Do two measures of frailty identify the same people? An age-gender comparison.
Most frailty assessments have been developed for people aged over 65 years. However, there is growing evidence that frailty is detectable in younger people. This paper tests the hypothesis that the Fried frailty phenotype and the CFS categories identify the same people in age-gender subgroups in community-dwelling 40 to 75-year-olds. Participants were recruited via comprehensive community-sampling strategies. They self-reported frailty using the Clinical Frailty Scale (CFS), and frailty was also estimated using the Fried phenotype (self-reported unintended weight loss, exhaustion and low regular exercise; observed slow gait speed and poor grip strength). CFS and Fried scores were compared overall, and for age-gender subgroups (40-49 years, 50-59 years, 60-69 years, and 70-75 years). Spearman rho and differences in mean integer Fried scores were calculated across CFS categories using ANOVA. Correlations were determined between Fried categories of not-frail, pre-frail, and frail and ranked CFS categories, using ranked scores (tau-c) and Cochran-Mantel-Haenszel (C-M-H) tests. Of 656 participants (67% female; mean age 59.9 years, SD 10.6), Fried phenotype classified 59.2% not frail, 39.0% pre-frail, and 1.8% frail, with no gender or age differences. CFS data were missing for 25 participants, with N = 631 reporting categories of very well (24.6%), well (44.6%), managing well (21.9%), vulnerable (6.3%), mildly frail (0.5%), and moderately frail (0.2%). Overall, the mean Fried frailty scores increased incrementally and significantly across ranked CFS categories (P < .01), with weak linear correlation (rho = 0.09). There were variable correlations in age-gender groups, with the best correlation found for women aged 50 years or older, and men aged 60 to 69 years. Frailty assessments using the two assessments became more consistent, as age increased. Pre-frailty was identified by both assessments in all age-gender groups. The validity of self-reported CFS, and of pre-frailty criteria relevant to people younger than 65 years, needs investigation.


Cross-language Transfer of Metalinguistic Skills: Evidence from Spelling English Words by Korean Students in Grades 4, 5 and 6.
The present study examined unique and shared contributions of Korean (first language) phonological, orthographic and morphological awareness (PA, OA and MA, respectively) to English (second/foreign language) spelling among 287 fourth-grade, fifth-grade and sixth-grade Korean children. Korean measures of PA, OA and MA were administered, in addition to English vocabulary and spelling measures. Results from structural equation modelling showed that PA, OA and MA were caused by one common construct, metalinguistic awareness (META), and the contribution of Korean META to English spelling was statistically significant, controlling for English vocabulary. In particular, Korean MA and PA played unique roles in explaining English spelling; whereas Korean OA did not significantly contribute to English spelling. Findings from the present study provided empirical evidence of first language META transfer effect on second/foreign language spelling development. Educational implications and future research ideas are discussed. Copyright © 2017 John Wiley & Sons, Ltd.


All-atom computations with irreversible Markov chains.
We apply the irreversible event-chain Monte Carlo (ECMC) algorithm to the simulation of dense all-atom systems with long-range Coulomb interactions. ECMC is event-driven and exactly samples the Boltzmann distribution. It neither uses time-step approximations nor spatial cutoffs on the range of the interaction potentials. Most importantly, it need not evaluate the total Coulomb potential and thus circumvents the major computational bottleneck of traditional approaches. It only requires the derivatives of the two-particle Coulomb potential, for which we discuss mutually consistent choices. ECMC breaks up the total interaction potential into factors. For particle systems made up of neutral dipolar molecules, we demonstrate the superior performance of dipole-dipole factors that do not decompose the Coulomb potential beyond the two-molecule level. We demonstrate that these long-range factors can nevertheless lead to local lifting schemes, where subsequently moved particles are mostly close to each other. For the simple point-charge water model with flexible molecules (SPC/Fw), which combines the long-ranged intermolecular Coulomb potential with hydrogen-oxygen bond-length vibrations, a flexible hydrogen-oxygen-hydrogen bond angle, and Lennard-Jones oxygen-oxygen potentials, we break up the potential into factors containing between two and six particles. For this all-atom liquid-water model, we demonstrate that the computational complexity of ECMC scales very well with the system size. This is achieved in a pure particle-particle framework, without the interpolating mesh required for the efficient implementation of other modern Coulomb algorithms. Finally, we discuss prospects and challenges for ECMC and outline several future applications.


Dynamic tuning of an optical resonator through MEMS-driven coupled photonic crystal nanocavities.
We present dynamic tuning of optical resonance using microelectromechanical systems (MEMS)-driven coupled photonic crystal (PhC) nanocavities. The device consists of an air-suspended one-dimensional PhC nanocavity coupled to input and output waveguides and a perturbing nanocavity attached to a submicrometer MEMS comb drive. Resonance tuning is achieved through varying the gap between the two coupled cavities. We demonstrate experimentally that resonance can be tuned up to 8nm with no significant deterioration in the Q factor. The proposed mechanism potentially enables a new platform of on-chip photonic devices that can achieve a large tuning range with low power and small footprint and may find useful applications in tunable optical/photonic devices.


Design and baseline characteristics of participants in the TRial of Economic Incentives to Promote Physical Activity (TRIPPA): a randomized controlled trial of a six month pedometer program with financial incentives.
Non-communicable diseases (NCDs) are emerging as the predominant global health challenge of this century. Physical inactivity is one of the primary risk factors for NCDs. Therefore, increasing physical activity levels is a public health imperative. The arrival of affordable wearable technologies, such as wireless pedometers, provides one strategy for encouraging walking. However, the effectiveness of these technologies in promoting sustained behavior change has not been established. Insights from economics suggest that incentives may be a useful strategy for increasing maintenance and effectiveness of behavior change interventions, including physical activity interventions that rely on wearable technologies. The aim of this trial is to test the effectiveness of a common wireless pedometer with or without one of two types of incentives (cash or donations to charity) for reaching weekly physical activity goals. We present here the design and baseline characteristics of participants of this four arm randomized controlled trial. 800 full-time employees (desk-bound office workers) belonging to 15 different worksites (on average, 53 (sd: 37) employees at each worksite) were successfully randomized to one of four study arms. If shown to be effective, wearable technologies in concert with financial incentives may provide a scalable and affordable health promotion strategy for governments and employers seeking to increase the physical activity levels of their constituents.


Constraints of space in plant development.
Like all forms in nature, plants are subject to the properties of space. On the one hand, space prevents configurations that would place more than one component in the same location at the same time. A generalization of this constraint limits proximity and density of organs. On the other hand, space provides a means for a plant to create three-dimensional forms by differentially controlling their growth. This results from a connection between the metric properties of surfaces and their Gaussian curvature. Three strategies used by plants to develop within the constraints of space are presented: expansion to another dimension, egalitarian partitioning of space, and competition for space. These strategies are illustrated with examples of curved surfaces of leaves and petals, self-similar branching structures of compound leaves and inflorescences, and tree architecture. The examples highlight the fundamental role of the constraints of space in plant development, and the complementary role of genetic regulation and space-dependent emergent phenomena in shaping a plant.


Hospital Variation in Intensive Care Resource Utilization and Mortality in Newly Diagnosed Pediatric Leukemia.
To evaluate hospital-level variability in resource utilization and mortality in children with new leukemia who require ICU support, and identify factors associated with variation. Retrospective cohort study. Children's hospitals contributing to the Pediatric Health Information Systems administrative database from 1999 to 2011. Inpatients less than 25 years old with newly diagnosed acute lymphocytic leukemia or acute myeloid leukemia requiring ICU support (n = 1,754). Evaluated exposures included leukemia type, year of diagnosis, and hospital-wide proportion of patients with public insurance. The main outcome was hospital mortality. Wide variability existed in the ICU resources used across hospitals. Combined acute lymphocytic leukemia and acute myeloid leukemia mortality varied by hospital from 0% (95% CI, 0-14.8%) to 42.9% (95% CI, 17.7-71.1%). A mixed-effects model with a hospital-level random effect suggests significant variation across hospitals in mortality (p = 0.007). When including patient and hospital factors as fixed effects into the model, younger age, acute myeloid leukemia versus acute lymphocytic leukemia diagnosis, leukemia diagnosis prior to 2005, hospital-wide proportion of public insurance patients, and hospital-level proportion of leukemia patients receiving ICU care are significantly associated with mortality. The variation across hospitals remains significant with all patient factors included (p = 0.021) but is no longer significant after adjusting for the hospital-level factors proportion of public insurance and proportion receiving ICU care (p = 0.48). Wide hospital-level variability in ICU resource utilization and mortality exists in the care of children with leukemia requiring ICU support. Hospital payer mix is associated with some mortality variability. Additional study into how ICU support could be standardized through clinical practice guidelines, impact of payer mix on hospital resources allocation to the ICU, and subsequent impact on patient outcomes is warranted.


Pharmacology of a new triazine antifolate in mice, rats, dogs, and monkeys.
Triazinate (TZT), a potent inhibitor of dihydrofolate reductase, was selected for detailed investigation to determine its mechanism of selective action as well as its metabolic fate in mice, rats, dogs, and monkeys. The serum disappearance of TZT in normal and tumor-bearing mice was similar, with a rapid tissue equilibration phase and a slower elimination phase. Serum disappearance in normal and tumor-bearing rats was 1.5 to 2.2 hr. Serum disappearance in dogs and monkeys was similar, with half-lives of 3 to 4 and 2 to 4 hr, respectively. Urinary excretion of TZT at 24 hr was only 5 to 6% of the injected dose in mice and rats; in contrast, the dogs excreted 60% of the injected dose in 8 hr. TZT accumulated to comparable degrees in the organs of rats and mice, with progressively lesser concentrations in liver, kidney, spleen, and brain. Dihydrofolate reductase activity became almost undectectable in all tissues studied within 15 min after drug adminsitration. An important difference in drug accumulation was in the ascites cells of tumor-bearing animals: in mice, the drug level was consistently lower in the L1210 cells than in the ascites fluid; in contrast, by 30 min after treatment with TZT the drug level in Walker 256 cells was 10-fold higher than the level in the ascites fluid. No evidence for drug metabolism was found in extracts of urine, feces, or organ tissues from either mice or rats. TZT and two related triazines were studied for their ability to accumulate in the cerbrospinal fluid of dogs after i.v. administration. TZT achieved a cerebrospinal fluid level of approximately 15% of the serum concentration at 1 hr; in contrast, the other two triazines reached maximum cerebrospinal fluid values of 1% at 1 hr.


Four-Year Efficacy and Safety of iTrack Ab-interno Canaloplasty as a Standalone Procedure and Combined with Cataract Surgery in Open-Angle Glaucoma.
To evaluate the long-term effectiveness of ab-interno canaloplasty (ABiC), performed with the iTrack microcatheter (Nova Eye Medical, Fremont, CA, USA), in reducing intraocular pressure (IOP) as well as the number of required glaucoma medications in patients with open-angle glaucoma (OAG). In this retrospective single-center consecutive case series, 27 eyes of 21 patients (mean age 77.3 ± 5.8 years) were treated with ABiC performed as a standalone procedure or combined with cataract surgery. Patients with uncontrolled IOP OAG or controlled IOP (≤ 18 mmHg) OAG with intolerance to medications or lack of compliance were included. Patients were followed for up to 4 years following the procedure. The iTrack microcatheter was used to perform a 360-degree circumferential intubation and viscodilation of Schlemm's canal. Primary efficacy endpoints included IOP and the number of glaucoma medications at 12, 24, 36, and 48 months after surgery. In all eyes, mean IOP and number of glaucoma medications were significantly reduced from 19.8 ± 5.2 mmHg and 1.9 ± 1.00 at baseline to 14.6 ± 3 mmHg and 0.9 ± 0.8, respectively, at the 48-month follow-up (p < 0.001). IOP was stable from 12 months to 48 months (p > 0.005). After 48 months, 39% of the eyes required zero medications compared to 3.7% at baseline, and 72.2% of eyes required only one medication or less. Of all eyes, 77.8% recorded an IOP ≤ 17 mmHg. No serious complications were recorded. iTrack ABiC performed as a standalone procedure or in combination with cataract surgery significantly reduced IOP and number of medications in patients with OAG up to 4 years after the procedure.


Hormonal and genetic control of behavioral integration in honey bee colonies.
The ability of insect colonies to adjust the division of labor among workers in response to changing environmental and colony conditions, coupled with research showing genetic effects on the division of labor in honey bee colonies, led to an investigation of the role of genetics and the environment in the integration of worker behavior. Measurements of juvenile hormone(JH) titers and allozyme analyses of worker honey bees suggest that two processes are involved in colony-level regulation of division of labor: (i) plasticity in age-dependent behavior is a consequence of modulation of JH titers by extrinsic factors, and (ii) stimuli that can affect JH titers and age-dependent behavior do elicit variable responses among genetically distinct subpopulations of workers within a colony. These results provide a new perspective on the developmental plasticity of insect colonies and support the emerging view that colony genetic structure affects behavioral organization.


Patterns of diabetic complications at jimma university specialized hospital, southwest ethiopia.
Diabetes Mellitus is common metabolic disease worldwide. Its complications in the Ethiopian care setup has not been well documented. The objective of this study was to assess the pattern and distribution of diabetic complications among patients having follow-up at Jimma University specialized Hospital diabetic clinic. A cross sectional study based on record review of 305 patients, selected using systematic sampling with replacement was carried out in October 2008. The data were analyzed using SPSS for Windows version 13.0. Larger proportion, 189 (62.0%), of patients had type II diabetes and 163 (53.4%) of them were diabetic for less than 5 years. Seventy three of the 76 (96.1%) patients with type II diabetes mellitus had hypertension. Acute complications were observed in 93 (30.5%) of the patients of which Diabetic Ketoacidosis was documented in 66(71.0%). Forty eight (45.7%) of patients had proteinuria, 90 (29.5%) had peripheral neuropathy, 13(6.8%) had impotence. Diabetic foot ulcer, skin and/or subcutaneous tissue infection, dental problems and tuberculosis were documented in 14(4.5%), 31(10.0%), 31(10.0%), and 17(5.6%) patients, respectively. Any of the chronic complications were not different by sex of the patient but age had statistically significant association with hypertension, visual disturbance and neuropathy (p< 0.05). Type of diabetes had statistically significant association with all the tested complications except infection (P<0.05) where most of the complications occurred in type II diabetics. Statistically significant association was observed between the duration of the diabetes and impotence and visual disturbances (p < 0.05). The majority of patients were type II diabetics. Acute complications were observed more commonly among type I diabetics and DKA was the commonest acute complication. The frequency of chronic complications was high. Increased occurrence of retinopathy, peripheral neuropathy, hypertension and nephropathy was observed with longer duration of illness. Impotence and diabetic nephropathy were more common in type II diabetics. The study showed that age, sex, type of diabetes mellitus and duration of diabetes were significantly associated with the development of diabetic complications.


Endocrine surgery during COVID-19 pandemic: do we need an update of indications in Italy?
The ongoing spread of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a significant threat to global health. As the coronavirus outbreak began spreading, hospitals were forced to relocate resources to treat the growing number of COVID-19 patients. As a consequence, doctors across the country canceled tens of thousands of nonurgent surgeries. However, recognizing that the COVID-19 situation may be highly variable and fluid in different communities across the country, elective surgery could be still allowed in some centers for patients included in the high-priority class. The majority of endocrine disorders requiring surgical treatment in patients identifiable as first-priority class, or needing hospitalization within 30 days, are generally represented by malignant thyroid tumors, hyperthyroidism, hyperparathyroidism, and some adrenal disorders. The need for urgent intervention is evaluated on a case-by-case basis according to the severity of the symptoms, the likelihood of progression, and global clinical judgment. On the basis of the above indications, during the last 4 weeks, we performed 18 planned surgical treatments in patients with thyroid cancer (total thyroidectomies, plus lymph node dissection if needed) or multinodular toxic goiter. In no case, postoperative ventilatory support was needed, and the average hospital stay was 3 days. The negative COVID-19 status for all the treated patients was appropriately evaluated beforehand. Nobody knows how long the current COVID-19 pandemic will be lasting. Certainly, we will be requested in the next future to incrementally offer surgical services for endocrine disorders that have been deferred for the COVID-19 pandemic.


Improving color constancy by selecting suitable set of training images.
With very simple implementation, regression-based color constancy (CC) methods have recently obtained very competitive performance by applying a correction matrix to the results of some low level-based CC algorithms. However, most regression-based methods, e.g., Corrected Moment (CM), apply a same correction matrix to all the test images. Considering that the captured image color is usually determined by various factors (e.g., illuminant and surface reflectance), it is obviously not reasonable enough to apply a same correction to different test images without considering the intrinsic difference among images. In this work, we first mathematically analyze the key factors that may influence the performance of regression-based CC, and then we design principled rules to automatically select the suitable training images to learn an optimal correction matrix for each test image. With this strategy, the original regression-based CC (e.g., CM) is clearly improved to obtain more competitive performance on four widely used benchmark datasets. We also show that although this work focuses on improving the regression-based CM method, a noteworthy aspect of the proposed automatic training data selection strategy is its applicability to several representative regression-based approaches for the color constancy problem.


Interleaflet organization of membrane nanodomains: What can(not) be resolved by FRET?
Plasma membranes as well as their simplified model systems show an inherent nanoscale heterogeneity. As a result of strong interleaflet interactions, these nanoheterogeneities (called here lipid nanodomains) can be found in perfect registration (i.e., nanodomains in the inner leaflet are registered with the nanodomains in the outer leaflet). Alternatively, they might be interleaflet independent, antiregistered, or located asymmetrically in one bilayer leaflet only. To distinguish these scenarios from each other appears to be an experimental challenge. In this work, we analyzed the potential of Förster resonance energy transfer to characterize interleaflet organization of nanodomains. We generated in silico time-resolved fluorescence decays for a large set of virtual as well as real donor/acceptor pairs distributed over the bilayer containing registered, independent, antiregistered, or asymmetrically distributed nanodomains. In this way, we were able to identify conditions that gave satisfactory or unsatisfactory resolution. Overall, Förster resonance energy transfer appears as a robust method that, when using donor/acceptor pairs with good characteristics, yields otherwise difficult-to-reach characteristics of membrane lipid nanodomains.


Antimalarial β-carbolines from the New Zealand ascidian Pseudodistoma opacum.
One tetrahydro-β-carboline, (-)-7-bromohomotrypargine (1), and three alkylguanidine-substituted β-carbolines, opacalines A, B, and C (2-4), have been isolated from the New Zealand ascidian Pseudodistoma opacum. The structures of the metabolites were determined by analysis of mass spectrometric and 2D NMR spectroscopic data. Natural products 2 and 3, synthetic debromo analogues 8 and 9, and intermediate 16 exhibited moderate antimalarial activity toward a chloroquine-resistant strain of Plasmodium falciparum, with an IC50 range of 2.5-14 μM. The biosynthesis of 1-4 is proposed to proceed via a Pictet-Spengler condensation of 6-bromotryptamine and the α-keto acid transamination product of either arginine or homoarginine. Cell separation and 1H NMR analysis of P. opacum identified tetrahydro-β-carboline 1 to be principally located in the zooids, while fully aromatized analogues 2-4 were localized to the test.


Xenopus cadherin 5 is specifically expressed in endothelial cells of the developing vascular system.
Vasculogenesis is an important, multistep process leading to the formation of a functional primary network of blood vessels in the developing embryo. A series of interactions between secreted growth factors and their specific receptors leads to the specification of mesodermal cells to become hemangioblasts, which then differentiate into angioblasts. These subsequently proliferate, coalesce into cords and finally form tubular vascular structures. For proper function of these primary blood vessels, the close connection of endothelial cells is required. This is conferred by the interaction of an endothelium specific cadherin (Cadherin-5), starting during early vascular development. However, this interaction remains important throughout life and ageing. Therefore, cadherin-5 is a useful marker for late stages of vasculogenesis in several vertebrate species. To establish cadherin-5 as a marker for vascular studies in Xenopus, we cloned the Xenopus laevis ortholog and analyzed its expression pattern during embryogenesis.


Fragment Molecular Orbital Calculations with Implicit Solvent Based on the Poisson-Boltzmann Equation: II. Protein and Its Ligand-Binding System Studies.
In this study, the electronic properties of bioactive proteins were analyzed using an ab initio fragment molecular orbital (FMO) methodology in solution: coupling with an implicit solvent model based on the Poisson-Boltzmann surface area called as FMO-PBSA. We investigated the solvent effects on practical and heterogeneous targets with uneven exposure to solvents unlike deoxyribonucleic acid analyzed in our recent study. Interfragment interaction energy (IFIE) and its decomposition analyses by FMO-PBSA revealed solvent-screening mechanisms that affect local stability inside ubiquitin protein: the screening suppresses excessiveness in bare charge-charge interactions and enables an intuitive IFIE analysis. The electrostatic character and associated solvation free energy also give consistent results as a whole to previous studies on the explicit solvent model. Moreover, by using the estrogen receptor alpha (ERα) protein bound to ligands, we elucidated the importance of specific interactions that depend on the electric charge and activatability as agonism/antagonism of the ligand while estimating the influences of the implicit solvent on the ligand and helix-12 bindings. The predicted ligand-binding affinities of bioactive compounds to ERα also show a good correlation with their in vitro activities. The FMO-PBSA approach would thus be a promising tool both for biological and pharmaceutical research targeting proteins.


Loss of IRA2 suppresses the growth defect on low glucose caused by the snf3 mutation in Saccharomyces cerevisiae.
SNF3 encodes a low-glucose sensor in Saccharomyces cerevisiae that regulates the expression of a subset of hexose transporter genes. Deletion of SNF3 prevents rapid adaptation to low glucose concentration. Novel spontaneous suppressor mutants of the snf3Delta phenotype were isolated. The mutations isolated fell into one of two groups: those that increase the expression of transporters regulated by Snf3p, and those that show no detectable effect on the regulation of these genes. The physiologic role of one mutation, rgg2 (restoration of growth on glucose), that did not affect HXT gene expression was assessed by transcriptome analysis. Genes involved in glycogen metabolism and cAMP pathways were affected by the rgg2 mutation, suggesting a cellular role as a regulatory protein. Attempts to clone the wild-type RGG2 allele were unsuccessful. The glycogen phenotype and genetic crossing allowed rgg2 to be identified as an allele of the IRA2 gene. Suppression of the snf3 mutant phenotype by deletion of IRA2 was confirmed. A possible mechanism of the suppression of the snf3 growth defect by mutation of ira2 is discussed.


Two AAA family peroxins, PpPex1p and PpPex6p, interact with each other in an ATP-dependent manner and are associated with different subcellular membranous structures distinct from peroxisomes.
Two peroxins of the AAA family, PpPex1p and PpPex6p, are required for peroxisome biogenesis in the yeast Pichia pastoris. Cells from the corresponding deletion strains (Pp delta pex1 and Pp delta pex6) contain only small vesicular remnants of peroxisomes, the bulk of peroxisomal matrix proteins is mislocalized to the cytosol, and these cells cannot grow in peroxisome-requiring media (J. A. Heyman, E. Monosov, and S. Subramani, J. Cell Biol. 127:1259-1273, 1994; A. P. Spong and S. Subramani, J. Cell Biol. 123:535-548, 1993). We demonstrate that PpPex1p and PpPex6p interact in an ATP-dependent manner. Genetically, the interaction was observed in a suppressor screen with a strain harboring a temperature-sensitive allele of PpPEX1 and in the yeast two-hybrid system. Biochemially, these proteins were coimmunoprecipitated with antibodies raised against either of the proteins, but only in the presence of ATP. The protein complex formed under these conditions was 320 to 400 kDa in size, consistent with the formation of a heterodimeric PpPex1p-PpPex6p complex. Subcellular fractionation revealed PpPex1p and PpPex6p to be predominantly associated with membranous subcellular structures distinct from peroxisomes. Based on their behavior in subcellular fractionation experiments including flotation gradients and on the fact that these structures are also present in a Pp delta pex3 strain in which no morphologically detectable peroxisomal remnants have been observed, we propose that these structures are small vesicles. The identification of vesicle-associated peroxins is novel and implies a role for these vesicles in peroxisome biogenesis. We discuss the possible role of the ATP-dependent interaction between PpPex1p and PpPex6p in regulating peroxisome biogenesis events.


Insulin Receptor Signaling in POMC, but Not AgRP, Neurons Controls Adipose Tissue Insulin Action.
Insulin is a key regulator of adipose tissue lipolysis, and impaired adipose tissue insulin action results in unrestrained lipolysis and lipotoxicity, which are hallmarks of the metabolic syndrome and diabetes. Insulin regulates adipose tissue metabolism through direct effects on adipocytes and through signaling in the central nervous system by dampening sympathetic outflow to the adipose tissue. Here we examined the role of insulin signaling in agouti-related protein (AgRP) and pro-opiomelanocortin (POMC) neurons in regulating hepatic and adipose tissue insulin action. Mice lacking the insulin receptor in AgRP neurons (AgRP IR KO) exhibited impaired hepatic insulin action because the ability of insulin to suppress hepatic glucose production (hGP) was reduced, but the ability of insulin to suppress lipolysis was unaltered. To the contrary, in POMC IR KO mice, insulin lowered hGP but failed to suppress adipose tissue lipolysis. High-fat diet equally worsened glucose tolerance in AgRP and POMC IR KO mice and their respective controls but increased hepatic triglyceride levels only in POMC IR KO mice, consistent with impaired lipolytic regulation resulting in fatty liver. These data suggest that although insulin signaling in AgRP neurons is important in regulating glucose metabolism, insulin signaling in POMC neurons controls adipose tissue lipolysis and prevents high-fat diet-induced hepatic steatosis.


Use of bone morphogenetic protein-2 for adult spinal deformity.
Prospective, single-center, nonblinded clinical and radiographic analysis of consecutive adult deformity patients treated with recombinant human bone morphogenetic protein-2 (rhBMP-2) without iliac or rib bone graft supplementation. To determine the ability of rhBMP-2 to achieve both anterior and posterior spinal fusion in patients undergoing multilevel fusions for adult spinal deformity. The literature concerning one-level anterior fusions, and potentially one-level posterior fusions, using rhBMP-2 has demonstrated clinical efficacy. No published data exist on the use of rhBMP-2 in multilevel spine fusions. Prospective analysis of patients treated with rhBMP-2 in multilevel anterior and posterior fusions with a minimum 1-year follow-up. There were a total of 95 patient samples (70 total patients; 25 patients had rhBMP-2 used circumferentially): 46 anterior fusions (Group 1), 41 posterior fusions (Group 2), and 8 patients were "compassionate use" fusions (Group 3). In the anterior fusion group (n = 46), mean rhBMP-2/level was 10.8 mg in titanium mesh cages without any bone graft or other substance. The posterior fusion group had only local bone graft, no harvested rib or iliac bone graft (n = 41). The mean rhBMP-2/level was 13.7 mg. The "compassionate use" group (n = 8 patients) consisted of patients who had prior surgeries, prior iliac harvesting, and substantial comorbidities and therefore a higher concentration and different carrier was used. No local bone graft, no harvested bone was used. The mean rhBMP-2/level was 28.6 mg. The median dose was 40 mg for Group 3. For the anterior fusion group (n = 46), operative levels were deemed fused in 89 of the 93 (96%) levels. For the posterior fusion group (n = 41), a solid fusion was assessed in 110 of the 118 (93%) operative levels. For the "compassionate-use" patients, the overall fusion rate was 100% (52 of 52 operative levels). With the use of rhBMP-2, a high rate of apparent fusion was observed for anterior (96%) and posterior (93%) fusions in adult spinal deformity patients. Use of rhBMP-2 results in a promising early fusion rate without the graft harvest site morbidity.


Moiré patterns of curved line quasi-periodic structures.
In this work, by using a local reciprocal vector concept, we introduce a considerable number of quasi-periodic structures where each of them is constructed by a set of curved lines with varying period. By using a simple and very comprehensive recently proposed method, formulations and characterizations of the various moiré patterns of different pairs of curved line quasi-periodic structures are presented. Some advantages of the concept of local reciprocal vector in the area of curved line quasi-periodic structures are clarified.


Role of tenascin-C in lesion formation in early peritoneal endometriosis.
To identify cytokines or extracellular matrix (ECM) components that contribute to adhesion to, and invasion of, the peritoneum, proximal to lesions in the early phase of endometriosis. Laboratory-based study SETTING: University Hospital and Laboratory of Animal Science PATIENTS AND ANIMALS: Five women with ovarian endometrioma, 138 wild-type (WT) C57BL/6N mice, and 48 Tenascin C (Tnc) knockout (TncKO) mice. To establish a murine endometriosis model, 20 pieces of minced uterine tissue fragments from each horn were administered intraperitoneally to syngeneic mice. Three days later, endometriotic lesions and peritoneal tissues were collected. Separately, we transfected human peritoneal mesothelial cells (HMrSV5) or human endometrial stromal cells (hESCs) with Tnc small interfering RNA (siRNA). We employed a PCR array to profile gene expression in the murine peritoneum, in both peritoneum distal to lesions (PDL) and peritoneum surrounding endometriotic lesions (PSL). The expression of upregulated genes in the PSL was verified in the peritoneal samples by real-time RT-PCR. TncKO mice were used to investigate the role of Tnc in the development of endometriosis. We evaluated the proliferative activity or inflammatory state of lesions by Ki-67 or CD3 immunostaining. Intraperitoneal distribution of macrophages was assessed by fluorescence-activated cell sorting (FACS). Using Tnc siRNA, we examined the invasive capacity of hESCs in a co-culture system with HMrSV5. Tnc gene expression was significantly higher in PSL than in PDL. The weight and number of TncKO lesions in TncKO hosts were lower than those of WT lesions in WT hosts. In contrast, the weight and number of non-attached TncKO lesions in TncKO hosts were greater than those of non-attached WT lesions in WT hosts. We observed decreased Ki-67-positive cells or H-scores for CD3, a lower proportion of M1 macrophages, and a higher proportion of M2 macrophages in TncKO lesions in TncKO recipients. Silencing of Tnc expression in hESCs and HMrSV5 diminished the invasivity of hESCs. Tnc may be a crucial factor in the development of early peritoneal endometriosis.


Separation of cationic proteins via charge reversal in capillary electrophoresis.
Analysis of proteins by capillary electrophoresis requires strategies which minimize coulombic interactions with the capillary surface. Thus buffers with pH's above the isoelectric points (pI) of proteins, or near the pI of silanol are required for efficient separation. Covalent modification of the capillary surface is also effective; however, this strategy is technically difficult, abolishes endosmotic flow and suffers from the inherent lability of the siloxane bond. Finally, "dynamic coating" agents, which interact weakly with the capillary surface and therefore, must be included in the separation buffer, suffer from the potential interaction of coating agent with analytes, altering the selectivity of the system. In the following paper, we describe another approach which overcomes all of these difficulties, and demonstrate the ease of use, nondenaturing property, stability and selectivity of the coating strategy with several model protein systems.


Linking childhood abuse and hypertension: sleep disturbance and inflammation as mediators.
The indirect association of childhood abuse with prevalent hypertension in adulthood through sleep disturbance and pro-inflammatory biomarkers was investigated in 589 community-dwelling, middle-aged adults. Participants completed the Childhood Trauma Questionnaire and self-reported current sleep disturbance and medical diagnoses including hypertension. Blood pressure was taken and blood samples were analyzed for C-reactive protein, interleukin-6, and fibrinogen. Hypertension was present in 41.3 % of the sample. In the full multiple mediation model, tested using structural equation modeling, all hypothesized pathways were significant (p's < 0.05). Childhood abuse was significantly related to both body mass index and sleep disturbance, which, both in turn, were significantly associated with inflammation, which was subsequently associated with hypertension status. The model demonstrated good fit [χ(2) (122) = 352.0, p < 0.001, CFI = 0.918, RMSEA = 0.057] and the indirect effect of all mediators was significant (indirect effect: 0.02, 95 % CI 0.005-0.03, p = 0.001). Sleep disturbance, body mass, and inflammation may be independent, intermediate steps between childhood abuse and subsequent hypertension that may be amenable to biobehavioral interventions.


Effect of hemin on the physiology and virulence of Bacteroides gingivalis W50.
Bacteroides gingivalis W50 was grown in a chemostat under steady-state conditions at pH 7.5 +/- 0.2 and a constant growth rate of 6.9 h for periods of up to 6 weeks (146 bacterial generations) in a complex medium. Hemin was capable of limiting the growth of cells up to a concentration of approximately 0.5 micrograms/ml since higher concentrations of hemin did not increase cell yields; cells grew in the absence of exogenously added vitamin K1. Only a limited number of amino acids was metabolized during growth, but because none of these was totally depleted, the limiting nutrient under hemin excess conditions was probably a peptide. A range of fermentation products was produced under all conditions of growth; higher concentrations of cytotoxic metabolites such as propionate and butyrate were formed under hemin excess conditions, although more ammonia was released under hemin limitation. When viewed by electron microscopy, cells grown under hemin limitation appeared to be either coccobacillary or short rods and possessed few fimbriae per cell, but large numbers of extracellular vesicles could be seen both surrounding the cell surface and free in the environment. In contrast, cells grown under hemin excess conditions were more commonly coccus shaped and were more heavily fimbriated but had fewer extracellular vesicles. Marked differences were found in the susceptibility of mice to infection with cells grown under different concentrations of hemin. Cells transferred to media without any added hemin were avirulent, whereas those grown under conditions of hemin limitation (0.33 and 0.40 micrograms/ml) produced a 20 and 50% mortality in mice, respectively. In contrast cells grown under hemin excess always caused 100% mortality in mice, although this virulence was dose dependent. When virulent, the bacteria caused an extensive, spreading infection with necrosis of the skin and subcutaneous tissues. Collagen disintegration was seen histologically, implying a role for collagenase production in the pathogenicity of these bacteria.


Rearrangement-mediated cis-regulatory alterations in advanced patient tumors reveal interactions with therapy.
The global impact of somatic structural variants (SVs) on gene regulation in advanced tumors with complex treatment histories has been mostly uncharacterized. Here, using whole-genome and RNA sequencing from 570 recurrent or metastatic tumors, we report the altered expression of hundreds of genes in association with nearby SV breakpoints, including oncogenes and G-protein-coupled receptor-related genes such as PLEKHG2. A significant fraction of genes with SV-expression associations correlate with worse patient survival in primary and advanced cancers, including SRD5A1. In many instances, SV-expression associations involve retrotransposons being translocated near genes. High overall SV burden is associated with treatment with DNA alkylating agents or taxanes and altered expression of metabolism-associated genes. SV-expression associations within tumors from topoisomerase I inhibitor-treated patients include chromatin-related genes. Within anthracycline-treated tumors, SV breakpoints near chromosome 1p genes include PDE4B. Patient treatment and history can help understand the widespread SV-mediated cis-regulatory alterations found in cancer.


Latex allergy: diagnosis and management.
Latex allergy is an IgE-mediated immediate hypersensitivity response to natural rubber latex (NRL) protein with a variety of clinical signs ranging from contact urticaria, angioedema, asthma, and anaphylaxis. Major allergens include dipped latex products such as gloves and balloons. In highest risk for NRL allergy are patients with spina bifida, but health care workers and others who wear latex gloves are also at risk. NRL allergic patients may also react to fruits/foods, especially banana, kiwi, and avocado. Diagnosis is made by a positive latex RAST and/or skin prick test or challenge test to NRL. Allergen avoidance and substitution and the use of latex-safe devices including synthetic gloves (vinyl, synthetic polyisoprene, neoprene, nitrile, block polymers, or polyurethane) are essential for the affected patient. Accommodation in the workplace may include the use of powder-free, low-allergen NRL gloves or synthetic gloves. These preventive measures have significantly reduced the prevalence of reported reactions to NRL. Hyposensitization is not yet feasible.


Sweet's syndrome: unique local response to streptococcal antigen.
Although hypersensitivity has been postulated, the etiology of Sweet's syndrome has never been elucidated. In the present case intradermal tesing with viridans streptococcus led to an immediate reaction and reproduced a lesion clinically and histologically identical to that of the primary disease. Other bacterial and fungal antigens failed to elicit any response. These findings provide further support for the role of hypersensitivity in the pathogenesis of this disorder. It would appear that immediate or humoral immunit


Functional improvements to beta-lactoglobulin by preparing an edible conjugate with cationic saccharide using microbial transglutaminase [corrected] (MTGase).
Bovine beta-lactoglobulin (BLG) was conjugated with cationic saccharides to improve its functions. We used a polylysine-dextran conjugate (PL-Dex) as the cationic saccharide which had been prepared by the Maillard reaction. The molar ratio of PL:Dex was 1:1. The emulsifying property of PL in the acidic pH range was improved by conjugating with Dex. BLG and PL-Dex were conjugated by using microbial transglutaminase (MTGase), the effective conjugation being confirmed by SDS-PAGE. The molar ratio of BLG:PL-Dex was 1:1. Structural analyses by a fluorescence study, ELISA with monoclonal antibodies and measurement of the retinol-binding activity indicated that the conjugates had almost retained the native structure of BLG. The emulsifying property of BLG in the acidic pH range and in the presence of NaCl was improved by conjugating with PL-Dex. The immunogenicity of BLG was reduced by this conjugation, while the antigenicity of the BLG-PL-Dex conjugate was similar to that of BLG in BALB/c mice.


Community health workers as an integral strategy in the REACH U.S. program to eliminate health inequities.
Mounting evidence indicates that community health workers (CHWs) contribute to improved behavioral and health outcomes and reductions in health disparities. We provide an overview (based on grantee reports and community action plans) that describe CHW contributions to 22 Racial and Ethnic Approaches to Community Health (REACH) programs funded by the Centers for Disease Control and Prevention from 2007 to 2012, offering additional evidence of their contributions to the effectiveness of community public health programs. We then highlight how CHWs helped deliver REACH U.S. community interventions to meet differing needs across communities to bridge the gap between health care services and community members, build community and individual capacity to plan and implement interventions addressing multiple chronic health conditions, and meet community needs in a culturally appropriate manner. The experience, skills, and success gained by CHWs participating in the REACH U.S. program have fostered important individual community-level changes geared to increase health equity. Finally, we underscore the importance of CHWs being embedded within these communities and the flexibility they offer to intervention strategies, both of which are characteristics critical to meeting needs of communities experiencing health disparities. CHWs served a vital role in facilitating and leading changes and will continue to do so.


Quantitative trait loci for tibial bone strength in C57BL/6J and C3H/HeJ inbred strains of mice.
Three-point bending technology has been widely used in the measurement of bone strength. Quantitative trait loci (QTLs) for bone strength have been identified using mouse femurs. In this study, we investigate the use of mouse tibiae in identification of QTLs that regulate bone strength. Mouse tibiae were from a F(2) population derived from C57BL/6J (B6) and C3H/HeJ (C3H). Three-point bending was measured using ISO 4049, with the support width adjustable to accommodate specimen sizes outside the scope of ISO 4049. The strain rate is selectable from 0.05 to 500 mm per min. All stress strain diagrams are recorded and retrieved in digital electronic form. Genome scan was performed in The Jackson Laboratory (TJL). QTL mapping was conducted using Map Manager QTX software. Data show that (i) both elastic modulus (stiffness) and maximum loading (strength) value appear as normal distributions, suggesting that multiple genetic factors control the bone strength; (ii) 11 QTLs, accounting for 90% of variation for strength, have been detected. More than half QTLs of three-point bending are located on the same locations of bone density earlier identified from mouse femurs; (iii) a major QTL of femoral and vertebral bone mineral density (BMD) was not detected for bone strength of tibiae; (iv) the QTL on chromosome 4 has extremely high LOD score of 31.8 and represents 60% of the variation of bone strength; and (v) four QTLs of stiffness (chromosomes 2, 11, 15 and 19) have been identified.


Detection of maltodextrin and its discrimination from sucrose are independent of the T1R2 + T1R3 heterodimer.
Maltodextrins, such as Maltrin and Polycose, are glucose polymer mixtures of varying chain lengths that are palatable to rodents. Although glucose and other sugars activate the T1R2 + T1R3 "sweet" taste receptor, recent evidence from T1R2- or T1R3-knockout (KO) mice suggests that maltodextrins, despite their glucose polymer composition, activate a separate receptor mechanism to generate a taste percept qualitatively distinguishable from that of sweeteners. However, explicit discrimination of maltodextrins from prototypical sweeteners has not yet been psychophysically tested in any murine model. Therefore, mice lacking T1R2 + T1R3 and wild-type controls were tested in a two-response taste discrimination task to determine whether maltodextrins are 1) detectable when both receptor subunits are absent and 2) perceptually distinct from that of sucrose irrespective of viscosity, intensity, and hedonics. Most KO mice displayed similar Polycose sensitivity as controls. However, some KO mice were only sensitive to the higher Polycose concentrations, implicating potential allelic variation in the putative polysaccharide receptor or downstream pathways unmasked by the absence of T1R2 + T1R3. Varied Maltrin and sucrose concentrations of approximately matched viscosities were then presented to render the oral somatosensory features, intensity, and hedonic value of the solutions irrelevant. Although both genotypes competently discriminated Maltrin from sucrose, performance was apparently driven by the different orosensory percepts of the two stimuli in control mice and the presence of a Maltrin but not sucrose orosensory cue in KO mice. These data support the proposed presence of an orosensory receptor mechanism that gives rise to a qualitatively distinguishable sensation from that of sucrose.


[Effect of lomefloxacin on the synthesis of antibodies to vaccine EV fraction I and hemagglutinins].
Multifactor analysis of the lomefloxacin effect on the primary immune response to T-independent bacterial antigen (vaccine EV fraction 1) and to T-dependent cellular antigen (SRBC) in mice was performed with the use of a wide range of the antibiotic concentrations and the dosage time. It was shown that lomefloxacin in the doses corresponding to the average therapeutic ones used for 3-9 days had no effect on the content of the IgG antibodies, was able to increase the level of the IgM antibodies and insignificantly lowered the concentration of the IgA antibodies.


Effect of motion-graphic video-based training on the performance of operating room nurse students in cataract surgery in Iran: a randomized controlled study.
The present study was conducted to determine the effect of motion-graphic video-based training on the performance of operating room nurse students in cataract surgery using phacoemulsification at Kermanshah University of Medical Sciences in Iran. This was a randomized controlled study conducted among 36 students training to become operating room nurses. The control group only received routine training, and the intervention group received motion-graphic video-based training on the scrub nurse's performance in cataract surgery in addition to the educator's training. The performance of the students in both groups as scrub nurses was measured through a researcher-made checklist in a pre-test and a post-test. The mean scores for performance in the pre-test and post-test were 17.83 and 26.44 in the control group and 18.33 and 50.94 in the intervention group, respectively, and a significant difference was identified between the mean scores of the pre- and post-test in both groups (P=0.001). The intervention also led to a significant increase in the mean performance score in the intervention group compared to the control group (P=0.001). Considering the significant difference in the performance score of the intervention group compared to the control group, motion-graphic video-based training had a positive effect on the performance of operating room nurse students, and such training can be used to improve clinical training.


Fatal biliary-systemic air embolism during endoscopic retrograde cholangiopancreatography: a case with multifocal liver abscesses and choledochoduodenostomy.
We report a rare case of a massive fatal embolism that occurred in the middle of endoscopic retrograde cholangiopancreatography (ERCP) and retrospectively examine the significant causes of the event. The patient was a 50-year old female with an uncertain history of previous abdominal surgery for multiple biliary stones 20 years prior. The patient presented with acute right upper quadrant pain. An abdominal computed tomographic (CT) scan revealed the presence of multiple stones in the common bile duct (CBD) and intra-hepatic duct (IHD) with biliary obstruction, multifocal liver abscesses, and air-biliarygram. Emergency ERCP showed a wide and straight opening of choledochoduodenostomy, which may have been created during a previous surgery, and multiple filling defects in the CBD. With the use of a forward endoscope, mud stones were extracted through the opening of the choledochoduodenostomy. Cardiac arrest suddenly developed during the procedure, and despite immediate resuscitation, the patient died due to a massive systemic air embolism. We reviewed previously reported fatal cases and accessed factors facilitating air embolisms in this case.


Visit-to-visit SBP variability and cardiovascular disease in a multiethnic primary care setting: 10-year retrospective cohort study.
The current study aims to determine the relationship of long-term visit-to-visit variability of SBP to cardiovascular disease (CVD) in a multiethnic primary care setting. This is a retrospective study of a cohort of 807 hypertensive patients over a period of 10 years. Three-monthly clinic blood pressure readings were used to derive blood pressure variability (BPV), and CVD events were captured from patient records. Mean age at baseline was 57.2 ± 9.8 years with 63.3% being women. The BPV and mean SBP over 10 years were 14.7 ± 3.5 and 142 ± 8 mmHg, respectively. Prevalence of cardiovascular event was 13%. In multivariate logistic regression analysis, BPV was the predictor of CVD events, whereas the mean SBP was not independently associated with cardiovascular events in this population. Those with lower SBP and lower BPV had fewer cardiovascular events than those with the same low mean SBP but higher BPV (10.5 versus 12.8%). Similarly those with higher mean SBP but lower BPV also had fewer cardiovascular events than those with the same high mean and higher BPV (11.6 versus 16.7%). Other variables like being men, diabetes and Indian compared with Chinese are more likely to be associated with cardiovascular events. BPV is associated with an increase in CVD events even in those who have achieved lower mean SBP. Thus, we should prioritize not only control of SBP levels but also BPV to reduce CVD events further.


Kinetic profile of overall elimination of 5-methyltetrahydropteroylglutamate in rats.
The in vivo biliary and urinary excretion kinetics of 5-methyltetrahydropteroylglutamate (5-CH3-H4PteGlu) were studied in rats. During infusion at various rates (48-965 nmol. h-1. kg-1), the total body clearance (CLtotal) of 5-CH3-H4PteGlu could be attributed almost entirely to the sum of the biliary and urinary (CLurine,p) excretion clearances. After a 4-h infusion at the highest rate, the 5-CH3-H4PteGlu in the liver was 10 times higher than the endogenous level, whereas its polyglutamate form did not increase, suggesting that most of the infused 5-CH3-H4PteGlu is not incorporated in the polyglutamate pool but is eliminated by excretion. The parallel increase in CLtotal and CLurine,p with the increase in infusion rate might result from saturation of reabsorption at the renal proximal tubules, since the urinary excretion clearance, defined with respect to the kidney concentration, also increased while the biliary excretion clearance, defined with respect to the liver concentration, remained almost constant. We conclude that the hepatobiliary excretion is a relatively low-affinity process with a constant clearance, whereas the renal tubular reabsorption is saturated at higher plasma 5-CH3-H4PteGlu concentration ( approximately 0.5 microM). Urinary excretion becomes the predominant elimination route for any excess 5-CH3-H4PteGlu in the body.


Risk Factors for Colistin-Associated Acute Kidney Injury: A Multicenter Study from Turkey.
The aim of this study was to investigate the incidence of acute kidney injury (AKI) and risk factors due to colistin use in patients infected with multidrug-resistant pathogens. This multicenter, retrospective, observational study was conducted in Turkey, at 5 different research and university hospitals. Cox regression analyses were performed, to determine independent predictors of AKI. From April 2012 to July 2014, a total of 216 patients aged between 18-94 years, treated with colistimethate sodium (CMS) were included in the study. The mean age of the patients was 60.3 ± 20.1 years. The overall incidence of AKI was 34.3% (74/216) at any time during treatment. Concomitant use of loop diuretics, baseline creatinine level, and CMS dosage were independently associated with AKI. According to our results, patients with higher baseline creatinine levels, or patients who had to use concomitant loop diuretics may need to be monitored more closely, and dose adjustment should be done promptly. More comprehensive studies are, however, still needed to evaluate the efficacy of low-dose colistin since higher doses tend to increase the risk of AKI.


Discriminative Transformation for Multi-Dimensional Temporal Sequences.
Feature space transformation techniques have been widely studied for dimensionality reduction in vector-based feature space. However, these techniques are inapplicable to sequence data because the features in the same sequence are not independent. In this paper, we propose a method called max-min inter-sequence distance analysis (MMSDA) to transform features in sequences into a low-dimensional subspace such that different sequence classes are holistically separated. To utilize the temporal dependencies, MMSDA first aligns features in sequences from the same class to an adapted number of temporal states, and then, constructs the sequence class separability based on the statistics of these ordered states. To learn the transformation, MMSDA formulates the objective of maximizing the minimal pairwise separability in the latent subspace as a semi-definite programming problem and provides a new tractable and effective solution with theoretical proofs by constraints unfolding and pruning, convex relaxation, and within-class scatter compression. Extensive experiments on different tasks have demonstrated the effectiveness of MMSDA.


Orientation-dependent imaging of electronically excited quantum dots.
We previously demonstrated that we can image electronic excitations of quantum dots by single-molecule absorption scanning tunneling microscopy (SMA-STM). With this technique, a modulated laser beam periodically saturates an electronic transition of a single nanoparticle, and the resulting tunneling current modulation ΔI(x0, y0) maps out the SMA-STM image. In this paper, we first derive the basic theory to calculate ΔI(x0, y0) in the one-electron approximation. For near-resonant tunneling through an empty orbital "i" of the nanostructure, the SMA-STM signal is approximately proportional to the electron density φix0,y02 of the excited orbital in the tunneling region. Thus, the SMA-STM signal is approximated by an orbital density map (ODM) of the resonantly excited orbital at energy Ei. The situation is more complex for correlated electron motion, but either way a slice through the excited electronic state structure in the tunneling region is imaged. We then show experimentally that we can nudge quantum dots on the surface and roll them, thus imaging excited state electronic structure of a single quantum dot at different orientations. We use density functional theory to model ODMs at various orientations, for qualitative comparison with the SMA-STM experiment. The model demonstrates that our experimentally observed signal monitors excited states, localized by defects near the surface of an individual quantum dot. The sub-nanometer super-resolution imaging technique demonstrated here could become useful for mapping out the three-dimensional structure of excited states localized by defects within nanomaterials.


Efficient quality assurance method with automated data acquisition of a single phantom setup to determine radiation and imaging isocenter congruence.
We developed a quality assurance (QA) method to determine the isocenter congruence of Optical Surface Monitoring System (OSMS, Varian, CA, USA), kilovoltage (kV), and megavoltage (MV) imaging, and the radiation isocenter using a single setup of the OSMS phantom for frameless Stereotactic Radiosurgery (SRS) treatment. After aligning the phantom to the OSMS isocenter, a cone-beam computed tomography (CBCT) of the phantom was acquired and registered to a computed tomography (CT) scan of the phantom to determine the CBCT isocenter. Without moving the phantom, MV and kV images were simultaneously acquired at four gantry angles to localize MV and kV isocenters. Then, Winston-Lutz (W-L) test images of the central BB in the phantom were acquired to analyze the radiation isocenter. The gantry and couch were automatically controlled using the TrueBeam Developer Mode during MV, kV, and W-L image acquisition. All the images were acquired weekly for 17 weeks to track the congruence of all the imaging modalities' isocenter in six-dimensional (6D) translations and rotations, and the radiation isocenter in three-dimensional (3D) translations. The shifts of isocenters of all imaging modalities and the radiation isocenter from the OSMS isocenter were within 0.2 mm and 0.2° on average over 17 weeks. The maximum discrepancy between OSMS and other imaging modalities or radiation isocenters was 0.8 mm and 0.3°. However, systematic shifts of radiation isocenter anteriorly and laterally relative to the OSMS isocenter were observed. The measured discrepancies were consistent from week-to-week except for two weeks when the isocenter discrepancies of 0.8 mm were noted due to drifts of the OSMS isocenter. Once recalibration was performed on OSMS, the discrepancy was reduced to 0.3 mm and 0.2°.By performing the proposed QA on a weekly basis, the isocenter congruencies of multiple imaging systems and radiation isocenter were validated for a linear accelerator.


Application of real-time PCR-based SNP detection for mapping of Net2, a causal D-genome gene for hybrid necrosis in interspecific crosses between tetraploid wheat and Aegilops tauschii.
Available information on genetically assigned molecular markers is not sufficient for efficient construction of a high-density linkage map in wheat. Here, we report on application of high resolution melting (HRM) analysis using a real-time PCR apparatus to develop single nucleotide polymorphism (SNP) markers linked to a hybrid necrosis gene, Net2, located on wheat chromosome 2D. Based on genomic information on barley chromosome 2H and wheat expressed sequence tag libraries, we selected wheat cDNA sequences presumed to be located near the Net2 chromosomal region, and then found SNPs between the parental Ae. tauschii accessions of the synthetic wheat mapping population. HRM analysis of the PCR products from F(2) individuals' DNA enabled us to assign 44.4% of the SNP-representing cDNAs to chromosome 2D despite the presence of the A and B genomes. In addition, the designed SNP markers were assigned to chromosome 2D of Ae. tauschii. The order of the assigned SNP markers in synthetic hexaploid wheat was confirmed by comparison with the markers in barley and Ae. tauschii. Thus, the SNP-genotyping method based on HRM analysis is a useful tool for development of molecular markers at target loci in wheat.


Retrosigmoid intradural suprameatal approach: advantages and disadvantages from an anatomical perspective.
To assess the advantages and disadvantages of the retrosigmoid intradural suprameatal approach by studying the microsurgical anatomy. This study was performed primarily to assess the advantages of the retrosigmoid intradural suprameatal approach by measuring the amount of increased exposure it provides for lesions of the cerebellopontine and petroclival region as well as to identify the disadvantages of the approach. Twenty sides of 10 cadaver heads (embalmed and injected) were dissected under x3 to x40 magnification. A standard retrosigmoid craniotomy was made. The cerebellopontine cistern was entered to expose the neurovascular structures, and the internal auditory canal was opened by drilling the margin of the internal auditory meatus. After this, the suprameatal tubercle was drilled, followed by additional drilling to resect the petrous apex. The trigeminal root was mobilized completely after opening Meckel's cave. During drilling, care was taken to preserve the posterior and superior semicircular canals, petrosal sinus, and the internal carotid artery. The approach enhanced the exposure of the cerebellopontine cistern and Meckel's cave. There was an additional exposure of 10.7 +/- 1.16 mm length of trigeminal nerve on the right side and an additional 10.7 +/- 1.25 mm on the left. This helped to mobilize and further retract the trigeminal root. Although it facilitated the view of the neurovascular structures medial to the internal acoustic meatus, the depth of exposure did not vary much from a traditional retrosigmoid approach nor did it increase the angle of exposure or the visualization of the clivus and more medially located structures. This approach is suitable for lesions mainly in the posterior fossa with some extension into the middle fossa in the anterolateral direction. The key benefits of this approach are the length of trigeminal nerve exposure and the subsequent mobilization that improves visualization of the structures medial to the internal auditory canal, to the petrous apex, Meckel's cave, and the posterior end of the cavernous sinus.


Detailed physiological characterization of the development of type 2 diabetes in Hispanic women with prior gestational diabetes mellitus.
To identify physiological and clinical variables associated with development of type 2 diabetes up to 12 years after pregnancies complicated by gestational diabetes. Seventy-two islet cell antibody-negative nondiabetic Hispanic women had oral (oGTT) and intravenous (ivGTT) glucose tolerance tests, glucose clamps, and body composition assessed between 15 and 30 months after pregnancies complicated by gestational diabetes mellitus (GDM). They returned for oGTTs at 15-month intervals until they dropped out, developed diabetes, or reached 12 years postpartum. Cox regression analysis was used to identify baseline predictors and changes during follow-up that were associated with development of type 2 diabetes. At baseline, relatively low insulin sensitivity, insulin response, and β-cell compensation for insulin resistance were independently associated with development of diabetes. During follow-up, weight and fat gain and rates of decline in β-cell compensation were significantly associated with diabetes, while additional pregnancy and use of progestin-only contraception were marginally associated with diabetes risk. In Hispanic women, GDM represents detection of a chronic disease process characterized by falling β-cell compensation for chronic insulin resistance. Women who are farthest along at diagnosis and/or deteriorating most rapidly are most likely to develop type 2 diabetes within 12 years after the index pregnancy. Weight gain, additional pregnancy, and progestin-only contraception are potential modifiable factors that increase diabetes risk.


CF(3)-bearing aromatic and heterocyclic building blocks.
Fluorine remains an insiders' tip in the life sciences as it enables the fine-tuning of biological properties. However, the synthesis of fluorine-substituted target compounds is not always trivial. Virtually any fluorine atom attached to an organic backbone has ultimately to be imported from inorganic sources. Crucial for the entire synthetic planning in medicinal and agricultural research is the decision on at what stage and how the halogen will be introduced. Standard technical processes, in particular the displacement of chlorine using anhydrous hydrogen fluoride or potassium fluoride, can hardly be implemented rationally on the laboratory scale. Universal methods that are applicable by both industrial and academic researchers thus have great appeal. If a trifluoromethyl-substituted arene or heterocycle is the target compound, two splendid options exist. The CF(3) group can be delivered packagewise by coupling an appropriate substrate with in situ generated (trifluoromethyl)copper. Alternatively, one may start from a CF(3)-substituted arene or heterocycle as a core and complete it with the missing parts of the ultimate structure.


Nocodazole-Induced Expression and Phosphorylation of Anillin and Other Mitotic Proteins Are Decreased in DNA-Dependent Protein Kinase Catalytic Subunit-Deficient Cells and Rescued by Inhibition of the Anaphase-Promoting Complex/Cyclosome with proTAME but Not Apcin.
The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has well-established roles in DNA double-strand break repair, and recently, nonrepair functions have also been reported. To better understand its cellular functions, we deleted DNA-PKcs from HeLa and A549 cells using CRISPR/Cas9. The resulting cells were radiation sensitive, had reduced expression of ataxia-telangiectasia mutated (ATM), and exhibited multiple mitotic defects. Mechanistically, nocodazole-induced upregulation of cyclin B1, anillin, and securin was decreased in DNA-PKcs-deficient cells, as were phosphorylation of Aurora A on threonine 288, phosphorylation of Polo-like kinase 1 (PLK1) on threonine 210, and phosphorylation of targeting protein for Xenopus Klp2 (TPX2) on serine 121. Moreover, reduced nocodazole-induced expression of anillin, securin, and cyclin B1 and phosphorylation of PLK1, Aurora A, and TPX2 were rescued by inhibition of the anaphase-promoting complex/cyclosome (APC/C) by proTAME, which prevents binding of the APC/C-activating proteins Cdc20 and Cdh1 to the APC/C. Altogether, our studies suggest that loss of DNA-PKcs prevents inactivation of the APC/C in nocodazole-treated cells.


Human bone derived cell culture on PLGA flat sheet membranes of different lactide:glycolide ratio.
Providing a scaffold that can supply nutrients on a large scale (several cubic centimeters) is the key to successfully regenerating vascularized tissue: biodegradable membranes are a promising new scaffold suited to this purpose. Poly(lactic-co-glycolic-acid) (PLGA) flat sheet membranes of different lactide:glycolide ratios, prepared by phase inversion using 1-methyl-2-pyrrolidinone (NMP) as the solvent and water as the nonsolvent, were compared by assessing attachment, proliferation and osteogenic function of human bone derived cells (HBDC). Three different lactide:glycolide ratios, 50:50, 75:25, and 100:0, were compared to tissue culture polystyrene (TCPS). For attachment, 50:50 and 75:25 had similar numbers to TCPS but 100:0 had significantly fewer cells than TCPS. 50:50 and 75:25 had significantly lower HBDC numbers after 7 days but 100:0 had similar numbers compared to TCPS. For proliferation the cell number on the membranes were similar to each other. After 3 weeks, osteoblastic function of the HBDC, shown by mineralization and alkaline phosphatase activity, was present but was significantly lower compared to the TCPS control but similar when the membranes were compared. PLGA membranes fabricated from a range of ratios support HBDC culture so the optimum scaffold composition can be selected based on other factors, such as degradation rate.


Preparation, structural analysis, and properties of tenoxicam cocrystals.
Cocrystals of tenoxicam, a non-steroidal anti-inflammatory drug, are screened, prepared, and characterized in this study. Nine tenoxicam cocrystals were identified using solvent-drop grinding (SDG) techniques. Structural characterization was performed using powder X-ray diffraction (PXRD), differential scanning calorimetry, and multinuclear solid-state NMR (SSNMR). Thermal analysis, PXRD, and 1D SSNMR are used to detect solvates and phase mixtures encountered in SDG cocrystal screening. 2D SSNMR methods are then used to confirm cocrystal formation and determine structural aspects for selected cocrystals formed with saccharin, salicylic acid, succinic acid, and glycolic acid in comparison to Forms I and III of tenoxicam. Molecular association is demonstrated using cross-polarization heteronuclear dipolar correlation (CP-HETCOR) methods involving (1)H and (13)C nuclei. Short-range (1)H-(13)C CP-HETCOR and (1)H-(1)H double-quantum interactions between atoms of interest, including those engaged in hydrogen bonding, are used to reveal local aspects of the cocrystal structure. (15)N SSNMR is used to assess ionization state and the potential for zwitterionization in the selected cocrystals. The tenoxicam saccharin cocrystal was found to be similar in structure to a previously-reported cocrystal of piroxicam and saccharin. The four selected cocrystals yielded intrinsic dissolution rates that were similar or reduced relative to tenoxicam Form III.


Natural Killer Cells Integrate Signals Received from Tumour Interactions and IL2 to Induce Robust and Prolonged Anti-Tumour and Metabolic Responses.
Natural Killer (NK) cells are lymphocytes with an important role in anti-tumour responses. NK cells bridge the innate and adaptive arms of the immune system; they are primed for immediate anti-tumour function but can also have prolonged actions alongside the adaptive T cell response. However, the key signals and cellular processes that are required for extended NK cell responses are not fully known. Herein we show that murine NK cell interaction with tumour cells induces the expression of CD25, the high affinity IL2 receptor, rendering these NK cells highly sensitive to the T cell-derived cytokine IL2. In response to IL2, CD25high NK cells show robust increases in metabolic signalling pathways (mTORC1, cMyc), nutrient transporter expression (CD71, CD98), cellular growth and in NK cell effector functions (IFNγ, granzyme B). Specific ligation of an individual activating NK cell receptor, NK1.1, showed similar increases in CD25 expression and IL2-induced responses. NK cell receptor ligation and IL2 collaborate to induce mTORC1/cMyc signalling leading to high rates of glycolysis and oxidative phosphorylation (OXPHOS) and prolonged NK cell survival. Disrupting mTORC1 and cMyc signalling in CD25high tumour interacting NK cells prevents IL2-induced cell growth and function and compromises NK cell viability. This study reveals that tumour cell interactions and T cell-derived IL2 cooperate to promote robust and prolonged NK cell anti-tumour metabolic responses.


The association of 25-hydroxyvitamin D3 and D2 with behavioural problems in childhood.
Higher serum concentrations of 25-hydroxyvitamin D (25(OH)D), an indicator of vitamin D synthesis and intake, have been associated with better mental health and cognitive function. Concentrations of 1,25-dihydroxyvitamin D(3) (the active vitamin D(3) metabolite) have been associated with openness and extrovert behaviour, but 25(OH)D concentrations have not been associated with behavioural problems in humans. We investigated the prospective association between the different forms of 25(OH)D - 25(OH)D(3) and 25(OH)D(2)- and childhood behavioural problems in Avon Longitudinal Study of Parents and Children (ALSPAC). Serum 25(OH)D(3) and 25(OH)D(2) concentrations were assessed at mean age 9.9 years. Incident behavioural problems were assessed with Strengths and Difficulties Questionnaire (SDQ; emotional symptoms, conduct problems, hyperactivity-inattention problems, peer relationship problems and pro-social behaviour subscales and total difficulties score) at mean age 11.7. Sample sizes varied between 2413-2666 depending on the outcome. Higher 25(OH)D(3) concentrations were weakly associated with lower risk of prosocial problems (fully adjusted odds ratio: OR (95% confidence interval: CI) 0.85 (0.74, 0.98)). Serum 25(OH)D(3) or 25(OH)D(2) concentrations were not associated with other subscales of SDQ or total difficulties score after adjusting for concfounders and other measured analytes related to vitamin D. Our findings do not support the hypothesis that 25-hydroxyvitamin D status in childhood has important influences on behavioural traits in humans.


CTLA-4 exon 1 +49 polymorphism alone and in a haplotype with -318 promoter polymorphism may confer susceptibility to chronic HBV infection in Chinese Han patients.
Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) plays a pivotal role in regulating T cell activation, which is believably critical for the outcome of hepatitis B virus (HBV) infection. The expression and function of CTLA-4 may be affected by gene polymorphisms. This study investigated the influence of CTLA-4 polymorphisms on disease susceptibility in Chinese Han patients with chronic HBV infection. CTLA-4 +49A/G and -318C/T polymorphisms were evaluated by DNA amplification with polymerase chain reaction followed by the restriction fragment length polymorphism analysis. The patients with chronic HBV infection had higher frequencies of genotype AA and allele A of CTLA-4 +49A/G polymorphism. The haplotype +49A-318C was significantly over-represented (P < 0.001) and haplotype +49G-318C under-represented (P = 0.006) in the patients. The +49GG genotype was more frequent (P = 0.009) and +49A allele was less frequent in patients with lower ALT levels (P = 0.012) in HBeAg positive chronic hepatitis B. It is indicated that CTLA-4 +49A/G polymorphism alone and in a haplotype with -318C allele may confer susceptibility to chronic HBV infection in Chinese Han patients.


Has Rural-Urban Migration Promoted the Health of Chinese Migrant Workers?.
The relationship between health and migration has always been an important theme in immigration research. This research develops a new approach to test the healthy migrant hypothesis and the salmon bias hypothesis in China by examining an interaction term combining agricultural hukou and migrant status, non-agricultural employment history, and subsequent area of residence. Based on two Chinese micro-databases, CGSS 2015 and Harmonized CHARLS, we conducted an empirical test on the relationship between migration and health. Our empirical evidence suggests that the initial health advantage among Chinese rural migrant workers was largely due to self-selection rather than migration effects. After controlling for demographic and socioeconomic characteristics, this advantage disappeared. After their health deteriorated, migrant workers returned to their original location. This could exacerbate the contradiction between the allocation of medical resources and the demand in rural and urban China, further intensifying the already widening health status gap between rural and urban residents.


Overcoming multidrug resistance by activating unfolded protein response of the endoplasmic reticulum in cisplatin-resistant A2780/CisR ovarian cancer cells.
Cisplatin is a widely used anti-cancer agent. However, the effectiveness of cisplatin has been limited by the commonly developed drug resistance. This study aimed to investigate the potential effects of endoplasmic reticulum (ER) stress to overcome drug resistance using the cisplatin-resistant A2780/CisR ovarian cancer cell model. The synthetic chalcone derivative (E)-3-(3,5-dimethoxyphenyl)-1-(2-methoxyphenyl)prop-2-en-1-one (named DPP23) is an ER stress inducer. We found that DPP23 triggered apoptosis in both parental cisplatinsensitive A2780 and cisplatin-resistant A2780/CisR ovarian cancer cells due to activation of reactive oxygen species (ROS)-mediated unfolded protein response (UPR) pathway in the endoplasmic reticulum. This result suggests that ROSmediated UPR activation is potential in overcoming drug resistance. DPP23 can be used as a target pharmacophore for the development of novel chemotherapeutic agents capable of overcoming drug resistance in cancer cells, particularly ovarian cancer cells. [BMB Reports 2020; 53(2): 88-93].


Pathogenic mutations in the kinesin-3 motor KIF1A diminish force generation and movement through allosteric mechanisms.
The kinesin-3 motor KIF1A functions in neurons, where its fast and superprocessive motility facilitates long-distance transport, but little is known about its force-generating properties. Using optical tweezers, we demonstrate that KIF1A stalls at an opposing load of ~3 pN but more frequently detaches at lower forces. KIF1A rapidly reattaches to the microtubule to resume motion due to its class-specific K-loop, resulting in a unique clustering of force generation events. To test the importance of neck linker docking in KIF1A force generation, we introduced mutations linked to human neurodevelopmental disorders. Molecular dynamics simulations predict that V8M and Y89D mutations impair neck linker docking. Indeed, both mutations dramatically reduce the force generation of KIF1A but not the motor's ability to rapidly reattach to the microtubule. Although both mutations relieve autoinhibition of the full-length motor, the mutant motors display decreased velocities, run lengths, and landing rates and delayed cargo transport in cells. These results advance our understanding of how mutations in KIF1A can manifest in disease.


Optimal pollinator attraction strategies in Trollius ranunculoides Hemsl. (Ranunculaceae) at different altitudes: increased floral display or promotion of nectar output?
For alpine plant species, patterns of resource allocation to functional floral traits for pollinator attraction can be highly significant in adaptation to low pollinator abundance and consequent pollen limitation. Increased pollination can be achieved either through a larger floral display or production of more pollen rewards. In this study, variation in resource allocation to different components for pollinator attraction was studied along an altitudinal gradient in Trollius ranunculoides, an obligate self-incompatible out-crosser of the Qinghai-Tibet Plateau. We compared resource allocation to conspicuous yellow sepals (which mainly provide visual attraction) and degenerate petals (which provide the major nectar reward) between populations at four altitudes. Furthermore, we investigated the contribution of sepals and petals to pollinator attraction and female reproductive success in an experiment with sepal or petal removal at sites at different altitudes. At the level of single flowers, resource allocation increased to sepals but decreased to petals with increasing altitude. Consistent with these results, sepals contributed much more to visitation rate and seed set than petals, as confirmed in the sepal or petal removal experiment. Sepals and petals contributed to female reproductive success by ensuring visitation rate rather than visitation duration. To alleviate increasing pollen limitation with increasing altitude, resource allocation patterns of T. ranunculoides altered to favour development of sepals rather than petals. This strategy may improve pollination and reproductive success through visual attraction (sepal) rather than nectar reward (petal) over a gradient of decreasing pollinator abundance.


Exploring awareness and prevalence of chronic viral hepatitis in a UK based Nepali population - lessons learned for future models in engaging migrant communities.
The burden of chronic viral hepatitis (CVH) in the UK Nepali population is unknown. We aimed to determine knowledge of liver disease (LD) and prevalence of CVH in this community. This was a mixed method (qualitative and quantitative) study guided by a multidisciplinary stakeholder group. Focus groups (FG) led by Nepali community leaders explored LD knowledge. Thereafter, a prospective community-based cohort study utilising dried-blood spot testing was conducted. Thematic analysis explored FG data with categorical data analysed with Excel and R Studio. FG data showed a lack of LD knowledge, with conflict between the roles of traditional and modern practices; 1,005 participants (525 male, 480 female) were tested for CVH, with a mean age of 63 years (range:19-86). Rates of CVH infection were low: 0.3% had current hepatitis B, with no active hepatitis C. Key drivers for enthusiastic participation were development of peer support networks and advisory groups to disseminate information, including hepatitis B vaccine recommendations.


Contact network topology in tapped granular media.
We analyze the contact network of simulated two-dimensional granular packings in different states of mechanical equilibrium obtained by tapping. We show that topological descriptors of the contact network allow one to distinguish steady states of the same mean density obtained with different tap intensities. These equal-density states were recently proven to be distinguishable through the mean force moment tensor. In contrast, geometrical descriptors, such as radial distribution functions, bond order parameters, and Voronoi cell distributions, can hardly discriminate among these states. We find that small-order loops of contacts-the polygons of the network-are especially sensitive probes for the contact structure.


Association Between Marijuana Use and Sexual Frequency in the United States: A Population-Based Study.
Marijuana use is increasingly prevalent in the United States. Effects of marijuana use on sexual function are unclear, with contradictory reports of enhancement and detriment existing. To elucidate whether a relation between marijuana use and sexual frequency exists using a nationally representative sample of reproductive-age men and women. We analyzed data from cycle 6 (2002), cycle 7 (2006-2010), and continuous survey (2011-2015) administrations of the National Survey of Family Growth, a nationally representative cross-sectional survey. We used a multivariable model, controlling for demographic, socioeconomic, and anthropographic characteristics, to evaluate whether a relationship between marijuana use and sexual frequency exists. Sexual frequency within the 4 weeks preceding survey administration related to marijuana use and frequency in the year preceding survey administration. The results of 28,176 women (average age = 29.9 years) and 22,943 men (average age = 29.5) were analyzed. More than 60% of men and women were Caucasian, and 76.1% of men and 80.4% of women reported at least a high school education. After adjustment, female monthly (incidence rate ratio [IRR] = 1.34, 95% CI = 1.07-1.68, P = .012), weekly (IRR = 1.36, 95% CI = 1.15-1.60, P < .001), and daily (IRR = 1.16, 95% CI = 1.01-1.32, P = .035) marijuana users had significantly higher sexual frequency compared with never users. Male weekly (IRR = 1.22, 95% CI = 1.06-1.41, P = .006) and daily (IRR = 1.36, 95% CI = 1.21-1.53, P < .001) users had significantly higher sexual frequency compared with never users. An overall trend for men (IRR = 1.08, 95% CI = 1.05-1.11, P < .001) and women (IRR = 1.07, 95% CI = 1.04-1.10, P < .001) was identified showing that higher marijuana use was associated with increased coital frequency. Marijuana use is independently associated with increased sexual frequency and does not appear to impair sexual function. Our study used a large well-controlled cohort and clearly defined end points to describe a novel association between marijuana use and sexual frequency. However, survey responses were self-reported and represent participants only at a specific point in time. Participants who did not answer questions related to marijuana use and sexual frequency were excluded. A positive association between marijuana use and sexual frequency is seen in men and women across all demographic groups. Although reassuring, the effects of marijuana use on sexual function warrant further study. Sun AJ, Eisenberg ML. Association Between Marijuana Use and Sexual Frequency in the United States: A Population-Based Study. J Sex Med 2017;14:1342-1347.


[Development and validation of the Korean patient safety culture scale for nursing homes].
The purpose of this study was to develop a tool to evaluate patient safety culture in nursing homes and to test its validity and reliability. A preliminary tool was developed through interviews with focus group, content validity tests, and a pilot study. A nationwide survey was conducted from February to April, 2011, using self-report questionnaires. Participants were 982 employees in nursing homes. Data were analyzed using Cronbach's alpha, item analysis, factor analysis, and multitrait/multi-Item analysis. From the results of the analysis, 27 final items were selected from 49 items on the preliminary tool. Items with low correlation with total scale were excluded. The 4 factors sorted by factor analysis contributed 63.4% of the variance in the total scale. The factors were labeled as leadership, organizational system, working attitude, management practice. Cronbach's alpha for internal consistency was .95 and the range for the 4 factors was from .86 to .93. The results of this study indicate that the Korean Patient Safety Culture Scale has reliability and validity and is suitable for evaluation of patient safety culture in Korean nursing homes.


[Selective application of tumor markers PSA].
Tumor markers are being used in the early detection of cancer disease, diagnostics, prognosis, therapy and disease follow-up. A lot of clinical studies would not be nowadays possible without tumor markers. As in clinical practice the informative value of results is limited (by limited sensitivity and/or specificity) those markers should be selectively used, i.e. in such clinical setting where there is a clear benefit. Prostate specific antigen (PSA) has become the most important tumor marker in oncology. Its importance ranges from early detection of prostate cancer until therapy decision making in hormone refractory cancer. To prevent initial PSA- "terrorism" in early detection the patient must be well informed about risk of prostate cancer and therapeutic options inclusively possible side effects. Does the man at risk agree further evaluation by biopsy has to be performed directly above a PSA-cut-off 4.0 ng/ml. A high percentage of free PSA is not allowed to prolong diagnostic procedure. On the opposite, in PSA range 3.0-3.9 ng/ml and free-to-total PSA ratio less than 12% a prostate biopsy is also indicated. The diagnostic "grey zone" 4.0-10 ng/ml does not exist any more. Further follow-up should be done if the estimated life expectancy exceeds 10 years and should be performed in the PSA-range 2.0-3.9 ng/ml annually, in the PSA-range 1.0-1.9 ng/ml biannually and in the PSA range less that 1.0ng/ml triennially. About 3-25% of newly detected cancers are clinically insignificant. Models based on PSA, Gleason Score and tumor load of biopsies are helpful in identifying these men for "active surveillance" in curative intent. "Not every early detected cancer must be cured, but cancer where cure is necessary, must be early detected!" After primary therapy (operation/radiotherapy) one third of men will document a PSA only relapse. 30% of them will develop clinical symptoms and possible die from disease. PSA and especially PSA doubling time is a promising marker to identify these men at risk for whom salvage-radiotherapy, salvage prostatectomy or hormonal therapy can be an option. However the benefit in survival must be weight against a possible loss in quality of life.


An optimization principle for determining movement duration.
Movement duration is an integral component of motor control, but nearly all extant optimization models of motor planning prefix duration instead of explaining it. Here we propose a new optimization principle that predicts movement duration. The model assumes that the brain attempts to minimize movement duration under the constraint of meeting an accuracy criterion. The criterion is task and context dependent but is fixed for a given task and context. The model determines a unique duration as a trade-off between speed (time optimality) and accuracy (acceptable endpoint scatter). We analyzed the model for a linear motor plant, and obtained a closed-form equation for determining movement duration. By solving the equation numerically with specific plant parameters for the eye and arm, we found that the model can reproduce saccade duration as a function of amplitude (the main sequence), and arm-movement duration as a function of the ratio of target distance to size (Fitts's law). In addition, it explains the dependency of peak saccadic speed on amplitude and the dependency of saccadic duration on initial eye position. Furthermore, for arm movements, the model predicts a scaling relationship between peak velocity and distance and a reduction in movement duration with a moderate increase in viscosity. Finally, for a linear plant, our model predicts a neural control signal identical to that of the minimum-variance model set to the same movement duration. This control signal is a smooth function of time (except at the endpoint), in contrast to the discontinuous bang-bang control found in the time-optimal control literature. We suggest that one aspect of movement planning, as revealed by movement duration, may be to assign an endpoint accuracy criterion for a given task and context.


Medical diagnosis aboard submarines. Use of a computer-based Bayesian method of analysis in an abdominal pain diagnostic program.
The medical issues that arise in the isolated environment of a submarine can occasionally be grave. While crewmembers are carefully screened for health problems, they are still susceptible to serious acute illness. Currently, the submarine medical department representative, the hospital corpsman, utilizes a history and physical examination, clinical acumen, and limited laboratory testing in diagnosis. The application of a Bayesian method of analysis to an abdominal pain diagnostic system utilizing an onboard microcomputer is described herein. Early results from sea trials show an appropriate diagnosis in eight of 10 cases of abdominal pain, but the program should still be viewed as an extended "laboratory test" until proved effective at sea.


Working memory performance is correlated with local brain morphology in the medial frontal and anterior cingulate cortex in fibromyalgia patients: structural correlates of pain-cognition interaction.
Fibromyalgia (FM) is a disorder of unknown aetiology, characterized by chronic widespread pain, stiffness and sleep disturbances. In addition, patients frequently complain of memory and attention deficits. Accumulating evidence suggests that FM is associated with CNS dysfunction and with an altered brain morphology. However, few studies have specifically investigated neuropsychological issues in patients suffering from FM. We therefore sought to determine whether neuropsychological deficits found in FM patients may be correlated with changes in local brain morphology specifically in the frontal, temporal or cingulate cortices. Twenty FM patients underwent extensive testing for potential neuropsychological deficits, which demonstrated significantly reduced working memory and impaired non-verbal long-term memory (limited to free recall condition) in comparison with normative data from age- and education-matched control groups. Voxel-based morphometry (VBM) was used to evaluate for potential correlations between test results and local brain morphology. Performance on non-verbal working memory was positively correlated with grey matter values in the left dorsolateral prefrontal cortex, whereas performance on verbal working memory (digit backward) was positively correlated with grey matter values in the supplementary motor cortex. On the other hand, pain scores were negatively correlated with grey matter values in the medial frontal gyrus. White matter analyses revealed comparable correlations for verbal working memory and pain scores in the medial frontal and prefrontal cortex and in the anterior cingulate cortex. Our data suggest that, in addition to chronic pain, FM patients suffer from neurocognitive deficits that correlate with local brain morphology in the frontal lobe and anterior cingulate gyrus, which may be interpreted to indicate structural correlates of pain-cognition interaction.


Monitoring metabolic health of dairy cattle in the transition period.
This paper reviews the importance of energy metabolism in transition dairy cows, its associations with disease and reproduction, and strategies for monitoring cows under field conditions during this critical time. Essentially all dairy cattle experience a period of insulin resistance, reduced feed intake, negative energy balance, hypocalcemia, reduced immune function, and bacterial contamination of the uterus soon before, or in the weeks after calving. One-third of dairy cows may be affected by some form of metabolic or infectious disease in early lactation. Routine, proactive actions, observations, or analysis are intended to accurately and efficiently provide early detection of problems, to provide an opportunity for investigation and intervention in order to limit the consequences and costs of health problems and reduced animal performance or welfare. Methods of early detection include monitoring of disease and culling records, feed intake, milk production, body condition, and simple metabolic tests. Methods, strategies, and interpretation of measurement of peripartum concentrations of non-esterified fatty acids (NEFA) and beta-hydroxybutyrate (BHB) as indicators of aspects of energy status and disease risk are reviewed. High NEFA (> 0.4 mmol/l) in the last 7 to 10 days before expected calving is associated with increased risk of displaced abomasum (DA), retained placenta, culling before 60 days in milk, and less milk production in the first 4 months of lactation. Subclinical ketosis (serum BHB >1200 to 1400 micromol/l) in the first or second week after calving is associated with increased risk of DA, metritis, clinical ketosis, endometritis, prolonged postpartum anovulation, increased severity of mastitis, and lower milk production in early lactation. There are several validated and practical tools for cow-side measurement of ketosis.