Interpersonal violence is associated with depression and chronic physical health problems in midlife women.
This research describes interpersonal violence (IPV) exposure in a community-based sample of midlife women from three ethnic groups and explores relationships among these exposures and variables associated with health outcomes. IPV, physical health, depression, and social support were measured by self-report questionnaires. More than 33% reported a history of physical abuse or sexual abuse and at least 20% reported both. Approximately 20% experienced sexual harassment in the past year. IPV exposure was associated with more chronic health problems and depressive symptoms. IPV, whenever it occurs, is detrimental to women's health regardless of socioeconomic status or ethnicity.


Stem cell differentiation and lumen formation in colorectal cancer cell lines and primary tumors.
Single cancer stem-like cells (CSC) from colorectal cancers can be functionally identified by their ability to form large lumen-containing colonies in three-dimensional Matrigel cultures. These colonies contain the three types of differentiated colorectal epithelial cells, and single cells obtained from them can reproduce themselves and form tumors efficiently in immunodeficient mice. In this study, we show how hypoxia affects these CSC-derived lumens to control differentiation of stem-like cells and enterocytes via the homeobox gene CDX1. Lumens were identified by F-actin staining and they expressed many characteristics associated with normal differentiated intestinal epithelium, including brush border enzymes, polarization, and tight junctions. RNA interference-mediated silencing of CDX1 reduced lumen formation. Inhibitory effects of hypoxia on lumen formation and stem cell differentiation, including suppression of CDX1 expression, could be mimicked by inhibiting prolyl-hydroxylases that activate HIF1, suggesting that HIF1 is a critical mediator of the effects of hypoxia in this setting. Cell line-derived lumens were phenotypically indistinguishable from colorectal tumor glandular structures used by pathologists to grade tumor differentiation. Parallel results to those obtained with established cell lines were seen with primary cultures from fresh tumors. This in vitro approach to functional characterization of CSCs and their differentiation offers a valid model to study colorectal tumor differentiation and differentiation of colorectal CSCs, with additional uses to enable high-throughput screening for novel anticancer compounds.


Cardiac hypertrophy and performance of Dahl hypertensive rats on graded salt diets.
The relationship between arterial pressure and left ventricular (LV) functional capacity and LV mass during the natural development of cardiac hypertrophy was assessed in Dahl-resistant (R) and -sensitive (S) hypertensive rats maintained on three dietary NaCl regimens (0.4%, 4.0%, and 8.0% for 9 weeks, then 4.0%) from 5 until 20 weeks of age. In R rats, arterial pressure and LV mass were unaffected by diet. In contrast, S rats demonstrated levels of arterial pressure and LV hypertrophy that were graded according to dietary NaCl. Hemodynamic studies on rats under ether anesthesia demonstrated that the graded pressure elevation in S rats was produced by corresponding increases in total peripheral resistance, as cardiac output did not vary. During acute volume loading, the S rats on all diets achieved the same maximum stroke volume as did R rats, despite the marked increase in the arterial pressure of S rats. An analysis of the ejection fraction/afterload relationship demonstrated preserved contractile state. The ability of the left ventricle to generate pressure was increased in S rats in direct proportion to the degree of LV hypertrophy. Thus, in young adult S rats, cardiac performance was well compensated since pump and contractile functions were maintained and pressure-generating capacity was increased in relation to the degree of LV hypertrophy.


Dose-volume histogram prediction using density estimation.
Knowledge of what dose-volume histograms can be expected for a previously unseen patient could increase consistency and quality in radiotherapy treatment planning. We propose a machine learning method that uses previous treatment plans to predict such dose-volume histograms. The key to the approach is the framing of dose-volume histograms in a probabilistic setting.The training consists of estimating, from the patients in the training set, the joint probability distribution of some predictive features and the dose. The joint distribution immediately provides an estimate of the conditional probability of the dose given the values of the predictive features. The prediction consists of estimating, from the new patient, the distribution of the predictive features and marginalizing the conditional probability from the training over this. Integrating the resulting probability distribution for the dose yields an estimate of the dose-volume histogram.To illustrate how the proposed method relates to previously proposed methods, we use the signed distance to the target boundary as a single predictive feature. As a proof-of-concept, we predicted dose-volume histograms for the brainstems of 22 acoustic schwannoma patients treated with stereotactic radiosurgery, and for the lungs of 9 lung cancer patients treated with stereotactic body radiation therapy. Comparing with two previous attempts at dose-volume histogram prediction we find that, given the same input data, the predictions are similar.In summary, we propose a method for dose-volume histogram prediction that exploits the intrinsic probabilistic properties of dose-volume histograms. We argue that the proposed method makes up for some deficiencies in previously proposed methods, thereby potentially increasing ease of use, flexibility and ability to perform well with small amounts of training data.


Arginine 104 is a key catalytic residue in leukotriene C4 synthase.
Human leukotriene C(4) synthase (hLTC(4)S) is an integral membrane enzyme that conjugates leukotriene (LT) A(4) with glutathione to form LTC(4), a precursor to the cysteinyl leukotrienes (LTC(4), LTD(4), and LTE(4)) that are involved in the pathogenesis of human bronchial asthma. From the crystal structure of hLTC(4)S, Arg-104 and Arg-31 have been implicated in the conjugation reaction. Here, we used site-directed mutagenesis, UV spectroscopy, and x-ray crystallography to examine the catalytic role of Arg-104 and Arg-31. Exchange of Arg-104 with Ala, Ser, Thr, or Lys abolished 94.3-99.9% of the specific activity against LTA(4). Steady-state kinetics of R104A and R104S revealed that the K(m) for GSH was not significantly affected. UV difference spectra of the binary enzyme-GSH complex indicated that GSH ionization depends on the presence of Arg-104 because no thiolate signal, with λ(max) at 239 nm, could be detected using R104A or R104S hLTC(4)S. Apparently, the interaction of Arg-104 with the thiol group of GSH reduces its pK(a) to allow formation of a thiolate anion and subsequent nucleophilic attack at C6 of LTA(4). On the other hand, exchange of Arg-31 with Ala or Glu reduced the catalytic activity of hLTC(4)S by 88 and 70%, respectively, without significantly affecting the k(cat)/K(m) values for GSH, and a crystal structure of R31Q hLTC(4)S (2.1 Å) revealed a Gln-31 side chain pointing away from the active site. We conclude that Arg-104 plays a critical role in the catalytic mechanism of hLTC(4)S, whereas a functional role of Arg-31 seems more elusive. Because Arg-104 is a conserved residue, our results pertain to other homologous membrane proteins and represent a structure-function paradigm probably common to all microsomal GSH transferases.


Mutational analysis of an archaeal minichromosome maintenance protein exterior hairpin reveals critical residues for helicase activity and DNA binding.
The mini-chromosome maintenance protein (MCM) complex is an essential replicative helicase for DNA replication in Archaea and Eukaryotes. While the eukaryotic complex consists of six homologous proteins (MCM2-7), the archaeon Sulfolobus solfataricus has only one MCM protein (ssoMCM), six subunits of which form a homohexamer. We have recently reported a 4.35A crystal structure of the near full-length ssoMCM. The structure reveals a total of four beta-hairpins per subunit, three of which are located within the main channel or side channels of the ssoMCM hexamer model generated based on the symmetry of the N-terminal Methanothermobacter thermautotrophicus (mtMCM) structure. The fourth beta-hairpin, however, is located on the exterior of the hexamer, near the exit of the putative side channels and next to the ATP binding pocket. In order to better understand this hairpin's role in DNA binding and helicase activity, we performed a detailed mutational and biochemical analysis of nine residues on this exterior beta-hairpin (EXT-hp). We examined the activities of the mutants related to their helicase function, including hexamerization, ATPase, DNA binding and helicase activities. The assays showed that some of the residues on this EXT-hp play a role for DNA binding as well as for helicase activity. These results implicate several current theories regarding helicase activity by this critical hexameric enzyme. As the data suggest that EXT-hp is involved in DNA binding, the results reported here imply that the EXT-hp located near the exterior exit of the side channels may play a role in contacting DNA substrate in a manner that affects DNA unwinding.


Germline SDHB and SDHD mutations in pheochromocytoma and paraganglioma patients.
Pheochromocytoma and paragangliomas (PCC/PGL) are neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and sympathetic/parasympathetic ganglia, respectively. Of clinical relevance regarding diagnosis is the highly variable presentation of symptoms in PCC/PGL patients. To date, the clear-cut correlations between the genotypes and phenotypes of PCC/PGL have not been entirely established. In this study, we reviewed the medical records of PCC/PGL patients with pertinent clinical, laboratory and genetic information. Next-generation sequencing (NGS) performed on patient samples revealed specific germline mutations in the SDHB (succinate dehydrogenase complex iron-sulfur subunit B) and SDHD (succinate dehydrogenase complex subunit D) genes and these mutations were validated by Sanger sequencing. Of the 119 patients, two were identified with SDHB mutation and one with SDHD mutation. Immunohistochemical (IHC) staining was used to analyze the expression of these mutated genes. The germline mutations identified in the SDH genes were c343C>T and c.541-542A>G in the SDHB gene and c.334-337delACTG in the SDHD gene. IHC staining of tumors from the c.343C>T and c.541-2A>G carriers showed positive expression of SDHB. Tumors from the c.334-337delACTG carrier showed no expression of SDHD and a weak diffused staining pattern for SDHB. We strongly recommend genetic testing for suspected PCC/PGL patients with a positive family history, early onset of age, erratic hypertension, recurrence or multiple tumor sites and loss of SDHB and/or SDHD expression. Tailored personal management should be conducted once a patient is confirmed as an SDHB and/or SDHD mutation carrier or diagnosed with PCC/PGL.


Change in Misperception of Child's Body Weight among Parents of American Preschool Children.
Little is known about parental recognition of their child's overweight status over time. The aim of this study was to examine the prevalence of parental misperceptions related to preschool children's weight in the last two decades. Data come from the National Health and Nutrition Examination Survey from 1988 to 1994 (early survey; n=3839) and 2007 to 2012 (recent survey; n=3153). Parents were asked whether they considered their child, ages 2-5 years, to be overweight, underweight, or just about the right weight. We estimated the probability ratio (PR) between the two surveys for parents perceiving their overweight child as overweight. Percentages of parents who inappropriately perceived their overweight child as just about the right weight was 96.6% and 94.9% for the early and recent survey, respectively. As high as 78.4% of parents perceived their obese child as just about the right weight in the recent survey. The probability of overweight/obese children being perceived as overweight in the early survey was 0.18 (95% confidence interval [CI]=0.14-0.22) and further lowered to 0.14 (95% CI=0.11-0.17) in the recent survey. After adjustment for sociodemographics and BMI z-scores of directly measured body weight, probability of being appropriately perceived by the parents declined by 30% between surveys (PR=0.70 [0.63, 0.78]). There was a declining tendency among parents to perceive overweight children appropriately. Strategies are needed to explore how to encourage clinician discussions with parents about appropriate weight for their child and strengthen capacity for childhood obesity prevention.


City-level climate change mitigation in China.
As national efforts to reduce CO2 emissions intensify, policy-makers need increasingly specific, subnational information about the sources of CO2 and the potential reductions and economic implications of different possible policies. This is particularly true in China, a large and economically diverse country that has rapidly industrialized and urbanized and that has pledged under the Paris Agreement that its emissions will peak by 2030. We present new, city-level estimates of CO2 emissions for 182 Chinese cities, decomposed into 17 different fossil fuels, 46 socioeconomic sectors, and 7 industrial processes. We find that more affluent cities have systematically lower emissions per unit of gross domestic product (GDP), supported by imports from less affluent, industrial cities located nearby. In turn, clusters of industrial cities are supported by nearby centers of coal or oil extraction. Whereas policies directly targeting manufacturing and electric power infrastructure would drastically undermine the GDP of industrial cities, consumption-based policies might allow emission reductions to be subsidized by those with greater ability to pay. In particular, sector-based analysis of each city suggests that technological improvements could be a practical and effective means of reducing emissions while maintaining growth and the current economic structure and energy system. We explore city-level emission reductions under three scenarios of technological progress to show that substantial reductions (up to 31%) are possible by updating a disproportionately small fraction of existing infrastructure.


Evaluating physiological responses of plants to salinity stress.
Because soil salinity is a major abiotic constraint affecting crop yield, much research has been conducted to develop plants with improved salinity tolerance. Salinity stress impacts many aspects of a plant's physiology, making it difficult to study in toto Instead, it is more tractable to dissect the plant's response into traits that are hypothesized to be involved in the overall tolerance of the plant to salinity. We discuss how to quantify the impact of salinity on different traits, such as relative growth rate, water relations, transpiration, transpiration use efficiency, ionic relations, photosynthesis, senescence, yield and yield components. We also suggest some guidelines to assist with the selection of appropriate experimental systems, imposition of salinity stress, and obtaining and analysing relevant physiological data using appropriate indices. We illustrate how these indices can be used to identify relationships amongst the proposed traits to identify which traits are the most important contributors to salinity tolerance. Salinity tolerance is complex and involves many genes, but progress has been made in studying the mechanisms underlying a plant's response to salinity. Nevertheless, several previous studies on salinity tolerance could have benefited from improved experimental design. We hope that this paper will provide pertinent information to researchers on performing proficient assays and interpreting results from salinity tolerance experiments.


Orbitofrontal cortex lesions alter anxiety-related activity in the primate bed nucleus of stria terminalis.
In children, behavioral inhibition (BI) in response to potential threat predicts the development of anxiety and affective disorders, and primate lesion studies suggest involvement of the orbitofrontal cortex (OFC) in mediating BI. Lesion studies are essential for establishing causality in brain-behavior relationships, but should be interpreted cautiously because the impact of a discrete lesion on a complex neural circuit extends beyond the lesion location. Complementary functional imaging methods assessing how lesions influence other parts of the circuit can aid in precisely understanding how lesions affect behavior. Using this combination of approaches in monkeys, we found that OFC lesions concomitantly alter BI and metabolism in the bed nucleus of stria terminalis (BNST) region and that individual differences in BNST activity predict BI. Thus it appears that an important function of the OFC in response to threat is to modulate the BNST, which may more directly influence the expression of BI.


Transmission of the parasitic dinoflagellate Hematodinium sp. infection in blue crabs Callinectes sapidus by cannibalism.
Infection with the parasitic dinoflagellate Hematodinium sp. can be devastating to blue crab Callinectes sapidus populations. Morbidity and mortality appear to depend on the burden of parasitic organisms. Heavily infected crabs become lethargic and, if not preyed upon, succumb to overwhelming infection. We report on the transmission of Hematodinium sp. into blue crabs that were fed pieces of infected tissues and examined for evidence of infection at time periods from 1 to 48 h and for the general state of their health after 4 d. During the first 16 h after feeding, Hematodinium sp. was found in the gut, followed by large increases in hemolymph hemocytes and the appearance of hemocytic nodules in tissues. By 16 h, the hemocytic nodules appeared poorly circumscribed and disorganized. No nodules were seen in a heavily infected crab after 24 h. By the end of the 48 h after feeding, 73% (11 of 15) of the crabs had shown evidence of infection with Hematodinium sp. Those crabs with infection intensities (Hematodinium sp. as percent of cells in hemolymph) higher than 20% were dead within 4 d.


Relative Values: Perspectives on a Neuroimaging Technology From Above and Within the Ethical Landscape.
In this paper we contribute to "sociology in bioethics" and help clarify the range of ways sociological work can contribute to ethics scholarship. We do this using a case study of an innovative neurotechnology, functional magnetic resonance imaging, and its use to attempt to diagnose and communicate with severely brain-injured patients. We compare empirical data from interviews with relatives of patients who have a severe brain injury with perspectives from mainstream bioethics scholars. We use the notion of an "ethical landscape" as an analogy for the different ethical positions subjects can take-whereby a person's position relative to the landscape makes a difference to the way they experience and interact with it. We show that, in comparison to studying abstract ethics "from above" the ethical landscape, which involves universal generalizations and global judgements, studying ethics empirically "from the ground," within the ethical landscape foregrounds a more plural and differentiated picture. We argue it is important not to treat empirical ethics as secondary to abstract ethics, to treat on-the-ground perspectives as useful only insofar as they can inform ethics from above. Rather, empirical perspectives can illuminate the plural vantage points in ethical judgments, highlight the "lived" nature of ethical reasoning, and point to all ethical vantage points as being significant. This is of epistemic importance to normative ethics, since researchers who pay attention to the various positions in and trajectories through the ethical landscape are unlikely to think about ethics in terms of abstract agency-as can happen with top-down ethics-or to elide agency with the agency of policymakers. Moreover, empirical perspectives may have transformative implications for people on the ground, especially where focus on the potential harms and benefits they face brings their experiences and interests to the forefront of ethical and policy discussion.


Vitalising porous inorganic silica networks with organic functions--PMOs and related hybrid materials.
Mesoporous organic-inorganic hybrid materials are an interesting class of materials, which combine the advantages of two worlds; the inorganic part builds a robust substrate while organic functions make them alive in a way that they can be potentially used in a number of applications. In this tutorial review, we provide an overview of how mesoporous materials are synthesised via the 'soft template' path and how the incorporation of organic functions can be achieved. Furthermore, a colourful survey full of examples is presented, providing a small overview of field of applications that can potentially benefit from the use of periodic mesoporous organosilicas (PMOs) and related materials.


Light scattering levels from intraocular lenses extracted from donor eyes.
To assess light scatter levels of intraocular lenses (IOLs) extracted from donor eyes to understand straylight elevation documented earlier in pseudophakic population studies and identify potential sources of light scattering in IOLs. Rotterdam Ophthalmic Institute, Rotterdam, the Netherlands. Experimental study. Light scattering in 74 donor IOLs was measured with the C-Quant device adapted for in vitro analysis of IOLs. Straylight was assessed at a 2.5-degree and 7.0-degree scatter angle, and results were compared with the straylight of a 20-year-old crystalline lens, a 70-year-old crystalline lens, and a lens with cataract. To identify potential changes to the IOL material, the IOLs were examined with a light microscope and a slitlamp. At 2.5 degrees and 7.0 degrees, the straylight parameter was 5.78 deg2/steradian (sr) ± 4.70 (SD) and 5.06 ± 4.01 deg2/sr, respectively. Forty-one percent of IOLs showed lower straylight than the 20-year-old lens. In 14%, the scattering intensity was higher than in the 70-year-old lens; none showed straylight comparable to that of the cataractous lens. Increased straylight was associated with surface deposits, snowflake-like degeneration, and glistenings. The incidence of IOL-related complications differed between the IOL groups. Microscopic structural alterations of IOLs play a major role in straylight elevations in pseudophakic eyes. A clear correlation with degeneration and/or alteration of implanted IOLs was found. Although these IOL-related complications would likely not affect visual acuity, they give rise to straylight and thus can cause disability glare and other symptoms.


The effects of ozone application on genotoxic damage and wound healing in bisphosphonate-applied human gingival fibroblast cells.
Medication-related osteonecrosis of the jaws (MRONJ) is an extremely therapy-resistant disease involving the jaws especially following bisphosphonate treatment. Bisphosphonates accumulate in bone in concentrations sufficient to be directly toxic to the oral epithelium. Current therapeutic options are inadequate for the prevention and treatment of MRONJ. The aim of this study was to investigate effects of ozone gas plasma therapy on wound healing in bisphosphonate-applied human fibroblasts. Human primary gingival fibroblasts were cultured. Cytotoxic concentrations (IC50) of bisphosphonates (pamidronate (PAM), alendronate (ALN), and zoledronate (ZOL)) were determined by MTT test. A 60 μg/μl for 30 s of ozone gas plasma application was performed to all experimental culture flasks after drug treatment at 24-h intervals as 3 s/cm2. Genotoxic damages were evaluated by comet assay and wound healing was determined by in vitro scratch assay. PAM, ALN, and ZOL applications caused genotoxic damage on primary human gingival fibroblast DNA. Ozone gas plasma therapy significantly decreased the genotoxic damage (p < 0.05), and this application provided 25, 29, and 27% less genotoxic damage in order of ALN, PAM, and ZOL groups. Ozone gas plasma therapy significantly increased wound healing rates both in postsurgical 24th and 48th hours for all doses of experimental drug groups (p < 0.05). The ozone gas plasma application decreased genotoxic damage effect of bisphosphonate usage while improved the wound closure rate on human gingival fibroblasts. Ozone gas plasma therapy may be helpful in prevention of gingival healing delay in MRONJ pathogenesis especially when applied simultaneously with surgical intervention.


Erythrocytes in multiple sclerosis - forgotten contributors to the pathophysiology?
Multiple sclerosis (MS) is an autoimmune disease characterised by lymphocytic infiltration of the central nervous system and subsequent destruction of myelin and axons. On the background of a genetic predisposition to autoimmunity, environmental triggers are assumed to initiate the disease. The majority of MS research has focused on the pathological involvement of lymphocytes and other immune cells, yet a paucity of attention has been given to erythrocytes, which may play an important role in MS pathology. The following review briefly summarises how erythrocytes may contribute to MS pathology through impaired antioxidant capacity and altered haemorheological features. The effect of disease-modifying therapies on erythrocytes is also reviewed. It may be important to further investigate erythrocytes in MS, as this could broaden the understanding of the pathological mechanisms of the disease, as well as potentially lead to the discovery of novel and innovative targets for future therapies.


Large replication study and meta-analyses of DVWA as an osteoarthritis susceptibility locus in European and Asian populations.
Recently, through a genome wide association study in Japanese knee osteoarthritis (OA) cases, a previously unknown gene, DVWA, was identified. The non-synonymous single nucleotide polymorphism (SNP) rs7639618 was subsequently found to be consistent and most significantly associated in Japanese and Han Chinese knee OA studies and functional relevant. Here, the association of the DVWA polymorphisms (rs7639618, rs11718863 and rs9864422) was genotyped in 1120 knee OA cases, 1482 hip OA cases and 2147 controls, all of white European descent from the Netherlands, the UK, Spain and Greece. Random effect DerSimonian and Laird meta-analyses were performed to assess the association in the different strata. To assess a more global effect, the original Japanese and Chinese data were included with the European. The meta-analyses provided evidence for global association of rs7639618 with knee OA with an odds ratio (OR) of 1.29, 95% confidence interval (CI) of 1.15-1.45 and a P-value of 2.70 x 10(-5). This effect, however, showed moderate heterogeneity, and rs7639618 was not independently associated with knee OA in Europeans, with an OR of 1.16, 95% CI of 0.99-1.35 and a P-value of 0.063. Furthermore, no association was observed with hip OA in Europeans, with a P-value of 0.851. Our results suggest that there may be global relevance for the DVWA SNP rs7639618 among knee OA cases, however, the apparent lower effect size in combination with the higher risk allele frequency in the European samples highlights again the ethnic differences in effects of discovered OA susceptibility genes.


Updating national standards for drinking-water: a Philippine experience.
The latest version of the Philippine National Standards for Drinking-Water (PNSDW) was issued in 2007 by the Department of Health (DOH). Due to several issues and concerns, the DOH decided to make an update which is relevant and necessary to meet the needs of the stakeholders. As an output, the water quality parameters are now categorized into mandatory, primary, and secondary. The ten mandatory parameters are core parameters which all water service providers nationwide are obligated to test. These include thermotolerant coliforms or Escherichia coli, arsenic, cadmium, lead, nitrate, color, turbidity, pH, total dissolved solids, and disinfectant residual. The 55 primary parameters are site-specific and can be adopted as enforceable parameters when developing new water sources or when the existing source is at high risk of contamination. The 11 secondary parameters include operational parameters and those that affect the esthetic quality of drinking-water. In addition, the updated PNSDW include new sections: (1) reporting and interpretation of results and corrective actions; (2) emergency drinking-water parameters; (3) proposed Sustainable Development Goal parameters; and (4) standards for other drinking-water sources. The lessons learned and insights gained from the updating of standards are likewise incorporated in this paper.


Na+/H+ exchanger-regulatory factor 1 mediates inhibition of phosphate transport by parathyroid hormone and second messengers by acting at multiple sites in opossum kidney cells.
The opossum kidney (OK) line displays PTH-mediated activation of adenylyl cyclase and phospholipase C and inhibition of phosphate (Pi) uptake via regulation of the type IIa sodium-phosphate cotransporter, consistent with effects in vivo. OKH cells, a subclone of the OK cell line, robustly activates PTH-mediated activation of adenylyl cyclase, but is defective in PTH-mediated inhibition of sodium-phosphate cotransport and signaling via phospholipase C. Compared with wild-type OK cells, OKH cells express low levels of the Na+/H+ exchanger regulatory factor 1 (NHERF-1). Stable expression of NHERF-1 in OKH cells (OKH-N1) rescues the PTH-mediated inhibition of sodium-phosphate cotransport. NHERF-1 also restores the capacity of 8-bromo-cAMP and forskolin to inhibit Pi uptake, but the PTH dose-response for cAMP accumulation and inhibition of Pi uptake differ by 2 orders of magnitude. NHERF-1, in addition, modestly restores phorbol ester-mediated inhibition of Pi uptake, which is much weaker than that elicited by PTH. A poor correlation exists between the inhibition of Pi uptake mediated by PTH ( approximately 60%) and the inhibition mediated by phorbol 12-myristate 13-acetate ( approximately 30%) and the ability of these molecules to activate the protein kinase C-responsive reporter gene. Furthermore, we show that NHERF-1 directly interacts with type IIa cotransporter in OK cells. Although, PTH-mediated inhibition of Pi uptake in OK cells is largely NHERF-1 dependent, the signaling pathway(s) by which this occurs is still unclear. These pathways may involve cooperativity between cAMP- and protein kinase C-dependent pathways or activation/inhibition of an unrecognized NHERF-1-dependent pathway(s).


Efficacy and tolerability of a once daily formulation of Ginkgo biloba extract EGb 761® in Alzheimer's disease and vascular dementia: results from a randomised controlled trial.
A 24-week randomised controlled trial was conducted to assess the efficacy of a 240 mg once-daily preparation of Ginkgo biloba extract EGb 761® in 404 outpatients ≥ 50 years diagnosed with mild to moderate dementia (SKT 9-23), Alzheimer's disease (AD) or vascular dementia (VaD), with neuropsychiatric features (NPI total score ≥ 5). Separate analyses were performed for diagnostic subgroups (probable or possible AD; VaD). 333 patients were diagnosed with AD and 71 with VaD. EGb 761® treatment was superior to placebo with respect to the SKT total score (drug-placebo differences: 1.7 for AD, p<0.001, and 1.4 for VaD, p<0.05) and the NPI total score (drug-placebo differences: 3.1 for AD, p<0.001 and 3.2 for VaD, p<0.05). Significant drug-placebo differences were found for most secondary outcome variables with no major differences between AD and VaD subgroups. Rates of adverse events in EGb 761® and placebo groups were essentially similar. EGb 761® improved cognitive functioning, neuropsychiatric symptoms and functional abilities in both types of dementia.


Three-dimensional alignment of schwann cells using hydrolysable microfiber scaffolds: strategies for peripheral nerve repair.
Injuries to the peripheral nervous system affect 1 in 1,000 individuals each year. The implication of sustaining such an injury is considerable with loss of sensory and/or motor function. The economic implications too are extensive running into millions of pounds (or dollars) annually for provision and support. The natural regrowth of peripheral nerves is possible for small gap injuries (of approximately 1-2 mm). However, patients with larger gap injuries require surgical intervention. The "gold standard" for repairing gap injuries is autografting; however, there are problems associated with this approach, and so, the use of nerve guidance conduits (NGC) is a realistic alternative. We outline in this chapter the development of an NGC that incorporates aligned poly-L-lactide fibres for supporting the growth of organised Schwann cells within a three-dimensional scaffold in vitro. A closed loop bioreactor for growing cells within NGC scaffolds is described together with a method of plasma deposition for modifying the microfibre surface chemistry (which improves the ability of Schwann cells to attach) and confocal microscopy for measuring cell viability and alignment within 3D constructs.


Development of heart failure is independent of K+ channel-interacting protein 2 expression.
Abnormal ventricular repolarization in ion channelopathies and heart disease is a major cause of ventricular arrhythmias and sudden cardiac death. K(+) channel-interacting protein 2 (KChIP2) expression is significantly reduced in human heart failure (HF), contributing to a loss of the transient outward K(+) current (Ito). We aim to investigate the possible significance of a changed KChIP2 expression on the development of HF and proarrhythmia. Transverse aortic constrictions (TAC) and sham operations were performed in wild-type (WT) and KChIP2(-/-) mice. Echocardiography was performed before and every 2 weeks after the operation. Ten weeks post-surgery, surface ECG was recorded and we paced the heart in vivo to induce arrhythmias. Afterwards, tissue from the left ventricle was used for immunoblotting. Time courses of HF development were comparable in TAC-operated WT and KChIP2(-/-) mice. Ventricular protein expression of KChIP2 was reduced by 70% after 10 weeks TAC in WT mice. The amplitudes of the J and T waves were enlarged in KChIP2(-/-) control mice. Ventricular effective refractory period, RR, QRS and QT intervals were longer in mice with HF compared to sham-operated mice of either genotype. Pacing-induced ventricular tachycardia (VT) was observed in 5/10 sham-operated WT mice compared with 2/10 HF WT mice with HF. Interestingly, and contrary to previously published data, sham-operated KChIP2(-/-) mice were resistant to pacing-induced VT resulting in only 1/10 inducible mice. KChIP2(-/-) with HF mice had similar low vulnerability to inducible VT (1/9). Our results suggest that although KChIP2 is downregulated in HF, it is not orchestrating the development of HF. Moreover, KChIP2 affects ventricular repolarization and lowers arrhythmia susceptibility. Hence, downregulation of KChIP2 expression in HF may be antiarrhythmic in mice via reduction of the fast transient outward K(+) current.


Regulatory T cells--a journey from rodents to the clinic.
Over the past decade our understanding about a subset of T lymphocytes, now termed regulatory T cells (Tregs) and previously known as suppressor T cells, has increased immensely. Tregs can induce and maintain immune tolerance and have the capacity to facilitate antigen-specific long-term graft survival successfully in animals receiving allogeneic organ transplants. The development of approaches to generate alloantigen reactive Tregs would provide an exciting and effective adjunct or alternative therapy to the life-long program of immunosuppression currently necessary to prevent graft rejection in the clinical setting. This review will focus on how rodent experimental models have helped us to figure out how Tregs could be induced in humans and harnessed to enable long-term transplant acceptance.


Reversible and controllable nanolocomotion of an RNA-processing machinery.
Molecular motors have inspired many avenues of research for nanotechnology but most molecular motors studied so far allow only unidirectional movement. The archaeal RNA-exosome is a reversible motor that can either polymerize or degrade an RNA strand, depending on the chemical environments. We developed a single molecule fluorescence assay to analyze the real time locomotion of this nanomachine on RNA. Despite the multimeric structure, the enzyme followed the Michaelis-Menten kinetics with the maximum speed of ∼3 nucleotides/s, showing that the three catalytic cylinders do not fire cooperatively. We also demonstrate rapid directional switching on demand by fluidic control. When the two reaction speeds are balanced on average, the enzyme shows a memory of the previous reaction it catalyzed and stochastically switches between primarily polymerizing and primarily degrading behaviors. The processive, reversible, and controllable locomotion propelled by this nanomachine has a promising potential in environmental sensing, diagnostic, and cargo delivery applications.


OCT2, SSX and SAGE1 reveal the phenotypic heterogeneity of spermatocytic seminoma reflecting distinct subpopulations of spermatogonia.
Spermatocytic seminoma (SS) is a rare testicular neoplasm that occurs predominantly in older men. In this study, we aimed to shed light on the histogenesis of SS by investigating the developmental expression of protein markers that identify distinct subpopulations of human spermatogonia in the normal adult testis. We analysed the expression pattern of OCT2, SSX2-4, and SAGE1 in 36 SS cases and four intratubular SS (ISS) as well as a series of normal testis samples throughout development. We describe for the first time two different types of SS characterized by OCT2 or SSX2-4 immunoexpression. These findings are consistent with the mutually exclusive antigenic profile of these markers during different stages of testicular development and in the normal adult testis. OCT2 was expressed predominantly in A(dark) spermatogonia, SSX2-4 was present in A(pale) and B spermatogonia and leptotene spermatocytes, whilst SAGE1 was exclusively present in a subset of post-pubertal germ cells, most likely B spermatogonia. The presence of OCT2 and SSX2-4 in distinct subsets of germ cells implies that these markers represent germ cells at different maturation stages. Analysis of SAGE1 and SSX2-4 in ISS showed spatial differences suggesting ongoing maturation of germ cells during progression of SS tumourigenesis. We conclude that the expression pattern of OCT2, SSX2-4, and SAGE1 supports the origin of SS from spermatogonia and provides new evidence for heterogeneity of this tumour, potentially linked either to the cellular origin of SS or to partial differentiation during tumour progression, including a hitherto unknown OCT2-positive variant of the tumour likely derived from A(dark) spermatogonia.


Light sheet microscopy for single molecule tracking in living tissue.
Single molecule observation in cells and tissue allows the analysis of physiological processes with molecular detail, but it still represents a major methodological challenge. Here we introduce a microscopic technique that combines light sheet optical sectioning microscopy and ultra sensitive high-speed imaging. By this approach it is possible to observe single fluorescent biomolecules in solution, living cells and even tissue with an unprecedented speed and signal-to-noise ratio deep within the sample. Thereby we could directly observe and track small and large tracer molecules in aqueous solution. Furthermore, we demonstrated the feasibility to visualize the dynamics of single tracer molecules and native messenger ribonucleoprotein particles (mRNPs) in salivary gland cell nuclei of Chironomus tentans larvae up to 200 microm within the specimen with an excellent signal quality. Thus single molecule light sheet based fluorescence microscopy allows analyzing molecular diffusion and interactions in complex biological systems.


Healthcare decision support system for administration of chronic diseases.
A healthcare decision-making support model and rule management system is proposed based on a personalized rule-based intelligent concept, to effectively manage chronic diseases. A Web service was built using a standard message transfer protocol for interoperability of personal health records among healthcare institutions. An intelligent decision service is provided that analyzes data using a service-oriented healthcare rule inference function and machine-learning platform; the rules are extensively compiled by physicians through a developmental user interface that enables knowledge base construction, modification, and integration. Further, screening results are visualized for the self-intuitive understanding of personal health status by patients. A recommendation message is output through the Web service by receiving patient information from the hospital information recording system and object attribute values as input factors. The proposed system can verify patient behavior by acting as an intellectualized backbone of chronic diseases management; further, it supports self-management and scheduling of screening. Chronic patients can continuously receive active recommendations related to their healthcare through the rule management system, and they can model the system by acting as decision makers in diseases management; secondary diseases can be prevented and health management can be performed by reference to patient-specific lifestyle guidelines.


Multicentre, double-blind, randomised, sham-controlled trial of 10 khz high-frequency spinal cord stimulation for chronic neuropathic low back pain (MODULATE-LBP): a trial protocol.
Chronic neuropathic low back pain (CNLBP) is a debilitating condition in which established medical treatments seldom alleviate symptoms. Evidence demonstrates that high-frequency 10 kHz spinal cord stimulation (SCS) reduces pain and improves health-related quality of life in patients with failed back surgery syndrome (FBSS), but evidence of this effect is limited in individuals with CNLBP who have not had surgery. The aim of this multicentre randomised trial is to assess the clinical and cost-effectiveness of 10 kHz SCS for this population. This is a multicentre, double-blind, randomised, sham-controlled trial with a parallel economic evaluation. A total of 96 patients with CNLBP who have not had spinal surgery will be implanted with an epidural lead and a sham lead outside the epidural space without a screening trial. Patients will be randomised 1:1 to 10 kHz SCS plus usual care (intervention group) or to sham 10 kHz SCS plus usual care (control group) after receiving the full implant. The SCS devices will be programmed identically using a cathodal cascade. Participants will use their handheld programmer to alter the intensity of the stimulation as per routine practice. The primary outcome will be a 7-day daily pain diary. Secondary outcomes include the Oswestry Disability Index, complications, EQ-5D-5 L, and health and social care costs. Outcomes will be assessed at baseline (pre-randomisation) and at 1 month, 3 months and 6 months after device activation. The primary analyses will compare primary and secondary outcomes between groups at 6 months, while adjusting for baseline outcome scores. Incremental cost per quality-adjusted life year (QALY) will be calculated at 6 months and over the lifetime of the patient. The outcomes of this trial will inform clinical practice and healthcare policy on the role of high-frequency 10 kHz SCS for use in patients with CNLBP who have not had surgery. Clinicaltrials.gov, NCT03470766. Registered on 20 March 2018. The views expressed here are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The NIHR had no role in the study design, writing of the manuscript or the decision to submit for publication. AK, SP, DP, SW, RST, AC, SE, LM, RD and JF all contributed to the trial design and to securing trial funding. AK, JR, SP, DP, and SE are involved in the recruitment, the intervention and the follow-up. SW will perform data collection and analysis. RST will be responsible for the statistical analysis, and RD will be responsible for the health economic analysis. All authors read and approved the final manuscript.


Regulation of 1-cys peroxiredoxin expression in the process of stromal wound healing after photorefractive keratectomy.
To investigate 1-cys peroxiredoxin (1-cysPrx) expression during the corneal wound-healing process after PRK and the effect of growth factors on 1-cysPrx expression in cultured bovine keratocytes (BKs). Rat corneas were excised at 4 hours, 12 hours, 1 day, 3 days, and 7 days after PRK. Expression of 1-cysPrx in the corneas was examined by immunohistochemical, Northern blot, and immunoblot analyses. Keratocytes were isolated from bovine corneas and subcultured to study the effects of TGF-beta1, keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), and H2O2 on 1-cysPrx expression at different concentrations and time intervals. Generation and proliferation of intracellular reactive oxygen species (ROS) in cultured BKs stimulated by these growth factors were measured by the DCF (2',7'-dichlorofluorescein) assay, the CCK-8 assay, and immunoblot analysis with a polyclonal proliferating cell nuclear antigen (PCNA) antibody, respectively. Intense staining of 1-cysPrx was observed in the epithelia and the anterior stromas of wounded corneas 4 hours after PRK and had extended to the entire stroma by day 3. By day 7, the expression almost returned to nonsurgical control level in epithelia, although notable expression was still detectable in the stroma. Concomitant augmentation of 1-cysPrx mRNA and protein was seen in the corneas at 12 hours to 7 days. Growth factor treatment in cultured BKs resulted in 1-cysPrx induction in a dose- and time-dependent manner. Growth factor-stimulated cells showed strong DCF fluorescence and increased proliferation during a 24-hour incubation, during which an upregulation of 1-cysPrx occurred. These observations provide new information for the regulation of 1-cysPrx expression during the corneal wound-healing process.


Epidermal growth factor induces rapid reorganization of the actin microfilament system in human A431 cells.
Double immunofluorescence microscopy reveals that epidermal growth factor (EGF) treatment of A431 cells results in more apparent co-localization of EGF receptor (EGFR) and actin filaments, as compared to control cells. This indicates that EGF induces actin polymerization as well as additional association of the EGFR with similar sites on the membrane-skeleton. We show that immunoprecipitation of the cytoskeleton-linked EGFR after fragmentation of the cytoskeleton results in specific co-precipitation of F-actin and a limited set of other unidentified proteins. Interestingly, EGF treatment of intact cells results in increased immunoprecipitation of cytoskeleton-associated EGFR as well as of F-actin, while actin does not co-precipitate with the non-ionic detergent-solubilized EGFR. These results demonstrate that the cytoskeleton-linked EGFR is associated with the actin microfilament system. EGF induces additional formation of protein complexes, containing the EGFR and F-actin and a limited set of other unidentified proteins. The increased co-precipitation of F-actin is most likely related to EGF-induced actin polymerization, which is specifically associated with the apical cortical microfilament system, as demonstrated by confocal laser scanning microscopy and a phallicidin-binding assay.


Prevention of Decline in Cognition after Stroke Trial (PODCAST): a study protocol for a factorial randomised controlled trial of intensive versus guideline lowering of blood pressure and lipids.
Stroke is a common cause of cognitive impairment and dementia. However, effective strategies for reducing the risk of post-stroke dementia remain undefined. Potential strategies include intensive lowering of blood pressure and/or lipids. multi-centre prospective randomised open-label blinded-endpoint controlled partial-factorial phase IV trial in secondary and primary care. 100 participants from 30 UK Stroke Research Network sites who are post- ischemic stroke or intracerebral haemorrhage by three to seven months. Interventions--all patients (1:1): intensive versus guideline blood pressure lowering (target systolic < 125 mmHg versus < 140 mmHg).Interventions--ischemic stroke (1:1): intensive versus guideline lipid lowering (target low density lipoprotein-cholesterol (LDL-c) < 1.4 mmol/l versus < 3 mmol/l). does 'intensive' blood pressure lowering therapy and/or 'intensive' lipid control reduce cognitive decline and dementia in people with ischemic stroke; and does 'intensive' blood pressure lowering therapy reduce cognitive decline and dementia in patients with hemorrhagic stroke. Addenbrooke's Cognitive Examination-Revised. feasibility of recruitment and retention of participants, tolerability and safety of the interventions, achieving and maintaining the blood pressure and lipid targets, maintaining differences in systolic blood pressure (> 10 mmHg) and low density lipoprotein-cholesterol (> 1 mmol/l) between the treatment groups, and performing clinic and telephone follow-up of cognition measures. Randomisation: using stratification, minimization and simple randomization. Blinding: participants receive open-label management. Cognition is assessed both unblinded (in clinic) and blinded (by telephone) to treatment. Adjudication of events (dementia, vascular, serious adverse events) is blinded to management. The PODCAST trial is ongoing with 78 patients recruited to date from 22 sites. Outcomes of cognitive impairment and dementia are accruing. ISRCTN85562386.


Distinctive glycerophospholipid profiles of human seminoma and adjacent normal tissues by desorption electrospray ionization imaging mass spectrometry.
Desorption electrospray ionization mass spectrometry (DESI-MS) has been successfully used to discriminate between normal and cancerous human tissue from different anatomical sites. On the basis of this, DESI-MS imaging was used to characterize human seminoma and adjacent normal tissue. Seminoma and adjacent normal paired human tissue sections (40 tissues) from 15 patients undergoing radical orchiectomy were flash frozen in liquid nitrogen and sectioned to 15 μm thickness and thaw mounted to glass slides. The entire sample was two-dimensionally analyzed by the charged solvent spray to form a molecular image of the biological tissue. DESI-MS images were compared with formalin-fixed, hematoxylin and eosin (H&E) stained slides of the same material. Increased signal intensity was detected for two seminolipids [seminolipid (16:0/16:0) and seminolipid (30:0)] in the normal tubule testis tissue; these compounds were undetectable in seminoma tissue, as well as from the surrounding fat, muscle, and blood vessels. A glycerophosphoinositol [PI(18:0/20:4)] was also found at increased intensity in the normal testes tubule tissue when compared with seminoma tissue. Ascorbic acid (i.e., vitamin C) was found at increased amounts in seminoma tissue when compared with normal tissue. DESI-MS analysis was successfully used to visualize the location of several types of molecules across human seminoma and normal tissues. Discrimination between seminoma and adjacent normal testes tubules was achieved on the basis of the spatial distributions and varying intensities of particular lipid species as well as ascorbic acid. The increased presence of ascorbic acid within seminoma compared with normal seminiferous tubules was previously unknown.


Conceptual design of dedicated road lighting for city park and housing estate.
We propose dedicated road lighting, which is significantly superior to the existing lighting technologies for the city park and housing estate. This dedicated lighting employs freeform surfaces to effectively control the optical field of the LED source to produce three kinds of illumination modes for the curved road, straight road, and the small public square, respectively, perfectly matching the road conditions of the city park and housing estate. A mathematical model of freeform illumination design is presented to achieve a conceptual design of this road lighting, and a numerical technology for solving this design problem is introduced for the first time, to our knowledge. An illumination model of this conceptual design is constructed. The experimental results of the conceptual design tally closely with the target. This dedicated road lighting, integrated with energy saving, healthy lighting and artistic beauty, provides a beautiful landscape for the city park and the housing estate at night, and will play an important role in improving quality of life of the urban inhabitants.


Functional analysis of novel androgen receptor mutations in a unique cohort of Indonesian patients with a disorder of sex development.
Mutations in the androgen receptor (AR) gene, rendering the AR protein partially or completely inactive, cause androgen insensitivity syndrome, which is a form of a 46,XY disorder of sex development (DSD). We present 3 novel AR variants found in a cohort of Indonesian DSD patients: p.I603N, p.P671S, and p.Q738R. The aim of this study was to determine the possible pathogenic nature of these newly found unclassified variants. To investigate the effect of these variants on AR function, we studied their impact on transcription activation, AR ligand-binding domain interaction with an FxxLF motif containing peptide, AR subcellular localization, and AR nuclear dynamics and DNA-binding. AR-I603N had completely lost its transcriptional activity due to disturbed DNA-binding capacity and did not show the 114-kDa hyperphosphorylated AR protein band normally detectable after hormone binding. The patient with AR-I603N displays a partial androgen insensitivity syndrome phenotype, which is explained by somatic mosaicism. A strongly reduced transcriptional activity was observed for AR-Q738R, together with diminished interaction with an FxxLF motif containing peptide. AR-P671S also showed reduced transactivation ability, but no change in DNA- or FxxLF-binding capacity and interferes with transcriptional activity for as yet unclear reasons.


Homophily in an Anonymous Online Community: Sociodemographic Versus Personality Traits.
In what traits do people interact with others who are similar to them in completely anonymous online communication? Can those traits contribute to greater exchange of opinion and information across the sociodemographic boundaries that often limit interaction between social strata? To answer this question concerning online homophily, we combined survey data on 7,287 users (aged 18 and above) of a Korean online dating advice platform with their behavioral data from June 2015 to August 2015 and explored whether advice exchange occurred between users with similar sociodemographic and personality traits. On this platform, two types of interactions occurred as follows: (1) responses to a randomly distributed problem submitted by an advice seeker and (2) the seeker's indication of approval of any of the responses given. The study found that (1) a receiver was more likely to respond to problems submitted by seekers of a comparable age and that (2) seekers were more likely to approve of a response if the seeker and receiver had similar educational backgrounds. By contrast, homophily based on personality traits was not observed even though some personality traits significantly affected the likelihood of both response and approval. Our findings suggest that online communication may breed sociodemographic homophily, whether based on age or education, more than expected or intended while not easily fostering alternative forms of homophily, such as personality homophily, which can potentially cut across borders dividing sociodemographic groups.


Activation of the Smk1 mitogen-activated protein kinase by developmentally regulated autophosphorylation.
Smk1 is a meiosis-specific mitogen-activated protein kinase (MAPK) in Saccharomyces cerevisiae that controls spore morphogenesis. Similar to other MAPKs, it is controlled by dual phosphorylation of its T-X-Y activation motif. However, Smk1 is not phosphorylated by a prototypical MAPK kinase. Here, we show that the T residue in Smk1's activation motif is phosphorylated by the cyclin-dependent kinase (CDK)-activating kinase, Cak1. The Y residue is autophosphorylated in an independent intramolecular reaction that requires the meiosis-specific protein Ssp2. Although both SMK1 and SSP2 are expressed as middle-meiosis-specific genes, Smk1 protein starts to accumulate before Ssp2. Thus, Smk1 exists in a low-activity (pT) form early in sporulation and a high-activity (pT/pY) form later in the program. Ssp2 must be present when Smk1 is being produced to activate the autophosphorylation reaction, suggesting that Ssp2 acts through a transitional intermediate form of Smk1. These findings provide a mechanistic explanation for how Smk1 activity thresholds are generated. They demonstrate that intramolecular autophosphorylation of MAPKs can be regulated and suggest new mechanisms for coupling MAPK outputs to developmental programs.


Oxidative stress and mitochondrial aldehyde dehydrogenase activity: a comparison of pentaerythritol tetranitrate with other organic nitrates.
Mitochondrial aldehyde dehydrogenase (ALDH-2) was recently identified to be essential for the bioactivation of glyceryl trinitrate (GTN). Here we assessed whether other organic nitrates are bioactivated by a similar mechanism. The ALDH-2 inhibitor benomyl reduced the vasodilator potency, but not the efficacy, of GTN, pentaerythritol tetranitrate (PETN), and pentaerythritol trinitrate in phenylephrine-constricted rat aorta, whereas vasodilator responses to isosorbide dinitrate, isosorbide-5-mononitrate, pentaerythritol dinitrate, pentaerythritol mononitrate, and the endothelium-dependent vasodilator acetylcholine were not affected. Likewise, benomyl decreased GTN- and PETN-elicited phosphorylation of the cGMP-activated protein kinase substrate vasodilator-stimulated phosphoprotein (VASP) but not that elicited by other nitrates. The vasodilator potency of organic nitrates correlated with their potency to inhibit ALDH-2 dehydrogenase activity in mitochondria from rat heart and increase mitochondrial superoxide formation, as detected by chemiluminescence. In contrast, mitochondrial ALDH-2 esterase activity was not affected by PETN and its metabolites, whereas it was inhibited by benomyl, GTN applied in vitro and in vivo, and some sulfhydryl oxidants. The bioactivation-related metabolism of GTN to glyceryl-1,2-dinitrate by isolated RAW macrophages was reduced by the ALDH-2 inhibitors benomyl and daidzin, as well as by GTN at concentrations >1 microM. We conclude that mitochondrial ALDH-2, specifically its esterase activity, is required for the bioactivation of the organic nitrates with high vasodilator potency, such as GTN and PETN, but not for the less potent nitrates. It is interesting that ALDH-2 esterase activity was inhibited by GTN only, not by the other nitrates tested. This difference might explain why GTN elicits mitochondrial superoxide formation and nitrate tolerance with the highest potency.


Classic and extracavitary primary effusion lymphoma in 51 HIV-infected patients from a single institution.
Human immunodeficiency virus (HIV)-associated primary effusion lymphoma (PEL) is a rare B-cell non-Hodgkin lymphoma with poor prognosis. Lymphoma cells are always infected with human herpesvirus-8 (HHV-8) and in most cases coinfected with Epstein-Barr virus. In classic presentation, PEL is characterized by body cavity effusions with or without mass lesions. A variant with only extracavitary localization has also been described. We report on a large single-center series of patients with PEL in the era of combined antiretroviral therapy (cART). The main objective was to compare the characteristics and the outcome of patients with classic (n = 34) and extracavitary (n = 17) variant PEL. At PEL diagnosis, no major difference was observed between the two groups in terms of demographic and HIV characteristics. Extracavitary localizations were exclusively nodal in six patients and involved various organs in 11 patients. Another HHV-8-associated disease was observed in 31 patients, Kaposi sarcoma in 25, and multicentric Castleman disease in 18 patients, without difference between the two groups. Thirty-two patients were treated with CHOP associated with high-dose methotrexate, 13 were treated with CHOP-derived regimen alone, and six patients received low-dose/no chemotherapy. Complete remission was achieved in 21 (62%) and seven (41%) patients of the classic and extracavitary groups, respectively. The median overall survival (OS) was 10.2 months. Despite a higher disease-free survival in the extracavitary group, there was no difference in OS between the two variants. Based on this series, characteristics of classic and extracavitary variants were very close. Although prognosis of PEL remains very severe in cART era, the median survival compares favorably with earlier series.


A new species of snub-nosed monkey, genus Rhinopithecus Milne-Edwards, 1872 (Primates, Colobinae), from northern Kachin state, northeastern Myanmar.
We describe a snub-nosed monkey that is new to science from the high altitudes of northeastern Kachin state, northeastern Myanmar, the Burmese snub-nosed monkey, Rhinopithecus strykeri sp. nov. Descriptions are based on a skin and skulls of four specimens obtained from local hunters. The new species is geographically isolated from other snub-nosed monkeys and separated from them by two major barriers--the Mekong and the Salween (Thanlwin) rivers. The species is chiefly diagnosed by its almost entirely blackish fur coloration with white fur only on ear tufts, chin beard, and perineal area, and its relatively long tail (140% of head and body length in the adult male). Preliminary surveys and interviews with hunters indicate that the new species is limited in distribution to the Maw River area, a small region of the Salween-N'mai Hka divide in northeastern Kachin state, northeastern Myanmar. The distribution area appears to cover about 270 km(2), and the species may consist of only three groups with a total population of approximately 260-330 individuals. Our data on hunting pressure suggest that the species is Critically Endangered.


Metagenomic analysis of gut microbial communities from a Central Asian population.
Changes in the gut microbiota are increasingly recognised to be involved in many diseases. This ecosystem is known to be shaped by many factors, including climate, geography, host nutrition, lifestyle and medication. Thus, knowledge of varying populations with different habits is important for a better understanding of the microbiome. We therefore conducted a metagenomic analysis of intestinal microbiota from Kazakh donors, recruiting 84 subjects, including male and female healthy subjects and metabolic syndrome (MetS) patients aged 25-75 years, from the Kazakh administrative centre, Astana. We characterise and describe these microbiomes, the first deep-sequencing cohort from Central Asia, in comparison with a global dataset (832 individuals from five countries on three continents), and explore correlations between microbiota, clinical and laboratory parameters as well as with nutritional data from Food Frequency Questionnaires. We observe that Kazakh microbiomes are relatively different from both European and East Asian counterparts, though similar to other Central Asian microbiomes, with the most striking difference being significantly more samples falling within the Prevotella-rich enterotype, potentially reflecting regional diet and lifestyle. We show that this enterotype designation remains stable within an individual over time in 82% of cases. We further observe gut microbiome features that distinguish MetS patients from controls (eg, significantly reduced Firmicutes to Bacteroidetes ratio, Bifidobacteria and Subdoligranulum, alongside increased Prevotella), though these overlap little with previously published reports and thus may reflect idiosyncrasies of the present cohort. Taken together, this exploratory study describes gut microbiome data from an understudied population, providing a starting point for further comparative work on biogeography and research on widespread diseases. ISRCTN37346212; Post-results.


Simple and inexpensive fluorescence-based technique for high-throughput antimalarial drug screening.
Radioisotopic assays involve expense, multistep protocols, equipment, and radioactivity safety requirements which are problematic in high-throughput drug testing. This study reports an alternative, simple, robust, inexpensive, one-step fluorescence assay for use in antimalarial drug screening. Parasite growth is determined by using SYBR Green I, a dye with marked fluorescence enhancement upon contact with Plasmodium DNA. A side-by-side comparison of this fluorescence assay and a standard radioisotopic method was performed by testing known antimalarial agents against Plasmodium falciparum strain D6. Both assay methods were used to determine the effective concentration of drug that resulted in a 50% reduction in the observed counts (EC(50)) after 48 h of parasite growth in the presence of each drug. The EC(50)s of chloroquine, quinine, mefloquine, artemisinin, and 3,6-bis-epsilon-(N,N-diethylamino)-amyloxyxanthone were similar or identical by both techniques. The results obtained with this new fluorescence assay suggest that it may be an ideal method for high-throughput antimalarial drug screening.


Up-conversion monodispersed spheres of NaYF4:Yb3+/Er3+: green and red emission tailoring mediated by heating temperature, and greatly enhanced luminescence by Mn2+ doping.
Submicron sized, monodispersed spheres of Mn2+, Yb3+/Er3+ and Mn2+/Yb3+/Er3+ doped α-NaYF4 were easily autoclaved from mixed solutions of the component nitrates and ammonium fluoride (NH4F), in the presence of EDTA-2Na. Detailed characterizations of the resultant phosphors were obtained using XRD, Raman spectroscopy, FE-SEM, HR-TEM, STEM, PLE/PL spectroscopy, and fluorescence decay analysis. Finer structure and better crystal perfection was observed at a higher calcination temperature, and the spherical shape and excellent dispersion of the original particles was retained at temperatures up to 600 °C. Under the 980 nm infrared excitation, the Yb3+/Er3+-doped sample (calcined at 400 °C) exhibits a stronger green emission centered at ∼524 nm (2H11/2 → 4I15/2 transition of Er3+) and a weaker red emission centered at ∼657 nm (4F9/2 → 4I15/2 transition of Er3+). A 200 °C increase in the temperature from 400 °C to 600 °C resulted in the dominant red emission originating from the 4F9/2 → 4I15/2 transition of Er3+, instead of the previously dominant green one. Mn2+ doping induced a remarkable more enhanced intensity at ∼657 nm and ∼667 nm (red emission area) than that at ∼524 nm and ∼546 nm (green emission area), because of the non-radiative energy transfer between Mn2+ and Er3+. However, a poor thermal stability was induced by Mn2+ doping. The observed upconversion luminescence of the samples calcined at 400 °C and 600 °C followed the two photon process and the four photon process, respectively.


[Effects of difenamizole on behavior maintained by schedule of positive reinforcement (author's transl)].
The anti-nociceptive dose of difenamizole, morphine, aminopyrine and aspirin was studied for effects on behavior maintained by schedule of positive reinforcement. Male, albino rats were trained to press a lever for food pellets on a fixed-ratio (FR) 10 and 30 schedule of reinforcement or a differential reinforcement of low rates of responding (DRL) schedule. Difenamizole (200 and 400 mg/kg, p.o.) produced a dose-related decrease in the response under FR-10 schedule. The response rate decrease observed under the FR-10 schedule was similar to that resulting from the oral administration of 400 mg/kg of aminopyrine. Response in the FR-30 schedule was not affected by any dose of difenamizole (100 approximately 400 mg/kg, p.o.) and aminopyrine (200 approximately 400 mg/kg, p.o.). In the response maintained by the DRL schedule, the overall response rate and the mean interresponse time were not altered significantly by most doses of difenamizole, aminopyrine and aspirin given, however, food reinforcement was decreased significantly with ingestion of these drugs. Morphine (20 mg/kg, p.o.) shortened the mean interresponse time and increased the response in DRL schedule. These results suggest that the central action of difenamizole is similar to that produced by aminopyrine, but not that produced by morphine.


Health Care Professionals' Perceptions of Home Telemonitoring in Heart Failure Care: Cross-Sectional Survey.
Noninvasive telemonitoring (TM) can be used in heart failure (HF) patients to perform early detection of decompensation at home, prevent unnecessary health care utilization, and decrease health care costs. However, the evidence is not sufficient to be part of HF guidelines for follow-up care, and we have no knowledge of how TM is used in the Nordic Baltic region. The aim of this study was to describe health care professionals' (HCPs) perception of and presumed experience with noninvasive TM in daily HF patient care, perspectives of the relevance of and reasons for applying noninvasive TM, and barriers to the use of noninvasive TM. A cross-sectional survey was performed between September and December 2016 in Norway and Lithuania with physicians and nurses treating HF patients at either a hospital ward or an outpatient clinic. A total of 784 questionnaires were sent nationwide by postal mail to 107 hospitals. The questionnaire consisted of 43 items with close- and open-ended questions. In Norway, the response rate was 68.7% (226/329), with 57 of 60 hospitals participating, whereas the response rate was 68.1% (310/455) in Lithuania, with 41 of 47 hospitals participating. Responses to the closed questions were analyzed using descriptive statistics, and the open-ended questions were analyzed using summative content analysis. This study showed that noninvasive TM is not part of the current daily clinical practice in Norway or Lithuania. A minority of HCPs responded to be familiar with noninvasive TM in HF care in Norway (48/226, 21.2%) and Lithuania (64/310, 20.6%). Approximately half of the HCPs in both countries perceived noninvasive TM to be relevant in follow-up of HF patients in Norway (131/226, 58.0%) and Lithuania (172/310, 55.5%). For physicians in both countries and nurses in Norway, the 3 most mentioned reasons for introducing noninvasive TM were to improve self-care, to reduce hospitalizations, and to provide high-quality care, whereas the Lithuanian nurses described ability to treat more patients and to reduce their workload as reasons for introducing noninvasive TM. The main barriers to implement noninvasive TM were lack of funding from health care authorities or the Territorial Patient Fund. Moreover, HCPs perceive that HF patients themselves could represent barriers because of their physical or mental condition in addition to a lack of internet access. HCPs in Norway and Lithuania are currently nonusers of TM in daily HF care. However, they perceive a future with TM to improve the quality of care for HF patients. Financial barriers and HF patients' condition may have an impact on the use of TM, whereas sufficient funding from health care authorities and improved knowledge may encourage the more widespread use of TM in the Nordic Baltic region and beyond.


Impact of Proactive Case Management by Multiple Sclerosis Specialist Nurses on Use of Unscheduled Care and Emergency Presentation in Multiple Sclerosis: A Case Study.
Multiple sclerosis (MS) affects approximately 100,000 people in the United Kingdom, with rising emergency admissions to the hospital. The multiple sclerosis specialist nurse plays a pivotal role in managing MS care in the United Kingdom, and there is anecdotal evidence that this role can help avoid emergency presentations and unnecessary hospital admissions. A retrospective service evaluation took place in one established MS nursing service. The impact of the introduction of proactive nurse-led management and a rapid response service on rates of emergency presentation, hospital admission, and bed use was examined. The primary intervention was the introduction of extra nursing hours (6 hours per week) and the reallocation of some routine administrative duties, which allowed the service to move to a proactive management model aimed at avoiding the need for unplanned care. In addition, a care pathway was implemented in the emergency department for patients with MS who did present. Reduction in utilization was from a mean of 2700 bed-days per year (2002-2006) to a mean of 198 bed-days per year (2007-2013). During a 10-year period, moving from reactive management to proactive management demonstrated an increase in complex specialist nursing interventions and led to a decrease in emergency presentation and bed use at the local acute-care center.


Non-equilibrium Dirac carrier dynamics in graphene investigated with time- and angle-resolved photoemission spectroscopy.
We have used time- and angle-resolved photoemission spectroscopy (tr-ARPES) to assess the influence of many-body interactions on the Dirac carrier dynamics in graphene. From the energy-dependence of the measured scattering rates we directly determine the imaginary part of the self-energy, visualizing the existence of a relaxation bottleneck associated with electron-phonon coupling. A comparison with static line widths obtained by high-resolution ARPES indicates that the dynamics of photo-excited carriers in graphene are solely determined by the equilibrium self-energy. Furthermore, the subtle interplay of different many-body interactions in graphene may allow for carrier multiplication, where the absorption of a single photon generates more than one electron-hole pair via impact ionization. We find that, after photo-excitation, the number of carriers in the conduction band along the ΓK-direction keeps increasing for about 40 fs after the pump pulse is gone. A definite proof of carrier multiplication in graphene, however, requires a more systematic study, carefully taking into account the contribution of momentum relaxation on the measured rise time.


Intestinal pouch complications in patients who underwent restorative proctocolectomy for ulcerative colitis and familial adenomatous polyposis in 1985-2008.
Restorative proctocolectomy is considered a surgical treatment of choice in ulcerative colitis (UC) and familial adenomatous polyposis (FAP).The aim of the study was to evaluate postoperative complications in patients who underwent surgery for familial adenomatous polyposis and ulcerative colitis, on the basis of a retrospective data analysis. Data of 138 patients after restorative proctocolectomy performed between 1985 and 2008 were collected at routine follow-up visits in 2004-2008. We evaluated the presence of pouchitis, the degree of ileal pouch mucosa atrophy, the presence of ileal pouch mucosal metaplasia, the presence of ileal pouch malignancies, the necessity for diverting ileostomy, the necessity for pouch resection, and severe faecal incontinence. Complications were observed in 45 (32.4%) patients. Thirty-seven patients developed pouchitis (26.6%). Low-degree dysplasia, severe dysplasia or malignancies were observed in total in 20 patients (14.4%). Six (4.3%) operated patients developed other analysed complications. The most common complications of restorative proctocolectomy were dysplasia and pouchitis. The most common complication in patients operated for UC was pouchitis. The low observed incidence of intestinal pouchitis may be attributed to the implemented prophylaxis of inflammation. Dysplasia was the most common complication in patients undergoing proctocolectomy for FAP. Due to an increased risk of dysplastic lesions as compared with UC patients, careful endoscopic follow-up examinations are obligatory in this patient group. Other analysed complications were uncommon and were mostly a consequence of chronic pouchitis. Clinical symptoms of pouch-related problems were similar in both analysed groups.


Resistance of Eight Different Clones of the Grape Cultivar Albariño to Plasmopara viticola.
Resistance to downy mildew (Plasmopara viticola) was studied in eight clones of the grape (Vitis vinifera) cultivar Albariño (confirmed as such by DNA and ampelographic analysis) growing at the Misión Biológica de Galicia, Spain. Resistance to downy mildew was quantified using an image processor. Some clones (CSIC-10 and CSIC-11) were more resistant than others to leaf infection by P. viticola. However, the susceptibility of grape clusters did not differ significantly among the clones.


Effects of dietary supplementation with red-pigmented leafy lettuce (Lactuca sativa) on lipid profiles and antioxidant status in C57BL/6J mice fed a high-fat high-cholesterol diet.
The present study was undertaken to assess the beneficial effects of a daily consumption of 8 % freeze-dried red-pigmented leafy lettuce (Lactuca sativa) on CVD. C57BL/6J mice were fed a high-fat high-cholesterol diet supplemented with or without red-pigmented leafy lettuce for 4 weeks. The present results showed that the red-pigmented leafy lettuce-supplemented diet significantly decreased the level of total and LDL-cholesterol and TAG in the plasma of the mice. The atherosclerotic index was calculated to be 46 % lower in the mice fed with the lettuce diet compared with the control diet. Lipid peroxidation measured by 2-thiobarbituric acid-reactive substances was markedly reduced in the plasma, liver, heart and kidney of the mice fed the lettuce diet. The content of antioxidants (total glutathione and beta-carotene) was significantly increased by lettuce supplementation. The antioxidant defence system by antioxidant enzymes including glutathione S-transferase, glutathione peroxidase, glutathione reductase, superoxide dismutase and paraoxanase in blood or liver tissues was also increased, and showed the improved oxidative stress in the mice fed the lettuce diet. The measurement of tail DNA (%), tail extent moment and olive tail moment indicated that the lettuce diet increased the resistance of hepatocyte and lymphocyte DNA to oxidative damage. The present study showed that the supplementation of a high-cholesterol high-fat diet with 8 % red-pigmented leafy lettuce resulted in an improvement of plasma cholesterol and lipid levels, prevention of lipid peroxidation and an increase of the antioxidant defence system and, therefore, could contribute to reduce the risk factors of CVD.


The art and science of surge: experience from Israel and the U.S. military.
In a disaster or mass casualty incident, health care resources may be exceeded and systems may be challenged by unusual requirements. These resources may include pharmaceuticals, supplies, and equipment as well as certain types of academic and administrative expertise. New agencies and decision makers may need to work together in an unfamiliar environment. Furthermore, large numbers of casualties needing treatment, newer therapies required to care for these casualties, and increased workforce and space available for these casualties all contribute to what is often referred to as "surge." Surge capacity in emergency care can be described in technical, scientific terms that are measured by numbers and benchmarks (e.g., beds, patients, and medications) or can take on a more conceptual and abstract form (e.g., decisions, authority, and responsibility). The former may be referred to as the "science" of surge, whereas the latter, an equal if not more important component of surge systems that is more conceptual and abstract, can be considered the "art" of surge. The experiences from Israel and the U.S. military may serve to educate colleagues who may be required to respond or react to an event that taxes the current health care system. This report presents concrete examples of surge capacity strategies used by both Israel and the U.S. military and provides solutions that may be applied to other health care systems when faced with similar situations.


Influence of cell surface characteristics on adhesion of Saccharomyces cerevisiae to the biomaterial hydroxylapatite.
The influence of the physicochemical properties of biomaterials on microbial cell adhesion is well known, with the extent of adhesion depending on hydrophobicity, surface charge, specific functional groups and acid-base properties. Regarding yeasts, the effect of cell surfaces is often overlooked, despite the fact that generalisations may not be made between closely related strains. The current investigation compared adhesion of three industrially relevant strains of Saccharomyces cerevisiae (M-type, NCYC 1681 and ALY, strains used in production of Scotch whisky, ale and lager, respectively) to the biomaterial hydroxylapatite (HAP). Adhesion of the whisky yeast was greatest, followed by the ale strain, while adhesion of the lager strain was approximately 10-times less. According to microbial adhesion to solvents (MATS) analysis, the ale strain was hydrophobic while the whisky and lager strains were moderately hydrophilic. This contrasted with analyses of water contact angles where all strains were characterised as hydrophilic. All yeast strains were electron donating, with low electron accepting potential, as indicated by both surface energy and MATS analysis. Overall, there was a linear correlation between adhesion to HAP and the overall surface free energy of the yeasts. This is the first time that the relationship between yeast cell surface energy and adherence to a biomaterial has been described.


Exome sequencing generates high quality data in non-target regions.
Exome sequencing using next-generation sequencing technologies is a cost efficient approach to selectively sequencing coding regions of human genome for detection of disease variants. A significant amount of DNA fragments from the capture process fall outside target regions, and sequence data for positions outside target regions have been mostly ignored after alignment. We performed whole exome sequencing on 22 subjects using Agilent SureSelect capture reagent and 6 subjects using Illumina TrueSeq capture reagent. We also downloaded sequencing data for 6 subjects from the 1000 Genomes Project Pilot 3 study. Using these data, we examined the quality of SNPs detected outside target regions by computing consistency rate with genotypes obtained from SNP chips or the Hapmap database, transition-transversion (Ti/Tv) ratio, and percentage of SNPs inside dbSNP. For all three platforms, we obtained high-quality SNPs outside target regions, and some far from target regions. In our Agilent SureSelect data, we obtained 84,049 high-quality SNPs outside target regions compared to 65,231 SNPs inside target regions (a 129% increase). For our Illumina TrueSeq data, we obtained 222,171 high-quality SNPs outside target regions compared to 95,818 SNPs inside target regions (a 232% increase). For the data from the 1000 Genomes Project, we obtained 7,139 high-quality SNPs outside target regions compared to 1,548 SNPs inside target regions (a 461% increase). These results demonstrate that a significant amount of high quality genotypes outside target regions can be obtained from exome sequencing data. These data should not be ignored in genetic epidemiology studies.


Early kinetics of C reactive protein for cancer-agnostic prediction of therapy response and mortality in patients treated with immune checkpoint inhibitors: a multicenter cohort study.
C reactive protein (CRP) kinetics have recently been suggested as predictive biomarkers for the efficacy of immune checkpoint inhibitor (ICI) therapy in selected cancer types. The aim of this study was to characterize early CRP kinetics as a tumor-agnostic biomarker for ICI treatment outcomes. In this multicenter retrospective cohort study, two independent cohorts of patients with various cancer types undergoing palliative ICI treatment at Austrian academic centers served as the discovery (n=562) and validation cohort (n=474). Four different patterns of CRP kinetics in the first 3 months of ICI therapy were defined (CRP-flare responders, CRP-responders, CRP non-responders, patients with all-normal CRP). Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were defined as coprimary endpoints. Univariable and multivariable logistic regression, landmark analysis and Cox regression including CRP kinetics as time-dependent variable were performed. The ORR in patients with all-normal CRP, CRP responders, CRP flare-responders and CRP non-responders was 41%, 38%, 31% and 12%, respectively. The median OS and PFS estimates were 24.5 months (95% CI 18.5 to not reached) and 8.2 months (95% CI 5.9 to 12.0) in patients with all-normal CRP, 16.1 months (95% CI 12.6 to 19-8) and 6.1 months (95% CI 4.9 to 7.2) in CRP-responders, 14.0 months (95% CI 8.5 to 19.4) and 5.7 months (95% CI 4.1 to 8.5) in CRP flare-responders and 8.1 months (95% CI 5.8 to 9.9) and 2.3 months (95% CI 2.2 to 2.8) in CRP non-responders (log-rank p for PFS and OS<0.001). These findings prevailed in multivariable analysis and could be fully confirmed in our validation cohort. Pooled subgroup analysis suggested a consistent predictive significance of early CRP kinetics for treatment efficacy and outcome independent of cancer type. Early CRP kinetics represent a tumor-agnostic predictor for treatment response, progression risk and mortality in patients with cancer undergoing ICI therapy.


Pyogenic granuloma in patients treated with selective BRAF inhibitors: another manifestation of paradoxical pathway activation.
Cutaneous toxicities under therapy with selective BRAF inhibitors such as vemurafenib or encorafenib (LGX818) are frequent, including plantar hyperkeratosis, squamous cell carcinoma, and second primary melanoma. Pyogenic granuloma is a benign, rapidly growing, eruptive hemangioma that often bleeds and ulcerates. Common causes are mechanical trauma and cast immobilization, as well as multiple drugs such as retinoids and antineoplastic agents. However, the development of pyogenic granuloma under treatment with encorafenib (LGX818) has not yet been reported. These three cases might be further examples for paradoxical activation of the mitogen-activated protein kinase pathway. We report three male patients with metastatic BRAFV600E-mutated melanoma who developed pyogenic granulomas 16, 10, and 12 weeks after treatment initiation with the selective BRAF inhibitors vemurafenib or encorafenib (LGX818). Except for one patient receiving retinoids, the clinical history for other frequent causes of pyogenic granuloma was negative. Pyogenic granulomas are not listed in the drugs investigator brochure but seem to be associated with selective BRAF inhibitors and might be a cutaneous phenomenon of paradoxical mitogen-activated protein kinase pathway activation. This correlation has to be confirmed by further observations.


Mobile Technology Affinity in Renal Transplant Recipients.
Medication nonadherence is a common problem in renal transplant recipients (RTRs). Mobile health approaches to improve medication adherence are a current trend, and several medication adherence apps are available. However, it is unknown whether RTRs use these technologies and to what extent. In the present study, the mobile technology affinity of RTRs was analyzed. We hypothesized significant age differences in mobile technology affinity and that mobile technology affinity is associated with better cognitive functioning as well as higher educational level. A total of 109 RTRs (63% male) participated in the cross-sectional study, with an overall mean age of 51.8 ± 14.2 years. The study included the Technology Experience Questionnaire (TEQ) for the assessment of mobile technology affinity, a cognitive test battery, and sociodemographic data. Overall, 57.4% of the patients used a smartphone or tablet and almost 45% used apps. The TEQ sum score was 20.9 in a possible range from 6 (no affinity to technology) to 30 (very high affinity). Younger patients had significantly higher scores in mobile technology affinity. The only significant gender difference was found in having fun with using electronic devices: Men enjoyed technology more than women did. Mobile technology affinity was positively associated with cognitive functioning and educational level. Young adult patients might profit most from mobile health approaches. Furthermore, high educational level and normal cognitive functioning promote mobile technology affinity. This should be kept in mind when designing mobile technology health (mHealth) interventions for RTRs. For beneficial mHealth interventions, further research on potential barriers and desired technologic features is necessary to adapt apps to patients' needs.


Glaucoma in a rural population of southern India: the Aravind comprehensive eye survey.
To determine the prevalence of glaucoma and risk factors for primary open-angle glaucoma in a rural population of southern India. A population-based cross-sectional study. A total of 5150 subjects aged 40 years and older from 50 clusters representative of three southern districts of Tamil Nadu in southern India. All participants had a comprehensive eye examination at the base hospital, including visual acuity using logarithm of the minimum angle of resolution illiterate E charts and refraction, slit-lamp biomicroscopy, gonioscopy, applanation tonometry, dilated fundus examinations, and automated central 24-2 full-threshold perimetry. Definite primary open-angle glaucoma (POAG) was defined as angles open on gonioscopy and glaucomatous optic disc changes with matching visual field defects, whereas ocular hypertension was defined as intraocular pressure (IOP) greater than 21 mmHg without glaucomatous optic disc damage and visual field defects in the presence of an open angle. Manifest primary angle-closure glaucoma (PACG) was defined as glaucomatous optic disc damage or glaucomatous visual field defects with the anterior chamber angle partly or totally closed, appositional angle closure or synechiae in the angle, and absence of signs of secondary angle closure. Secondary glaucoma was defined as glaucomatous optic nerve damage and/or visual field abnormalities suggestive of glaucoma with ocular disorders that contribute to a secondary elevation in IOP. The prevalence (95% confidence interval) of any glaucoma was 2.6% (2.2, 3.0), of POAG it was 1.7% (1.3, 2.1), and if PACG it was 0.5% (0.3, 0.7), and secondary glaucoma excluding pseudoexfoliation was 0.3% (0.2,0.5). On multivariate analysis, increasing age, male gender, myopia greater than 1 diopter, and pseudoexfoliation were significantly associated with POAG. After best correction, 18 persons (20.9%) with POAG were blind in either eye because of glaucoma, including 6 who were bilaterally blind and an additional 12 persons with unilateral blindness because of glaucomatous optic neuropathy in that eye. Of those identified with POAG, 93.0% had not been previously diagnosed with POAG. The prevalence of glaucoma in this population is not lower than that reported for white populations elsewhere. A large proportion of those with POAG had not been previously diagnosed. One fifth of those with POAG had blindness in one or both eyes from glaucoma. Early detection of glaucoma in this population will reduce the burden of blindness in India.


An evaluation of the outcomes of mutual health organizations in Benin.
Mutual health organizations (MHO) have been seen as a promising alternative to the fee-based funding model but scientific foundations to support their generalization are still limited. Very little is known about the extent of the impact of MHOs on health-seeking behaviours, quality and costs. We present the results of an evaluation of the effects attributable to membership in an MHO in a rural region of Benin. Two prospective studies of users (parturients and hospitalized patients) were conducted on the territory of an inter-mutual consisting of 10 MHOs and as many healthcare centres (one, Ouessé, serving as a referral hospital) and one hospital (Papané). Members and non-members were matched (142 pairs of parturients and 109 triads of hospitalized patients) and multilevel multiple regression was used. Results show that member parturients went to healthcare centres sooner (p = 0.049) and were discharged more quickly after delivery (p = 0.001) than non-members. Length of stay in some cases was longer for hospitalized member parturients (+41%). Being a member did not shorten hospital stay, total length of episode of care, or time between appearance of symptoms and recourse to care. Regarding expenses, member parturients paid one-third less than non-members for a delivery. For hospitalized patients, the average savings for members was around $35 US. Total expenses incurred by patients hospitalized at Papané Hospital were higher than at Ouessé but the two hospitals' relative advantages were comparable at -36% and -39%, respectively. These results confirm mutual health organizations' capacity to protect households financially, even if benefits for the poor have not been clearly determined. The search for scientific evidence should continue, to understand their impacts with regard to services obtained by their members.


Colon cancer detection: an algorithm using endoscopy and barium enema.
A review of findings on flexible sigmoidoscopy (FS), colonoscopy and selected double-contrast barium enema (DCBE) radiographs from a group of 66 patients with rectal bleeding was performed to test the value of an algorithm in the detection of colonic cancers and polyps. In this algorithm the FS findings would direct patients either to colonoscopy or to a modified DCBE which focused attention on the colon proximal to the sigmoid. Only patients with neoplasms diagnosed by FS, or by MDCBE after negative FS, would proceed to colonoscopy. The study population contained four cancers, 11 polyps > 5 mm and 11 polyps < or = 5 mm; FS+MDCBE missed four polyps, all < 5 mm. For polyps > 5 mm and cancer, FS+MDCBE had a sensitivity of 100%, a specificity of 82%, a negative predictive value of 1.0 and a positive predictive value of 0.62. Using the algorithm, 24 patients (36%) would have required colonoscopy. The results suggest that FS+MDCBE is a potentially valuable method for screening patients for colonic neoplasia.


Genotype-Associated Differential NKG2D Expression on CD56+CD3+ Lymphocytes Predicts Response to Pegylated-Interferon/Ribavirin Therapy in Chronic Hepatitis C.
Hepatitis C virus (HCV) genotype 1 infections are significantly more difficult to eradicate with PEG-IFN/ribavirin therapy, compared to HCV genotype 2. The aim of this work is to investigate the difference of immunological impairments underlying this phenomenon. Pre-treatment NKG2D expression on peripheral CD56+CD3+ lymphocytes and CD56+CD3- NK cells from cases of chronic hepatitis C were analyzed and assessed by treatment effect. Two strains of HCV were used to co-incubate with immune cells in vitro. NKG2D expression on peripheral CD56+CD3+ lymphocytes, but not NK cells, was significantly impaired in genotype 1 infection, compared to genotype 2. When peripheral blood mononuclear cells from healthy donors were co-incubated with TNS2J1, a genotype 1b/2a chimera strain, or with JFH1, a genotype 2a strain, genotype-specific decrease of NKG2D on CD56+CD3+ lymphocytes, but not NK cells, was observed. Pre-treatment NKG2D expression on peripheral CD56+CD3+ lymphocytes significantly correlated with reduction in serum HCV RNA levels from week 0 to week 4, and predicted treatment response. Ex vivo stimulation of peripheral CD56+CD3+ lymphocytes showed NKG2D expression-correlated IFN-γ production. In conclusion, Decreased NKG2D expression on CD56+CD3+ lymphocytes in chronic HCV genotype 1 infection predicts inferior treatment response to PEG-IFN/ribavirin therapy compared to genotype 2.