic methylene blue, alcian blue or toluidine blue. For the first time our study reveals that ZSF, a heavy metal fixative, preserves metachromatic staining of porcine MCs. Zamboni fixation was not suitable for histochemical visualization of MCs in the pig intestine. All other tested fixatives were suitable. Alcian blue and toluidine blue co-stained intestinal goblet cells which made a prima facie identification of MCs difficult. The polychromatic methylene blue proved to be the optimal staining. In order to compare MC counting results of the different fixation methods, tissue shrinkage was taken into account. As even the same fixation caused shrinkage-differences between tissue from small and large intestine, different factors for each single fixation and intestinal localization had to be calculated. Tissue shrinkage varied between 19% and 57%, the highest tissue shrinkage was found after fixation with ZSF in the large intestine, the lowest one in the small intestine after lead acetate fixation. Our study emphasizes that MC counting results from data using different fixation techniques can only be compared if the respective study-immanent shrinkage factor has been determined and quantification results are adjusted accordingly.


Consensus guidelines for primary health care of adults with developmental disabilities.
To develop practical Canadian guidelines for primary health care providers based on the best available evidence for addressing health issues in adults with developmental disabilities (DD). Authors of background papers synthesized information from their own clinical experience, from consultations with other experts, and from relevant professional publications. Based on discussions of these papers at a colloquium of knowledgeable health care providers, a consensus statement was developed. Standard criteria were used to select guidelines for consideration and to rank evidence supporting them. Most evidence was level III. People with DD have complex health issues, some differing from those of the general population. Adequate primary health care is necessary to identify these issues and to prevent morbidity and premature death. Physical, behavioural, and mental health difficulties should be addressed, and primary health care providers should be particularly attentive to the interactions of biological, psychological, and social factors contributing to health, since these interactions can easily be overlooked in adults with DD. Attention must also be paid to such ethical issues as informed consent and avoidance of harm. Developmental disabilities are not grounds for care providers to withhold or to withdraw medically indicated interventions, and decisions concerning such interventions should be based on patients' best interests. Implementing the guidelines proposed here would improve the health of adults with DD and minimize disparities in health and health care.


Genetic diversity and signatures of selection of drug resistance in Plasmodium populations from both human and mosquito hosts in continental Equatorial Guinea.
In Plasmodium, the high level of genetic diversity and the interactions established by co-infecting parasite populations within the same host may be a source of selection on pathogen virulence and drug resistance. As different patterns have already been described in humans and mosquitoes, parasite diversity and population structure should be studied in both hosts to properly assess their effects on infection and transmission dynamics. This study aimed to characterize the circulating populations of Plasmodium spp and Plasmodium falciparum from a combined set of human blood and mosquito samples gathered in mainland Equatorial Guinea. Further, the origin and evolution of anti-malarial resistance in this area, where malaria remains a major public health problem were traced. Plasmodium species infecting humans and mosquitoes were identified by nested-PCR of chelex-extracted DNA from dried blood spot samples and mosquitoes. Analysis of Pfmsp2 gene, anti-malarial-resistance associated genes, Pfdhps, Pfdhfr, Pfcrt and Pfmdr1, neutral microsatellites (STR) loci and Pfdhfr and Pfdhps flanking STR was undertaken to evaluate P. falciparum diversity. Prevalence of infection remains high in mainland Equatorial Guinea. No differences in parasite formula or significant genetic differentiation were seen in the parasite populations in both human and mosquito samples. Point mutations in all genes associated with anti-malarial resistance were highly prevalent. A high prevalence was observed for the Pfdhfr triple mutant in particular, associated with pyrimethamine resistance.Analysis of Pfdhps and Pfdhfr flanking STR revealed a decrease in the genetic diversity. This finding along with multiple independent introductions of Pfdhps mutant haplotypes suggest a soft selective sweep and an increased differentiation at Pfdhfr flanking microsatellites hints a model of positive directional selection for this gene. Chloroquine is no longer recommended for malaria treatment in Equatorial Guinea but sulphadoxine-pyrimethamine (SP) remains in use in combination with artesunate and is the only drug recommended in preventive chemotherapy in pregnancy. The high prevalence of point mutations in Pfdhfr and Pfdhps points to the danger of an eventual reduction in the efficacy of SP combined therapy in P. falciparum populations in Equatorial Guinea and to the essential continuous monitoring of these two genes.


Diversity of toxic and nontoxic nodularia isolates (cyanobacteria) and filaments from the Baltic Sea.
Cyanobacteria of the genus Nodularia form toxic blooms in brackish waters worldwide. In addition, Nodularia spp. are found in benthic, periphytic, and soil habitats. The majority of the planktic isolates produce a pentapeptide hepatotoxin nodularin. We examined the morphologic, toxicologic, and molecular characters of 18 nodularin-producing and nontoxic Nodularia strains to find appropriate markers for distinguishing the toxic strains from the nontoxic ones in field samples. After classical taxonomy, the examined strains were identified as Nodularia sp., Nodularia spumigena, N. baltica, N. harveyana, and N. sphaerocarpa. Morphologic characters were ambiguous in terms of distinguishing between the toxic and the nontoxic strains. DNA sequences from the short 16S-23S rRNA internally transcribed spacer (ITS1-S) and from the phycocyanin operon intergenic spacer and its flanking regions (PC-IGS) were different for the toxic and the nontoxic strains. Phylogenetic analysis of the ITS1-S and PC-IGS sequences from strains identified as N. spumigena, and N. baltica, and N. litorea indicated that the division of the planktic Nodularia into the three species is not supported by the ITS1-S and PC-IGS sequences. However, the ITS1-S and PC-IGS sequences supported the separation of strains designated N. harveyana and N. sphaerocarpa from one another and the planktic strains. HaeIII digestion of PCR amplified PC-IGS regions of all examined 186 Nodularia filaments collected from the Baltic Sea produced a digestion pattern similar to that found in toxic isolates. Our results suggest that only one planktic Nodularia species is present in the Baltic Sea plankton and that it is nodularin producing.


Maintaining energy homeostasis is an essential component of Wld(S)-mediated axon protection.
Wld(S) mutation protects axons from degeneration in diverse experimental models of neurological disorders, suggesting that the mutation might act on a key step shared by different axon degeneration pathways. Here we test the hypothesis that Wld(S) protects axons by preventing energy deficiency commonly encountered in many diseases. We subjected compartmentally cultured, mouse cortical axons to energy deprivation with 6mM azide and zero glucose. In wild-type (WT) culture, the treatment, which reduced axon ATP level ([ATP]axon) by 65%, caused immediate axon depolarization followed by gradual free calcium accumulation and subsequent irreversible axon damage. The calcium accumulation resulted from calcium influx partially via L-type voltage-gated calcium channel (L-VGCC). Blocking L-VGCC with nimodipine reduced calcium accumulation and protected axons. Without altering baseline [ATP]axon, the presence of Wld(S) mutation significantly reduced the axon ATP loss and depolarization, restrained the subsequent calcium accumulation, and protected axons against energy deprivation. Wld(S) neurons possessed higher than normal nicotinamide mononucleotide adenylyltransferase (NMNAT) activity. The intrinsic Wld(S) NMNAT activity was required for the Wld(S)-mediated energy preservation and axon protection during but not prior to energy deprivation. NMNAT catalyzes the reversible reaction that produces nicotinamide adenine dinucleotide (NAD) from nicotinamide mononucleotide (NMN). Interestingly, preventing the production of NAD from NMN with FK866 increased [ATP]axon and protected axons from energy deprivation. These results indicate that the Wld(S) mutation depends on its intrinsic Wld(S) NMNAT activity and the subsequent increase in axon ATP but not NAD to protect axons, implicating a novel role of Wld(S) NMNAT in axon bioenergetics and protection.


Platinum electrodeposition at unsupported electrochemically reduced nanographene oxide for enhanced ammonia oxidation.
The electrochemical reduction of highly oxidized unsupported graphene oxide nanosheets and its platinum electrodeposition was done by the rotating disk slurry electrode technique. Avoiding the use of a solid electrode, graphene oxide was electrochemically reduced in a slurry solution with a scalable process without the use of a reducing agent. Graphene oxide nanosheets were synthesized from carbon platelet nanofibers to obtain highly hydrophilic layers of less than 250 nm in width. The graphene oxide and electrochemically reduced graphene oxide/Pt (erGOx/Pt) hybrid materials were characterized through different spectroscopy and microscopy techniques. Pt nanoparticles with 100 facets, clusters, and atoms at erGOx were identified by high resolution transmission electron microscopy (HRTEM). Cyclic voltammetry was used to characterize the electrocatalytic activity of the highly dispersed erGOx/Pt hybrid material toward the oxidation of ammonia, which showed a 5-fold current density increase when compared with commercially available Vulcan/Pt 20%. This is in agreement with having Pt (100) facets present in the HRTEM images of the erGOx/Pt material.


Advances in nanoplasmonic biosensors for clinical applications.
Biomarkers are unquestionable biological indicators for diagnosis and therapeutic interventions providing appropriate classification of a wide range of health disorders and risk factors. Nonetheless, the detection and quantification of biomarkers need to be tested with sufficient reliability by robust analytical methods in order to assure clinical performance in health care settings. Since the analytical performance is determined by the sensitivity and specificity of the method employed, techniques have been intensively refined in order to avoid the misinterpretation of results and undesirable bias. Although biomarkers can be detected with the existing analytical techniques, to reproducibly quantify them in decentralized settings or remote locations with the required accuracy is still a challenge. Currently, only a few point-of-care devices for biomarker evaluation are commercially available. Thus, more focused research efforts are needed to overcome these limitations in order to provide universal patient-centered care platforms. To this end, plasmonic biosensors can be conveniently used as portable diagnostic devices for attaining timely and cost-effective clinical outcomes. The development of enhanced performance based on nanoplasmonics technology opens the way for sensor miniaturization, multiplexing and point of care testing. This review covers recent advances and applications of plasmonic and nanoplasmonic biosensors intended for biomarker diagnosis in clinical practice, including cancer, cardiovascular and neurodegenerative diseases. The review specially focuses on: (i) recent progress in plasmonics development including the design of singular nanostructured surfaces, (ii) novel chemical functionalization strategies for the appropriate incorporation of bioreceptors and (iii) plasmonic applications as real operative devices in the clinical field. Future prospects in the use of nanoplasmonic sensor platforms for personalised quantification and management of biomarkers directly in body fluids will also be discussed.


Concentration of Rat Bone Marrow Nucleated Cells Using Hypo-osmotic Hemolysis in Distilled Water.
Bone marrow aspirates contain primarily red blood cells. To achieve efficient cell transplantation for regeneration, the red blood cells need to be removed from the aspirates. Cell isolation is typically performed using density gradient centrifugation. However, this method entails issues of clinical safety and convenience. This study describes an efficient method to concentrate bone marrow nucleated cells by hypo-osmotic hemolysis. The optimal hemolysis conditions were determined by diluting the bone marrow suspensions with distilled water in various dilution ratios. Then, the resulting cell fractions were transplanted in a rat cranial defect model to evaluate their effects on bone formation and their angiogenic effects. The optimal hemolysis conditions were a 3.3-fold dilution in distilled water and a hypo-osmotic exposure time of 45 seconds. Nucleated cells obtained using this method included granulocytes and mononuclear cells. These cells contain cytoplasmic angiogenic factors, including vascular endothelial growth factor, basic fibroblast growth factor, and hepatocyte growth factor. In a rat cranial defect model, callus formation and angiogenesis were significantly increased following transplantation of concentrated marrow nucleated cells in this manner. These results suggest angiogenic and osteogenetic effects of transplanting marrow nucleated cells using this hypo-osmotic method.


Strong-field double ionization of rare gases.
We have studied the double ionization of helium and other rare gases using an electron-ion coincidence technique. With this scheme, the electron energy spectrum correlated to the creation of a doubly charged ion may be compiled. In all cases, the observed double ionization electron distributions are similar and enhanced at high energies, while the single ionization spectra exhibit distinct differences.


Predicting circadian phase across populations: a comparison of mathematical models and wearable devices.
From smart work scheduling to optimal drug timing, there is enormous potential in translating circadian rhythms research results for precision medicine in the real world. However, the pursuit of such effort requires the ability to accurately estimate circadian phase outside of the laboratory. One approach is to predict circadian phase noninvasively using light and activity measurements and mathematical models of the human circadian clock. Most mathematical models take light as an input and predict the effect of light on the human circadian system. However, consumer-grade wearables that are already owned by millions of individuals record activity instead of light, which prompts an evaluation of the accuracy of predicting circadian phase using motion alone. Here, we evaluate the ability of four different models of the human circadian clock to estimate circadian phase from data acquired by wrist-worn wearable devices. Multiple datasets across populations with varying degrees of circadian disruption were used for generalizability. Though the models we test yield similar predictions, analysis of data from 27 shift workers with high levels of circadian disruption shows that activity, which is recorded in almost every wearable device, is better at predicting circadian phase than measured light levels from wrist-worn devices when processed by mathematical models. In those living under normal living conditions, circadian phase can typically be predicted to within 1 h, even with data from a widely available commercial device (the Apple Watch). These results show that circadian phase can be predicted using existing data passively collected by millions of individuals with comparable accuracy to much more invasive and expensive methods.


Effect of 6% hydroxyethyl starch 130/0.4 as a priming solution on coagulation and inflammation following complex heart surgery.
Prolonged duration of cardiopulmonary bypass aggravates the degree of inflammation and coagulopathy. We investigated the influence of 6% hydroxyethyl starch (HES) 130/0.4 on coagulation and inflammation compared with albumin when used for both cardiopulmonary bypass priming and perioperative fluid therapy in patients undergoing complex valvular heart surgery. Fifty four patients were randomly allocated into albumin-HES, albumin-nonHES, and HES-HES groups. The cardiopulmonary bypass circuit was primed with 5% albumin in the albumin-HES and albumin-nonHES group, and with HES in the HES-HES group. As perioperative fluid, only plasmalyte was used in the albumin-nonHES group whereas HES was used up to 20 mL/kg in the albumin-HES and albumin-HES group. Serial assessments of coagulation profiles using the rotational thromboelastometry and inflammatory markers (tissue necrosis factor-α, interleukin-6, and interleukin-8) were performed. Patients' characteristics and the duration of cardiopulmonary bypass (albumin-HES; 137±34 min, HES-HES; 136±47 min, albumin-nonHES; 132±39 min) were all similar among the groups. Postoperative coagulation profiles demonstrated sporadic increases in clot formation time and coagulation time, without any differences in the actual amount of perioperative bleeding and transfusion requirements among the groups. Also, inflammatory markers showed significant activation after cardiopulmonary bypass without any differences among the groups. Even in the presence of prolonged duration of cardiopulmonary bypass, HES seemed to yield similar influence on the ensuing coagulopathy and inflammatory response when used for priming and perioperative fluid therapy following complex valvular heart surgery compared with conventional fluid regimen including albumin and plasmalyte.


Vitamin D - pivotal nutraceutical in the regulation of cancer metastasis and angiogenesis.
Various epidemiological studies have demonstrated that vitamin D may play important roles in the pathogenesis and progression of cancer. Vitamin D is one of the most pivotal nutraceuticals whose active metabolite, calcitriol (1,25-dihydroxyvitamin D3), possesses anti-proliferative, pro-apoptotic, and pro-differentiating capabilities. Accumulating evidence indicates that the potential benefits of using vitamin D in cancer are not only anti-cancer cell proliferation which is linked with its anti-inflammatory effects, including the suppression of prostaglandin metabolism and inhibition of NF-κB signaling, but also suppressing tumor metastasis and angiogenesis. Here, we present a systematic summary of the effects of vitamin D in the chemoprevention and chemotherapy of cancer, especially anti-metastatic and anti-angiogenic actions.


Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.
Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood-brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.