Quality management by state Medicaid agencies converting to managed care: plans and current practice.
Enrollment in Medicaid managed care plans has increased more than 5-fold in this decade, but how states monitor and encourage quality of care in these programs is not known. To characterize the quality monitoring and assurance activities of state Medicaid agencies for Medicaid beneficiaries enrolled in comprehensive prepaid managed care programs. Structured telephone survey conducted between October 1996 and January 1997. State Medicaid agencies. Representatives from all state Medicaid agencies, including the District of Columbia, with beneficiaries enrolled in comprehensive prepaid managed care plans as of July 1, 1996. Proportion of states with specific quality monitoring and assurance activities for Medicaid managed care. We surveyed all 34 states enrolling beneficiaries in comprehensive managed care programs. In 1996, all 34 states enrolled the population receiving assistance from the Aid to Families With Dependent Children (AFDC) program, while only 21 (62%) and 15 (44%) enrolled the disabled and elderly populations, respectively. In the period 1995 to 1996, 19 states (63%) collected data on satisfaction with care, and 25 states (83%) collected data on childhood immunizations. No more than half of the states collected data on other selected measures of access and quality, but a substantial number planned to collect such data in 1997. While at most 37% of states were providing comparative data to health plans, up to 80% were planning to provide such information in 1997. Similarly, while at most 10% of states provided beneficiaries with such information, up to 38% planned to do so in 1997. The breadth of contracting requirements designed to assure quality varied substantially across states. State Medicaid agencies have already begun adapting to their new roles as purchasers of health care. Continued monitoring is essential to ensure that state agencies implement planned programs and that quality of care for Medicaid enrollees is preserved or improved.


VEGF165b Mutant Promotes the Apoptosis of Murine Breast Cancer Cells Induced by Paclitaxel by Inducing Tumor Vessel Maturation.
The anti-angiogenic agent vascular endothelial growth factor 165b (VEGF165b) mutant (mVEGF165b), which was developed by our laboratory, has superior antitumor activity to that of native VEGF165b; however, its mechanism of action and druggability need further exploration. Using the commercial anti-angiogenic drug bevacizumab as a positive control, the mechanism and developability of mVEGF165b were evaluated and explored. The Cell Counting Kit-8 assay was performed to evaluate the effects of mVEGF165b and bevacizumab alone on the proliferation of human umbilical vein endothelial cells (HUVECs). Meanwhile, the inhibitory effects of mVEGF165b and bevacizumab combined with paclitaxel in a mouse model of breast cancer were assessed. Immunohistochemistry was used to detect their effects on tumor vascular maturation, and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to detect the apoptosis of tumor cells. In vitro cell experiments confirmed that mVEGF165b inhibited the proliferation of HUVECs with an efficacy equivalent to that of bevacizumab. mVEGF165b and bevacizumab combined with paclitaxel significantly delayed the growth of breast cancer in mice. Immunohistochemistry and the TUNEL assay showed that mVEGF165b and bevacizumab combined with paclitaxel-induced higher vascular maturity and more apoptosis than paclitaxel alone. mVEGF165b showed similar efficacy and mechanism of action as bevacizumab, indicating its potential to be developed into a safe and effective anti-angiogenic drug.


Synthetic aminopyrrolic receptors have apoptosis inducing activity.
We report two synthetic aminopyrrolic compounds that induce apoptotic cell death. These compounds have been previously shown to act as receptors for mannosides. The extent of receptor-induced cell death is greater in cells expressing a high level of high-mannose oligosaccharides than in cells producing lower levels of high-mannose glycans. The ability of synthetic receptors to induce cell death is attenuated in the presence of external mannosides. The present results provide support for the suggestion that the observed cell death reflects an ability of the receptors to bind mannose displayed on the cell surface. Signaling pathway studies indicate that the synthetic receptors of the present study promote JNK activation, induce Bax translocation to the mitochondria, and cause cytochrome c release from the mitochondria into the cytosol, thus promoting caspase-dependent apoptosis. Such effects are also observed in cells treated with mannose-binding ConA. The present results thus serve to highlight what may be an attractive new approach to triggering apoptosis via modes of action that differ from those normally used to promote apoptosis.


Qualitative and quantitative performance of ¹⁸F-FDG-PET/MRI versus ¹⁸F-FDG-PET/CT in patients with head and neck cancer.
MR imaging and PET/CT are integrated in the work-up of head and neck cancer patients. The hybrid imaging technology (18)F-FDG-PET/MR imaging combining morphological and functional information might be attractive in this patient population. The aim of the study was to compare whole-body (18)F-FDG-PET/MR imaging and (18)F-FDG-PET/CT in patients with head and neck cancer, both qualitatively in terms of lymph node and distant metastases detection and quantitatively in terms of standardized uptake values measured in (18)F-FDG-avid lesions. Fourteen patients with head and neck cancer underwent both whole-body PET/CT and PET/MR imaging after a single injection of (18)F-FDG. Two groups of readers counted the number of lesions on PET/CT and PET/MR imaging scans. A consensus reading was performed in those cases in which the groups disagreed. Quantitative standardized uptake value measurements were performed by placing spheric ROIs over the lesions in 3 different planes. Weighted and unweighted κ statistics, correlation analysis, and the Wilcoxon signed rank test were used for statistical analysis. κ statistics for the number of head and neck lesion lesions counted (pooled across regions) revealed interreader agreement between groups 1 and 2 of 0.47 and 0.56, respectively. Intrareader agreement was 0.67 and 0.63. The consensus reading provided an intrareader agreement of 0.63. For the presence or absence of metastasis, interreader agreement was 0.85 and 0.70. The consensus reading provided an intrareader agreement of 0.72. The correlations between the maximum standardized uptake value in (18)F-FDG-PET/MR imaging and (18)F-FDG-PET/CT for primary tumors and lymph node and metastatic lesions were very high (Spearman r = 1.00, 0.93, and 0.92, respectively). In patients with head and neck cancer, (18)F-FDG-PET/MR imaging and (18)F-FDG-PET/CT provide comparable results in the detection of lymph node and distant metastases. Standardized uptake values derived from (18)F-FDG-PET/MR imaging can be used reliably in this patient population.


Use of a participatory quality assessment and improvement tool for maternal and neonatal hospital care. Part 1: Review of implementation features and observed quality gaps in 25 countries.
A substantial proportion of maternal and neonatal mortality and morbidity is attributable to gaps in quality of care. A systematic, standard-based tool for quality assessment and improvement for maternal and neonatal hospital care (QA/QI MN tool) was developed in 2009 by the World Health Organization (WHO). The tool guides the assessment process along the whole continuum from admission to discharge, collects the views of the recipients of care and engages hospital mangers and staff in identifying gaps and drafting an action plan. Publications describing use of the WHO QA/QI MN tool from 2009 to 2017 and reports retrievable from WHO or other development partners' websites were searched and considered for inclusion in the review. Only assessments of hospitals were considered. Quality gaps were classified as regarding case management in maternal care, case management in neonatal care, hospital infrastructure, hospital policies and according to severity and frequency. Quotations from women regarding key issues in effective communication, respect and dignity, emotional support and costs incurred were selected. In the period 2009-2017, use of the WHO QA/QI MN tool was documented in 25 countries, belonging to Central and Eastern Europe (8), Central Asia (4), Sub-Saharan Africa (11), Latin America (1) and Middle East (1). Overall, 133 hospitals were assessed. The tool allowed to identify in great detail serious quality gaps including: insufficient or incomplete adherence to recommended evidence-based procedures for normal childbirth and maternal and neonatal complications; excess of inappropriate or unnecessary interventions; insufficient infection control; failure to provide respectful care, adequate communication and emotional support to mothers and babies; poor use of information generated locally to analyse processes and outcomes. These gaps were observed in all countries. Significant differences were observed among facilities belonging to the same health systems, ie, with very similar staffing, infrastructure and equipment. The experience made, the largest of this kind, provides comprehensive and detailed insight into the existing quality gaps in a wide variety of settings. QI cycles at facility level should be primarily based on assessments made by multidisciplinary teams of professionals to identify the parts of the care pathways which require improvement through a participatory approach involving managers, staff and patients.


[Reutilization of the right-side approach in commissurotomy in recurrent mitral stenosis].
Based on histotopographic studies of heart specimens taken from patients died after commissurotomy with a right-side approach, and the experience with eleven mitral commissurotomies using an access via the interatrial septum repeatedly, it is concluded that a close mitral commissurotomy for reccurrent mitral stenosis with the repeat use of a right-side approach seems to be anatomically grounded and easy to be performed from the point of view of the operative technic. This intervention should be accomplished in patients with recurrent mitral stenosis, previously operated upon with a right-side access. The opportunities of reused right-side approach offer prerequisites for its wider application in primary commissurotomy.


Outcomes after chemotherapy with WHO category II regimen in a population with high prevalence of drug resistant tuberculosis.
Standard short course chemotherapy is recommended by the World Health Organization to control tuberculosis worldwide. However, in settings with high drug resistance, first line standard regimens are linked with high treatment failure. We evaluated treatment outcomes after standardized chemotherapy with the WHO recommended category II retreatment regimen in a prison with a high prevalence of drug resistant tuberculosis (TB). A cohort of 233 culture positive TB patients was followed through smear microscopy, culture, drug susceptibility testing and DNA fingerprinting at baseline, after 3 months and at the end of treatment. Overall 172 patients (74%) became culture negative, while 43 (18%) remained positive at the end of treatment. Among those 43 cases, 58% of failures were determined to be due to treatment with an inadequate drug regimen and 42% to either an initial mixed infection or re-infection while under treatment. Overall, drug resistance amplification during treatment occurred in 3.4% of the patient cohort. This study demonstrates that treatment failure is linked to initial drug resistance, that amplification of drug resistance occurs, and that mixed infection and re-infection during standard treatment contribute to treatment failure in confined settings with high prevalence of drug resistance.


Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes.
Germline variants in tumor suppressor genes (TSGs) can result in RNA mis-splicing and predisposition to cancer. However, identification of variants that impact splicing remains a challenge, contributing to a substantial proportion of patients with suspected hereditary cancer syndromes remaining without a molecular diagnosis. To address this, we used capture RNA-sequencing (RNA-seq) to generate a splicing profile of 18 TSGs (APC, ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53) in 345 whole-blood samples from healthy donors. We subsequently demonstrated that this approach can detect mis-splicing by comparing splicing profiles from the control dataset to profiles generated from whole blood of individuals previously identified with pathogenic germline splicing variants in these genes. To assess the utility of our TSG splicing profile to prospectively identify pathogenic splicing variants, we performed concurrent capture DNA and RNA-seq in a cohort of 1000 patients with suspected hereditary cancer syndromes. This approach improved the diagnostic yield in this cohort, resulting in a 9.1% relative increase in the detection of pathogenic variants, demonstrating the utility of performing simultaneous DNA and RNA genetic testing in a clinical context.


Determination of unusual soya and non-soya phytoestrogen sources in beer, fish products and other foods.
Fish and fish products (14 samples), Indian foods and meals (10 samples), spices (30 samples) and beers (10 samples) were analysed for their phytoestrogen content, and a number of significant non-soya sources of dietary phytoestrogens were identified. No isoflavones were detected in unprocessed, farmed or ocean fish, but some samples of processed fish products contained soya isoflavones, which are assumed to come from coatings or protein addition. Additionally, some processed fish products contained, genistein glycocongugates not derived from soya. Genistein was detected in Indian meals such that, for example, a single portion of a vindalooo curry contained 11 mg genistein. The origin was most likely from the spices used, since the analysis of curry powders, chilli powder, crushed red chillies, garam masala and tandoori powder revealed that some contained genistein at more than 100 mg kg(-1). Cumin was the most likely source material, although not all individual samples of cumin tested contained high levels of genistein. Prenylnaringenin phytoestrogens were determined in UK hop-based beers at mean concentrations of 0.21 mg(-1) 6-prenylnaringenin and 0.06mg(-1) 8-prenylnaringenin. The beers also contained traces of daidzein, genistein and biochanin A. The significance of 'hidden soya' in processed foods and these non-soya sources of phytoestrogens is that UK dietary intake of phytoestrogens must be assumed to be higher than estimated previously and that some sources of phytoestrogens remain poorly characterized.


Childhood depression. Developmental considerations.
Childhood depression is becoming a more commonly recognized diagnosis in the pediatric population. The American Psychiatric Association purposes that the criteria for adult and childhood depression are the same. We question that position and emphasize the developmental aspects of depressive symptoms providing diagnostic guidelines for depression at five different stages from infancy through adolescence. Case examples are included to highlight the distinctive presentation of depression at each developmental stage. Specific treatment recommendations include psychotherapy, mobilization, and pharmacotherapy.


Single-step antibody-based affinity cryo-electron microscopy for imaging and structural analysis of macromolecular assemblies.
Single particle cryo-electron microscopy (cryo-EM) is an emerging powerful tool for structural studies of macromolecular assemblies (i.e., protein complexes and viruses). Although single particle cryo-EM requires less concentrated and smaller amounts of samples than X-ray crystallography, it remains challenging to study specimens that are low-abundance, low-yield, or short-lived. The recent development of affinity grid techniques can potentially further extend single particle cryo-EM to these challenging samples by combining sample purification and cryo-EM grid preparation into a single step. Here we report a new design of affinity cryo-EM approach, cryo-SPIEM, that applies a traditional pathogen diagnosis tool Solid Phase Immune Electron Microscopy (SPIEM) to the single particle cryo-EM method. This approach provides an alternative, largely simplified and easier to use affinity grid that directly works with most native macromolecular complexes with established antibodies, and enables cryo-EM studies of native samples directly from cell cultures. In the present work, we extensively tested the feasibility of cryo-SPIEM with multiple samples including those of high or low molecular weight, macromolecules with low or high symmetry, His-tagged or native particles, and high- or low-yield macromolecules. Results for all these samples (non-purified His-tagged bacteriophage T7, His-tagged Escherichiacoli ribosomes, native Sindbis virus, and purified but low-concentration native Tulane virus) demonstrated the capability of cryo-SPIEM approach in specifically trapping and concentrating target particles on TEM grids with minimal view constraints for cryo-EM imaging and determination of 3D structures.


Circular RNA circ_0001105 Inhibits Progression and Metastasis of Osteosarcoma by Sponging miR-766 and Activating YTHDF2 Expression.
Circular RNAs (circRNAs) play vital roles in the modulation of tumor progression. This study explored the biological functions of circ_0001105 in the progression of osteosarcoma (OS). qRT-PCR and in situ hybridization (ISH) were performed to detect the expression status of circ_0001105 in cells and tissues. Bioinformatics analysis, dual-luciferase reporter gene assay, Western blot and qRT-PCR were performed to determine the relationships among RNAs. The CCK-8, colony formation, EdU, transwell and wound healing assays were conducted to evaluate the cell growth, invasion and migration of OS cells. Tumor xenografts were established to investigate the effects of circ_0001105 on tumor growth in vivo. Lastly, the protein expression of YTHDF2 in OS tissues was measured using immunohistochemical staining. Data showed that circ_0001105 and YTHDF2 were significantly lower, while miR-766 was higher in OS tissues compared to adjacent tissues. Low expression of circ_0001105 or YTHDF2 was associated with poor survival of OS patients as demonstrated by the Kaplan-Meier analysis. In addition, miR-766 was identified as a direct binding target of circ_0001105 and YTHDF2. Ectopic overexpression of circ_0001105 or YTHDF2 significantly suppressed OS cell viability and invasion through regulating miR-766. Last, overexpression of circ_0001105 significantly attenuated in vivo tumor growth. Our findings suggest that circ_0001105 inhibits OS progression, at least partially, by regulating miR-766/YTHDF2 signaling pathway.


Human Papillomaviruses; Epithelial Tropisms, and the Development of Neoplasia.
Papillomaviruses have evolved over many millions of years to propagate themselves at specific epithelial niches in a range of different host species. This has led to the great diversity of papillomaviruses that now exist, and to the appearance of distinct strategies for epithelial persistence. Many papillomaviruses minimise the risk of immune clearance by causing chronic asymptomatic infections, accompanied by long-term virion-production with only limited viral gene expression. Such lesions are typical of those caused by Beta HPV types in the general population, with viral activity being suppressed by host immunity. A second strategy requires the evolution of sophisticated immune evasion mechanisms, and allows some HPV types to cause prominent and persistent papillomas, even in immune competent individuals. Some Alphapapillomavirus types have evolved this strategy, including those that cause genital warts in young adults or common warts in children. These strategies reflect broad differences in virus protein function as well as differences in patterns of viral gene expression, with genotype-specific associations underlying the recent introduction of DNA testing, and also the introduction of vaccines to protect against cervical cancer. Interestingly, it appears that cellular environment and the site of infection affect viral pathogenicity by modulating viral gene expression. With the high-risk HPV gene products, changes in E6 and E7 expression are thought to account for the development of neoplasias at the endocervix, the anal and cervical transformation zones, and the tonsilar crypts and other oropharyngeal sites. A detailed analysis of site-specific patterns of gene expression and gene function is now prompted.


Rotary versus reciprocating shaping files in bacterial elimination from long oval canals.
A comparison of the abilities of rotary versus reciprocating files to eliminate viable Enterococcus faecalis populations from the long oval root canals of extracted human teeth. Fifty teeth were contaminated and randomly distributed into two groups (n = 25 each): BT-RaCe group and WaveOne group. Two microbial samples were obtained from each tooth before (S1) and after (S2) instrumentation. The CFUs from the S1 and S2 measurements were calculated and compared between the groups. Both groups showed significantly fewer CFUs in the S2 samples (P < 0.001). In the S2 intragroup comparison, BT-RaCe resulted in significantly fewer CFUs than WaveOne (P = 0.010). In the direct comparison between the rotary multiple file shaping system and the reciprocating single-file system, the multiple file system was more efficient at reducing the microbiological load of viable E. faecalis from long oval root canals.


Factors affecting utilization of antenatal care among reproductive age group women (15-49 years) in an urban squatter settlement of Karachi.
To describe the socio-demographic characteristics and utilization pattern of antenatal care of reproductive age group women (15-49 years) in an urban squatter settlement of Karachi and to assess and compare the knowledge on antenatal care between women who received and those who did not receive antenatal care. A community-based cross sectional survey was conducted and a sample of 323 women was taken through systematic sampling. Two hundred ninety five (295) women were interviewed and 28 were excluded, as they never experienced a pregnancy. Socio-demographic characteristics and knowledge about antenatal care were compared on the basis of having received and not having received antenatal care, utilizing bivariate and multivariate analysis. Multivariate logistic regression analysis showed that higher income women were twice likely to use antenatal care services (AOR = 2.11 95% CI 1.14-3.89) than those of lower income. Women receiving antenatal care were more knowledgeable about the importance of dietary protein (AOR = 1.97 95% CI 1.16-3.33), intake of green leafy vegetables for the prevention of anemia (AOR = 2.34 95% CI 1.33-4.11), and reporting danger signs (AOR = 2.25 95% CI 1.07-4.74). Women of reproductive age need to recognize the importance of receiving antenatal care in the community. Uplifting the socio-economic status and literacy rate of women is required to provide community based education. There is a potential need to increase nutrition education, highlighting the importance of iron supplementation, appropriate food during pregnancy and recognition of signs and symptoms and danger signs in pregnancy.


Effect of Adding Pulses to Replace Protein Foods and Refined Grains in Healthy Dietary Patterns.
Pulses are dry seeds of legumes which are high in fiber and contain plant protein and several important macronutrients. Our aim was to model the nutritional effects of substituting servings of protein foods and/or refined grains with servings of beans and peas in the Healthy U.S.-Style Pattern identified in the Dietary Guidelines for Americans, 2020-2025. Dietary modeling was accomplished by substituting nutrients of protein foods and/or refined grains with nutrients of the USDA's beans and peas (pulses) composite in the 2000 kcal Healthy U.S.-Style Pattern. A 10% or more change was used as an indicator of meaningful differences. Cost implications were computed by adding the cost of pulses and subtracting the cost of protein foods/refined grains according to the modeling scenario. The substitution of 6-8 oz/week protein foods with 1.5-2.0 cups/week pulses increased fiber and decreased cholesterol. Higher amounts of pulses replacing refined grains or combinations of protein foods and refined grains generally increase fiber, iron, magnesium, potassium, and copper depending on the modeling scenarios. All modeling scenarios of substituting the servings of protein foods alone or in combination with refined grains with the servings of pulses were associated with cost savings. Our results suggest that encouraging increased pulse consumption may be an effective strategy for improving diet.


A novel pathway of epithelial sodium channel activation involves a serum- and glucocorticoid-inducible kinase consensus motif in the C terminus of the channel's alpha-subunit.
Aldosterone-induced serum- and glucocorticoid-inducible kinase isoform 1 (SGK1) contributes to the regulation of the epithelial sodium channel (ENaC), the activity of which is critical for long term blood pressure control. Aldosterone-induced SGK1 is thought to enhance ENaC surface expression by phosphorylating Nedd4-2 and thereby preventing ENaC retrieval and degradation. In outside-out membrane patches of Xenopus laevis oocytes heterologously expressing ENaC, amiloride-sensitive ENaC currents were enhanced by phosphatase inhibitors and were dependent on cytosolic Mg(2+). This indicates that a kinase is involved in channel regulation. Indeed, recombinant constitutively active SGK1, included in the pipette solution, caused a sustained 2- to 3-fold increase of ENaC currents. Deletion of the C terminus of alphaENaC largely reduced the stimulatory effect of SGK1, whereas stimulation by SGK1 did not require the presence of the C termini of the beta- or gamma-subunits. Replacing the serine residue Ser(621) of the SGK1 consensus motif in the C terminus of the alpha-subunit by an alanine specifically abolished the stimulatory effect of SGK. Our findings indicate that SGK1 can stimulate ENaC activity independently of an inhibition of Nedd4-2-mediated channel retrieval. This defines a novel regulatory pathway likely to be relevant for aldosterone-induced stimulation of ENaC in vivo.


Quantifying the reflective index of nanometer-thick thiolated molecular layers on nanoparticles.
To precisely measure the refractive index (RI) of molecular layers is of great help to understand their fundamental optical properties and to develop advanced molecular layer-based devices including biosensors, photodetectors, and metamaterials. However, accurate quantification of the RI of ultra-thin nanometer-thick molecular layers immobilized on the surface of aqueous nanoparticles (NPs) remains a challenge. Here we have developed a method to quantify the effective RI of ultra-thin thiolated molecular layers with a thickness down to a sub-nanometer scale on the surface of plasmonic gold (Au) NPs. This method is realized by measuring and calculating the localized surface plasmon resonance (LSPR) shift of NPs due to the change of the surrounding RI and by quantifying the accurate molecular layer thickness via the TEM visualization of a nanogap junction in core-shell nanomatryoshka particles. The effective RI of the molecular layer is determined by fitting the experimental and calculated LSPR shifts using the least squares method. We have applied this method to quantify the effective RI of 1,4-benzenedithiol, 4,4'-biphenyldithiol, and 4,4'-terpheyldithiol molecules, proving their effectiveness and feasibility in ultra-thin molecular layers adsorbed on the NPs.


Influence of plant root exudates on the mobility of fuel volatile compounds in contaminated soils.
Vegetation and its associated microorganisms play an important role in the behaviour of soil contaminants. One of the most important elements is root exudation, since it can affect the mobility, and therefore, the bioavailability of soil contaminants. In this study, we evaluated the influence of root exudates on the mobility of fuel derived compounds in contaminated soils. Samples of humic acid, montmorillonite, and an A horizon from an alumi-umbric Cambisol were contaminated with volatile contaminants present in fuel: oxygenates (MTBE and ETBE) and monoaromatic compounds (benzene, toluene, ethylbenzene and xylene). Natural root exudates obtained from Holcus lanatus and Cytisus striatus and ten artificial exudates (components frequently found in natural exudates) were added to the samples, individually and as a mixture, to evaluate their effects on contaminant mobility. Fuel compounds were analyzed by headspace-gas chromatography-mass spectrometry. In general, the addition of natural and artificial exudates increased the mobility of all contaminants in humic acid. In A horizon and montmorillonite, natural or artificial exudates (as a mixture) decreased the contaminant mobility. However, artificial exudates individually had different effects: carboxylic components increased and phenolic components decreased the contaminant mobility. These results established a base for developing and improving phytoremediation processes of fuel-contaminated soils.


Effect of Obesity on Left Ventricular Mass: Results from 320 Multi-Slices Computed Tomography.
To determine effects of obesity and gender on left ventricular mass in normotensive and hypertensive Thai patients using 320-slice cardiac computed tomography (CT). Left ventricular mass (LVM) obtained from 320-slice coronary CT angiogram was compared in 597 normotensive subjects (175 men [65 obese] and 422 women [133 obese], aged 55±7 years) and 483 hypertensive patients (180 men [104 obese] and 303 women [170 obese], aged 60±7 years). Obesity in Asian population was defined by body mass index (BMI) ≥ 25 kg/m2 in both genders. LV mass was normalized for body surface area (BSA)and height2.7. The upper normal limit of LVM/ height2.7 developed from 244 (197 women, 47 men) low risk subjects (non-smoking normal-weight adults free from hypertension, diabetes, coronary artery disease & dyslipidemia) was lower than the established criteria for left ventricular hypertrophy (LVH) (31 versus 44 g/m2.7 in women; 36 versus 48 g/m2.7 in men). There is statistical difference between men and women in all groups of analysis. Among both hypertensive and normotensive subjects, the prevalence of LVH and LVM/height2.7 are higher in the obese group than normal-weight group in both genders (LVM/height2.7p<0.001; prevalence of LVH – obese versus normal-weight hypertension: 58% versus 34% in women, 43% versus 14% in men; obese versus normal-weight normotension: 35% versus 16% in women, 40% versus 15% in men). The same differences between obese and normal-weight groups were also present when normalizing LVM for height but not with LVM/BSA. Logistic regression analysis revealed that systolic blood pressure and BMI were the main predictors of LVH in the entire population (p<0.001 in both genders). Equations for predicting LVH in men and women were: Risk of LVH = 1/(l+e-w) where w is as follows: w (men) = 0.02* systolic pressure + 0.25*BMI – 9.86, w (women) = 0.03* systolic pressure + 0.17*BMI – 8.82. Obesity is an independent stimulus to increase LVM in normo-tensive subjects, and its effect is additive in hypertensive patients. Gender and obesity affect LVM and prevalence of LVH.


Nationwide introduction of a new competency framework for undergraduate medical curricula: a collaborative approach.
Switzerland recently introduced PROFILES, a revised version of its national outcomes reference framework for the undergraduate medical curriculum. PROFILES is based on a set of competencies adapted from the CanMEDS framework and nine entrustable professional activities (EPAs) that students have to be able to perform autonomously in the context of a predefined list of clinical situations. The nationwide implementation of such a competency- and EPA-based approach to medical education is a complex process that represents an important change to the organisation of undergraduate training in the various medical schools. At the same time, the concepts underlying PROFILES also have to be reflected at the level of the Federal Licencing Examination (FLE) and the national accreditation process. The vice-deans for education mandated a Swiss Working Group for PROFILES Implementation (SWGPI) to elaborate a guide presenting the principles and best practices based on the current scientific literature, to ensure the coherence between the future developments of the medical curricula and the evolution of the FLE, and to propose a coordinated research agenda to evaluate the implementation process. On the basis of the literature and analysis of our national context, we determined the key elements important for a successful implementation. They can be grouped into several areas including curricular design and governance, the assessment system and entrustment process, faculty development and change management. We also identified two dimensions that will be of particular importance to create synergies and facilitate exchange between the medical schools: a systematic approach to curriculum mapping and the longitudinal integration of an e-portfolio to support the student learning process. The nationwide collaborative approach to define strategies and conditions for the implementation of a new reference framework has allowed to develop a shared understanding of the implications of PROFILES, to promote the establishment of Swiss mapping and e-portfolio communities, and to establish the conditions necessary for ensuring the continuous alignment of the FLE with the evolving medical curricula.


[Effect of electric stimulation of the septum of the rabbit brain on subiculum cells with different types of spontaneous activity].
Neuronal activity was recorded extracellularly in subiculum of unanaesthetized rabbits during stimulation of the medial septal nucleus and hippocampal field CA1. According to the pattern of the background activity subicular cells were divided into three groups: cells with theta-modulation, cells with delta-modulation and complex spikes, cells with irregular single-spike activity. The theta-cells were specifically related to the septal input: their reactivity to septal stimulation was higher and the latencies of their responses significantly shorter than those of the other groups of cells. Stability of the theta-modulation was increased during and after septal stimulation. Reactivity to CA1 stimulation, as well as latencies of responses were identical for all groups of subicular cells. Rhythmic theta-modulation was damped after CA1 stimulation. The data indicate specific properties of the septal input to the subicular cells with theta-modulation.


Tinnitus retraining therapy using portable music players.
We aimed to perform acoustic analysis of environmental sounds used in sound therapy for tinnitus retraining therapy (TRT) and to evaluate the efficacy of TRT performed by using a portable music player (PMP) with recorded environmental sounds as the sound generator. Acoustic analysis of environmental sounds was performed using a sound analyzer. The subjects were 23 patients with chronic tinnitus. Patients who had bilateral hearing loss and required hearing assistance were fitted with hearing aids (HAs). Patients with normal hearing or unilateral hearing loss were fitted with a tinnitus control instrument (TCI) or a PMP. The patients were divided into the PMP group, TCI group, and HA group. All subjects underwent audiometric evaluations prior to TRT and completed the tinnitus handicap inventory (THI). The THI scores were evaluated before treatment and 1 month, 3 months, 6 months, and 12 months after treatment. The sound spectrogram of the murmur of a stream showed a wide-frequency band with a constant strength, whereas that of a wave sound showed a wide-frequency band with variable strength. The THI score clearly decreased after 1 month, and this decrease tended to continue over 12 months. The TRT efficacy ratios in the PMP group, TCI group, and HA group at 12 months after treatment were 71%, 67%, and 70%, respectively. TRT using a PMP had efficacy similar to those of TCI and HA. The murmur of a stream was one of the most effective sounds in TRT. TRT using a PMP as the sound generator can provide the most cost-effective treatment option for tinnitus patients.


The clinical activity of arsenic trioxide, ascorbic acid, ifosfamide and prednisone combination therapy in patients with relapsed and refractory multiple myeloma.
This study aimed to investigate the activity of arsenic trioxide (As2O3) combined with ascorbic acid, ifosfamide, and prednisone chemotherapy in patients with repeatedly relapsed and refractory multiple myeloma (MM). Here, we retrospectively analyzed medical data of 30 MM patients showing progressive disease after receiving at least two previous lines of treatment including an immunomodulatory agent (thalidomide or lenalidomide) and a proteasome inhibitor. There were 19 men and eleven women, aged 54-73 (median 65) years, in this study. The distribution of different isotypes included immunoglobulin G(IgG) (12 patients), IgA (six patients), IgD (three), and light chain (nine patients). All the patients were Durie-Salmon stage III and had relapsed at least three times; the median cycles of prior therapies was 15 (range 10-18). The patients were treated with As2O3, ascorbic acid, and CP (ifosfamide 1 g on day 1, day 3, day 5, and day 7; prednisone 30 mg taken orally for 2 weeks). As2O3 was administered as an intravenous infusion at a dose of 10 mg/d and ascorbic acid at a dose of 2 g/d for 14 days of each 4-week cycle. The results showed that after 2 cycles of therapy, there were five patients that attained partial response, 15 had minimal response, five had no change, and five had progressive disease. The overall response rate was 66.7% (20/30 cases), 50% (10/20 cases), and 40% (2/5 cases), respectively, after 2, 4, and 6 cycles of the therapy. But there were no patients that attained complete remission. The median time of overall survival and progression-free survival were 48 (29-120) and 6 (2-8) months, respectively. The most common treatment-related adverse events included neutropenia, fatigue, anemia, thrombocytopenia, and infection that could be tolerated. The results showed that As2O3 combined with ascorbic acid, ifosfamide, and prednisone chemotherapy may be a choice treatment for repeatedly relapsed and refractory MM patients.


'Generic' physical mechanisms of morphogenesis and pattern formation.
The role of 'generic' physical mechanisms in morphogenesis and pattern formation of tissues is considered. Generic mechanisms are defined as those physical processes that are broadly applicable to living and non-living systems, such as adhesion, surface tension and gravitational effects, viscosity, phase separation, convection and reaction-diffusion coupling. They are contrasted with 'genetic' mechanisms, a term reserved for highly evolved, machine-like, biomolecular processes. Generic mechanisms acting upon living tissues are capable of giving rise to morphogenetic rearrangements of cytoplasmic, tissue and extracellular matrix components, sometimes leading to 'microfingers', and to chemical waves or stripes. We suggest that many morphogenetic and patterning effects are the inevitable outcome of recognized physical properties of tissues, and that generic physical mechanisms that act on these properties are complementary to, and interdependent with genetic mechanisms. We also suggest that major morphological reorganizations in phylogenetic lineages may arise by the action of generic physical mechanisms on developing embryos. Subsequent evolution of genetic mechanisms could stabilize and refine developmental outcomes originally guided by generic effects.


Analysis of maternal-offspring HLA compatibility, parent-of-origin effects, and noninherited maternal antigen effects for HLA-DRB1 in systemic lupus erythematosus.
Genetic susceptibility to systemic lupus erythematosus (SLE) is well established, with the HLA class II DRB1 and DQB1 loci demonstrating the strongest association. However, HLA may also influence SLE through novel biologic mechanisms in addition to genetic transmission of risk alleles. Evidence for increased maternal-offspring HLA class II compatibility in SLE and differences in maternal versus paternal transmission rates (parent-of-origin effects) and nontransmission rates (noninherited maternal antigen [NIMA] effects) in other autoimmune diseases have been reported. Thus, we investigated maternal-offspring HLA compatibility, parent-of-origin effects, and NIMA effects at DRB1 in SLE. The cohort comprised 707 SLE families and 188 independent healthy maternal-offspring pairs (total of 2,497 individuals). Family-based association tests were conducted to compare transmitted versus nontransmitted alleles (transmission disequilibrium test) and both maternally versus paternally transmitted (parent-of-origin) and nontransmitted alleles (using the chi-square test of heterogeneity). Analyses were stratified according to the sex of the offspring. Maternally affected offspring DRB1 compatibility in SLE families was compared with paternally affected offspring compatibility and with independent control maternal-offspring pairs (using Fisher's test) and was restricted to male and nulligravid female offspring with SLE. As expected, DRB1 was associated with SLE (P < 1 x 10(-4)). However, mothers of children with SLE had similar transmission and nontransmission frequencies for DRB1 alleles when compared with fathers, including those for the known SLE risk alleles HLA-DRB1*0301, *1501, and *0801. No association between maternal-offspring compatibility and SLE was observed. Maternal-offspring HLA compatibility, parent-of-origin effects, and NIMA effects at DRB1 are unlikely to play a role in SLE.


Point of care computing and its relevance to the United States' health care reform movement.
Reform of the U.S. health care delivery system is underway. In a nation spending close to 14% of its gross national product on health care, more than any other nation, and with an estimated 40 million Americans left uninsured, it is likely that significant changes will occur as part of this era of reform [1]. Innovative and judicious technology applications will serve as enablers as the U.S. seeks to provide universal access to health care services while controlling costs. The ability to access, collate, and interpret information at the point of care is essential to the basic restructuring of health care service delivery. This paper will present changes occurring within the U.S. health care industry and describe how information technology can be applied to reshaping the health care delivery system to optimize services at the point of care.


Influence of substrate on ultrafast water transport property of multilayer graphene coatings.
The ultrafast water transport in graphene nanoplatelets (GNPs) coating is attributed to the low friction passages formed by pristine graphene and the hydrophilic functional groups which provide a strong interaction force to the water molecules. Here, we examine the influence of the supporting substrate on the ultrafast water transport property of multilayer graphene coatings experimentally and by computational modelling. Thermally cured GNPs manifesting ultrafast water permeation are coated on different substrate materials, namely aluminium, copper, iron and glass. The physical and chemical structures of the GNPs coatings which are affected by the substrate materials are characterized using various spectroscopy techniques. Experimentally, the water permeation and absorption tests evidence the significant influence of the substrate on the rapid water permeation property of GNPs-coating. The water transport rates of the GNPs coatings correspond to the wettability and the free surface energy of their substrates where the most hydrophilic substrate induces the highest water transport rate. In addition, we conduct molecular dynamics (MD) simulations to investigate the transport rate of water molecules through multilayer GNPs adjacent to different substrate materials. The MD simulations results agree well with the experimental results inferring the strong influence of the substrate materials on the fast water transport of GNPs. Therefore, selection of substrate has to be taken into consideration when the GNPs-coating is placed into applications.


A morphometric study on the humerus for intramedullary fixation.
In recent years, the popularity of intramedullary humeral nailing is on the rise in spite of its handicaps. There are many problems in intramedullary humeral stabilization because of the anatomic structure of the bone. We performed various methods and measurements to determine shape, length and diameter and curvature of the medullary canal of the humerus in 57 human dry cadaver bones. Anterior angulation with an average of 21 cm apart from greater tubercle was found at 1/3 distal part. Mean degree of angulation was 9 degrees (max: 15, minutes: 5, S.D.: 2.84). Humerus bones with septal aperture (supratrochlear foramen) at the fossa coronoidea were observed to have very narrow medullary canal. The best point for nail insertion was found to be an area on the line from greater tubercle anteromedially to caput humeri. This study revealed that carefully evaluated structure of humeral medullary canal and various congenital constructions such as septal aperture, and correct selection of a nail with proper length and diameter are essential for successful nailing.


A Lys-Trp cation-π interaction mediates the dimerization and function of the chloride intracellular channel protein 1 transmembrane domain.
Chloride intracellular channel protein 1 (CLIC1) is a dual-state protein that can exist either as a soluble monomer or in an integral membrane form. The oligomerization of the transmembrane domain (TMD) remains speculative despite it being implicated in pore formation. The extent to which electrostatic and van der Waals interactions drive folding and association of the dimorphic TMD is unknown and is complicated by the requirement of interactions favorable in both aqueous and membrane environments. Here we report a putative Lys37-Trp35 cation-π interaction and show that it stabilizes the dimeric form of the CLIC1 TMD in membranes. A synthetic 30-mer peptide comprising a K37M TMD mutant was examined in 2,2,2-trifluoroethanol, sodium dodecyl sulfate micelles, and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine liposomes using far-ultraviolet (UV) circular dichroism, fluorescence, and UV absorbance spectroscopy. Our data suggest that Lys37 is not implicated in the folding, stability, or membrane insertion of the TMD peptide. However, removal of this residue impairs the formation of dimers and higher-order oligomers. This is accompanied by a 30-fold loss of chloride influx activity, suggesting that dimerization modulates the rate of chloride conductance. We propose that, within membranes, individual TMD helices associate via a Lys37-mediated cation-π interaction to form active dimers. The latter findings are also supported by results of modeling a putative TMD dimer conformation in which Lys37 and Trp35 form cation-π pairs at the dimer interface. Dimeric helix bundles may then associate to form fully active ion channels. Thus, within a membrane-like environment, aromatic interactions involving a polar lysine side chain provide a thermodynamic driving force for helix-helix association.


Tunneling nanotubes: The intercellular conduits contributing to cancer pathogenesis and its therapy.
Tunneling nanotubes (TNTs) are intercellular conduits which meet the communication needs of non-adjacent cells situated in the same tissue but at distances up to a few hundred microns. TNTs are unique type of membrane protrusion which contain F-actin and freely hover over substratum in the extracellular space to connect the distant cells. TNTs, known to form through actin remodeling mechanisms, are intercellular bridges that connect cytoplasm of two cells, and facilitate the transfer of organelles, molecules, and pathogens among the cells. In tumor microenvironment, TNTs act as communication channel among cancer, normal, and immune cells to facilitate the transfer of calcium waves, mitochondria, lysosomes, and proteins, which in turn contribute to the survival, metastasis, and chemo-resistance in cancer cells. Recently, TNTs were shown to mediate the transfer of nanoparticles, drugs, and viruses between cells, suggesting that TNTs could be exploited as a potential route for delivery of anti-cancer agents and oncolytic viruses to the target cells. The present review discusses the emerging concepts and role of TNTs in the context of chemo- and radio-resistance with implications in the cancer therapy.


Physical activity in a pandemic: A new treatment target for psychological therapy.
The COVID-19 pandemic and its management are placing significant new strains on people's well-being, particularly those with pre-existing mental health conditions. Physical activity has been shown to improve mental as well as physical health. Increasing activity levels should be prioritized as a treatment target, especially when the barriers to exercise are greater than ever. Promoting physical activity has not traditionally been the remit of psychologists. Yet psychological theory and therapeutic techniques can be readily applied to address physical inactivity. We present theoretical perspectives and therapy techniques relating to (1) beliefs about physical activity, (2) motivation to be physically active, and (3) the sense of reward achieved through being physically active. We outline strategies to initiate and maintain physical activity during the COVID-19 pandemic, thereby benefitting mental and physical health. COVID-19 is demanding rapid and substantial change across the whole health care system. Psychological therapists can respond creatively by addressing physical activity, a treatable clinical target which delivers both mental and physical health benefits. PRACTITIONER POINTS: Physical activity is essential for our mental and physical health. Yet COVID-19 presents novel barriers to physical activity. Psychological theory and techniques to address beliefs, motivation, and reward can be applied to increase physical activity during COVID-19. Physical activity is an important clinical target to sustain and improve mental health, especially in the current pandemic.


Pancreatic Collision Tumor of Desmoid-Type Fibromatosis and Mucinous Cystic Neoplasm: A Case Report.
Pancreatic collision tumors are rare neoplasm, and cases consisting of ductal adenocarcinoma with a neuroendocrine tumor, intraductal papillary mucinous neoplasm with a neuroendocrine tumor, and solid pseudopapillary neoplasm with a neuroendocrine tumor have been reported. We report a case of a rapidly growing pancreatic collision tumor consisting of desmoidtype fibromatosis and mucinous cystic neoplasm in a 30-year-old pregnant female. To the best of our knowledge, this is the first reported case of a pancreatic collision tumor consisting of desmoid-type fibromatosis and mucinous cystic neoplasm.


A fully Bayesian latent variable model for integrative clustering analysis of multi-type omics data.
Identification of clinically relevant tumor subtypes and omics signatures is an important task in cancer translational research for precision medicine. Large-scale genomic profiling studies such as The Cancer Genome Atlas (TCGA) Research Network have generated vast amounts of genomic, transcriptomic, epigenomic, and proteomic data. While these studies have provided great resources for researchers to discover clinically relevant tumor subtypes and driver molecular alterations, there are few computationally efficient methods and tools for integrative clustering analysis of these multi-type omics data. Therefore, the aim of this article is to develop a fully Bayesian latent variable method (called iClusterBayes) that can jointly model omics data of continuous and discrete data types for identification of tumor subtypes and relevant omics features. Specifically, the proposed method uses a few latent variables to capture the inherent structure of multiple omics data sets to achieve joint dimension reduction. As a result, the tumor samples can be clustered in the latent variable space and relevant omics features that drive the sample clustering are identified through Bayesian variable selection. This method significantly improve on the existing integrative clustering method iClusterPlus in terms of statistical inference and computational speed. By analyzing TCGA and simulated data sets, we demonstrate the excellent performance of the proposed method in revealing clinically meaningful tumor subtypes and driver omics features.


Defining routine fatigue care in Multiple Sclerosis in the United Kingdom: What treatments are offered and who gets them?
Fatigue is common and disabling in Multiple Sclerosis (MS). A recent meta-analytic systematic review reported 113 trials of exercise and behavioural interventions for fatigue, yet patients consistently describe fatigue being under-treated. The extent of the research-to-practice gap is yet to be documented. To describe what fatigue treatments people with MS (pwMS) in the United Kingdom (UK) have been offered. A cross-sectional survey of pwMS on the UK MS Register (UKMSR). Data on fatigue treatments offered were collected using an online questionnaire developed with patient input and summarised using descriptive statistics. Sociodemographic, MS-related, and psychological factors associated with treatment offered were evaluated using a logistic regression model. 4,367 respondents completed the survey, 90.3% reported experiencing fatigue. Of these, 30.8% reported having been offered at least one type of pharmacological/non-pharmacological treatment for fatigue. Pharmacological treatments were more commonly offered (22.4%) compared to non-pharmacological treatments (12.6%; 2.9% exercise and 5.9% behavioural therapy). In the logistic regression model, older age, working, shorter time since MS diagnosis, and lower fatigue were associated with lower odds of having been offered treatment for fatigue. This study accentuates the extent of the unmet need for fatigue treatment in MS in the UK.


Effects of Intergenerational Social Support Exchange and Self-efficacy on Level of Depression among Elderly Women.
This study was to examine the effects of intergenerational social support exchange (providing social support, receiving social support) and self-efficacy on the level of depression among elderly women. A cross-sectional survey design was used. The participants were 247 elderly women, over 60, living in Seoul. Data were collected by convenience sampling using self-reported questionnaires that consisted of items on general characteristics, depression, intergenerational social support exchange and self-efficacy. Data were analyzed with descriptive statistics, t-test, ANOVA, correlation, and multiple regression. Self-efficacy had the greatest impact on the level of depression among elderly women, followed by perceived health status and providing social support toward adult children. The model explained 39% of the variance. Results of the study suggest that as a way to prevent depression, the health administration needs to develop programs to enhance self-efficacy and to promote the supportive role of elderly women within the family.


Antibiotics to Prevent Relapse of Adjustable Gastric Balloon Hyperinflation: Feasible for Balloon Maintenance?
The placement of an intragastric balloon (IGB) plays an increasingly important role in the treatment of obesity. The authors describe the cases of 2 female patients, 34 and 62 years old, who were submitted to the implantation of a Spatz3® IGB to treat obesity. Ten to fourteen weeks later, the patients presented complaints of epigastric pain, vomiting, and abdominal distension. A bulging of the upper abdominal wall was noticed upon physical examination. Upper gastrointestinal endoscopy confirmed the clinical suspicion of IGB hyperinflation. It was decided to remove the 500 mL of saline solution with methylene blue from inside the balloon. During the same procedure, the IGB was refilled with 500 mL of fresh saline solution, methylene blue, and empiric β-lactam antibiotic. The extracted content of the hyperinflated IGB was sent for microbiological culturing and was found to be positive for Streptococcus viridans in one of the cases. In the other case, the culture examination was negative, and after 8 weeks, the patient presented again with hyperinflation of the IGB. It was then decided to substitute the IGB with another balloon; the procedure was uneventful. The content of the removed IGB was sent for microbiological testing, and colonization by Candida tropicaliswas confirmed. This is a rare but potentially serious complication of IGB placement. Randomized trials are needed to clarify the role of antibiotics and antifungals in primary and secondary prophylaxis against IGB hyperinflation.


PRMT5 as a druggable target for glioblastoma therapy.
In spite of standard multimodal therapy consisting of surgical resection followed by radiation and concurrent chemotherapy, prognosis for glioblastoma (GBM) patients remains poor. The identification of both differentiated and undifferentiated "stem cell like" populations in the tumor highlights the significance of finding novel targets that affect the heterogeneous tumor cell population. Protein arginine methyltransferase 5 (PRMT5) is one such candidate gene whose nuclear expression correlates with poor survival and has been reported to be required for survival of differentiated GBM cells and self-renewal of undifferentiated GBM cells. In the current study we screened the specificity and efficacy of 4 novel PRMT5 inhibitors in the treatment of GBM. Efficacies of these inhibitors were screened using an in vitro GBM neurosphere model and an in vivo intracranial zebrafish model of glioma. Standard molecular biology methods were employed to investigate changes in cell cycle, growth, and senescence. In vitro and in vivo studies revealed that among the 4 PRMT5 inhibitors, treatment of GBM cells with compound 5 (CMP5) mirrored the effects of PRMT5 knockdown wherein it led to apoptosis of differentiated GBM cells and drove undifferentiated primary patient derived GBM cells into a nonreplicative senescent state. In vivo antitumor efficacy combined with the specificity of CMP5 underscores the importance of developing it for translation.


[Occult Thyroid Cancer Diagnosed by Metastasis to an Upper Mediastinal Lymph Node Removed during Surgery for Primary Lung Cancer].
A computed tomography (CT) scan revealed 2 nodules in the right upper and middle lobes of the lung and swelling of an upper mediastinal lymph node (#2R) in a 77-year-old male. Positron emission tomography (PET)/CT showed abnormal uptake only in the right middle lobe nodule, so we suspected a double primary lung cancer (cT1bN0M0, stage ⅠA), and performed a right upper and middle lobectomy with ND2a-2 dissection. Pathological investigation revealed that the lung nodules were adenocarcinomas and the lymph node swelling #2R was a metastasis of thyroid cancer. After surgery, careful examination was done for thyroid but the primary lesion was not found. Careful observation for an occult thyroid cancer is continuing at the outpatient.


Determinants of resistance to antifolates: biochemical phenotypes, their frequency of occurrence and circumvention.
Biochemical alterations associated with acquired resistance of tumor cells to antifolates are diverse and multiple in number. These most often have included both quantitative and qualitative alterations at the level of membrane transport and of the primary intracellular target, dihydrofolate reductase (DHFR). More recent studies suggest determining biochemical alterations at the level of thymidylate synthase activity and 4-aminofolate polyglutamylation. Approaches to the circumvention of acquired antifolate resistance at the level of new drug design are described which incorporate a kinetic analysis of the various biochemical phenotypes and a systematic analysis of their structure-activity relationships. A consideration of the relative frequency of occurrence of individual phenotypes during therapy is also included. This introduces the notion of population genetics in an evaluation of resistance phenomenon and of clinically significant approaches for its circumvention.


Microdeposits of amyloid in sclerocalcific heart valves: a histochemical and immunofluorescence study.
Amyloid associated with seven sclerotic and two normal aortic and mitral valves was studied. The sclerotic valve amyloid contained microfibrils with typical random orientation and a fibril width of 9.5-12.5 nm. The amyloid deposits demonstrated permanganate-resistant Congophilia and contained the amino acid tryptophan. Immunofluorescence studies showed P-component in amyloid deposits of 6 of 7 valves, but none of the sclerotic valves contained amyloid fibril proteins of the AL (primary), AA (secondary), AEt (medullary thyroid carcinoma) or ASc1 (senile cardiac) types. Two non-sclerotic valves, removed from a patient with systemic amyloidosis, showed permanganate-sensitive Congophilic amyloid deposits which contained amyloid fibril protein AA.


[A new test for hemolysis related to tocopherol deficiency: hemolysis caused by sodium azide (NaN3). Results in cholestasis in children].
In patients suffering from intra or extrahepatic biliary obstruction defective absorption of liposoluble vitamins results in tocopherol deficiency. Erythrocyte membranes thus have an increased susceptibility to various oxydants. Erythrocytes from 28 infants and children with biliary atresia have been studied. The usual peroxide hemolysis test (H2O2) was compared with a new method using sodium azide (NaN3), an inhibitor of intraerythrocytic catalase, as the hemolyzing agent. A much more significant correlation was found between plasma tocopherol levels and NaN3--induced hemolysis (R. coefficient = -0.872; P = 99.9%) than tocopherol levels and peroxyde hemolysis (RC = -0.477; P = 95-99%). In severely tocopherol-deficient patients (plasma levels below 0.15 mg/dl compared to normal of 0.5 mg/dl) sodium azide hemolysis is completed by the 5th hour of incubation at 37 degrees C. After the 5th hour, hemolysis begin to appear in the control media and when measured at 20 hrs is almost complete especially in the isotonic saline solution (NaCl 0.9 g/l). When abnormal red cells are incubated in their own tocopherol-supplemented plasma a complete normalization of hemolysis due to NaN3, H2O and control media is obtained. The sodium azide hemolysis test is proposed as a new and simple means of measuring tocopherol deficiency in erythrocyte membranes.


The prevalence of encoded digital trace evidence in the nonfile space of computer media(,) (.).
Forensically significant digital trace evidence that is frequently present in sectors of digital media not associated with allocated or deleted files. Modern digital forensic tools generally do not decompress such data unless a specific file with a recognized file type is first identified, potentially resulting in missed evidence. Email addresses are encoded differently for different file formats. As a result, trace evidence can be categorized as Plain in File (PF), Encoded in File (EF), Plain Not in File (PNF), or Encoded Not in File (ENF). The tool bulk_extractor finds all of these formats, but other forensic tools do not. A study of 961 storage devices purchased on the secondary market and shows that 474 contained encoded email addresses that were not in files (ENF). Different encoding formats are the result of different application programs that processed different kinds of digital trace evidence. Specific encoding formats explored include BASE64, GZIP, PDF, HIBER, and ZIP.


Nongenotoxic antibody-drug conjugate conditioning enables safe and effective platelet gene therapy of hemophilia A mice.
Gene therapy offers the potential to cure hemophilia A (HA). We have shown that hematopoietic stem cell (HSC)-based platelet-specific factor VIII (FVIII) (2bF8) gene therapy can produce therapeutic protein and induce antigen-specific immune tolerance in HA mice, even in the presence of inhibitory antibodies. For HSC-based gene therapy, traditional preconditioning using cytotoxic chemotherapy or total body irradiation (TBI) has been required. The potential toxicity associated with TBI or chemotherapy is a deterrent that may prevent patients with HA, a nonmalignant disease, from agreeing to such a protocol. Here, we describe targeted nongenotoxic preconditioning for 2bF8 gene therapy utilizing a hematopoietic cell-specific antibody-drug conjugate (ADC), which consists of saporin conjugated to CD45.2- and CD117-targeting antibodies. We found that a combination of CD45.2- and CD117-targeting ADC preconditioning was effective for engrafting 2bF8-transduced HSCs and was favorable for platelet lineage reconstitution. Two thirds of HA mice that received 2bF8 lentivirus-transduced HSCs under (CD45.2+CD117)-targeting ADC conditioning maintained sustained therapeutic levels of platelet FVIII expression. When CD8-targeting ADC was supplemented, chimerism and platelet FVIII expression were significantly increased, with long-term sustained platelet FVIII expression in all primary and secondary recipients. Importantly, immune tolerance was induced and hemostasis was restored in a tail-bleeding test, and joint bleeding also was effectively prevented in a needle-induced knee joint injury model in HA mice after 2bF8 gene therapy. In summary, we show for the first time efficient engraftment of gene-modified HSCs without genotoxic conditioning. The combined cocktail ADC-mediated hematopoietic cell-targeted nongenotoxic preconditioning that we developed is highly effective and favorable for platelet-specific gene therapy in HA mice.


Dihydrotestosterone and bicalutamide do not affect periostin expression in androgen-dependent LNCaP prostate cancer cell lines.
To investigate periostin (POSTN) expression in the LNCaP cell line. Our LNCaP strain did not constitutively express the POSTN gene. Through cell transfection with a cloning vector, we developed an LNCaP cell line that stably expressed POSTN. LNCaP wild-type and transfected cells were incubated with dihydrotestosterone (DHT) in the presence/or absence of bicalutamide (BIC). POSTN mRNA was detected by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) and growth was measured with the MTT assay. POSTN transfection stimulated LNCaP cell growth. While POSTN transfection did not interfere with the stimulatory effect of DHT, BIC had an inhibitory effect on cell proliferation. However, exposure to either DHT and/or BIC was not able to interfere with POSTN expression per se. We confirmed the role of POSTN in promoting cancer cell growth. Although POSTN transcription is not likely to be androgen-dependent, the fact that increased cell proliferation POSTN-mediated was impaired by BIC suggests an androgen modulation of POSTN interaction proteins.


Comparison of four murine Eimeria species in immunocompetent and immunodeficient mice.
Factors associated with immune-mediated protection against coccidial parasites were examined in a series of experiments utilizing immunocompromised scid/scid(SCID) and scid/scid.beige/beige(SCID/Bg) mice, as well as immunocompetent BALB/c mice. Number of oocysts produced per g feces each day and prepatent and patent periods were assessed for 4 eimerian parasites (Eimeria papillata, Eimeria vermiformis, Eimeria falciformis, and Eimeria ferrisi) using the 3 murine strains. The number of infections required to elicit a protective immune response was also determined for each coccidial species in BALB/c mice. We report the first description of patent infections in inbred immunocompetent and immunodeficient mice infected with E. papillata. Results indicate that during primary infections, parasite replication is under partial immunological control for all Eimeria species. However, the control is mechanistically different for E. papillata because the adaptive immune response does not contribute to the control of primary infections. Both coccidial species infecting intestinal villar epithelial cells (E. papillata and E. ferrisi) were affected by the beige mutation using parasite output as an indicator, whereas E. falciformis, which infects intestinal crypt cells, is not. BALB/c mice were more resistant to challenge infections with upper intestinal parasites (E. papillata and E. vermiformis) in comparison to challenge infections with lower intestinal and cecal parasites (E. falciformis and E. ferrisi).


Requirement of a Tha4-conserved transmembrane glutamate in thylakoid Tat translocase assembly revealed by biochemical complementation.
The thylakoid Tat system employs three membrane components and the pH gradient to transport folded proteins. The translocase is signal-assembled, i.e. a receptor complex containing cpTatC and Hcf106 binds the precursor protein, and upon membrane energization, Tha4 is recruited to the precursor-receptor complex to effect translocation. We developed a two-step complementation assay to examine the implied central role of Tha4 in translocation. The first step results in the inactivation of endogenous Tha4 with specific antibodies. The second step involves integrating exogenous Tha4 and presenting the system with precursor protein. We verified this approach by confirming the results obtained recently with the Escherichia coli Tha4 ortholog TatA, i.e. that the carboxyl terminus is dispensable and the amphipathic helix essential for transport. We then investigated a conserved Tha4 transmembrane glutamate in detail. Substitution of glutamate 10 with alanine, glutamine, and even aspartate largely eliminated the ability of Tha4 to complement transport, whereas a conservative substitution elsewhere in the transmembrane domain was without effect. Chemical cross-linking assays showed that the mutated Tha4s failed to be recruited to the receptor complex under transport conditions, indicating a role for the transmembrane glutamate in translocase assembly. This assay promises an avenue into understanding the role of Tha4 in both the assembly and translocation steps of the Tat translocase.


Effects of hyaluronic acid on bleeding following third molar extraction.
To explore the effects of hyaluronic acid (HA) on bleeding and associated outcomes after third molar extraction. Forty patients who had undergone molar extraction were randomly divided into two groups; 0.8% (w/v) HA was applied to the HA group (n=20) whereas a control group (n=20) was not treated. Salivary and gingival tissue factor (TF) levels, bleeding time, maximum interincisal opening (MIO), pain scored on a visual analog scale (VAS), and the swelling extent were compared between the two groups. HA did not significantly affect gingival TF levels. Salivary TF levels increased significantly 1 week after HA application but not in the control group. Neither the VAS pain level nor MIO differed significantly between the two groups. The swelling extent on day 3 and the bleeding time were greater in the HA group than in the control group. Local injection of HA at 0.8% prolonged the bleeding time, and increased hemorrhage and swelling in the early postoperative period after third molar extractions.


[Characteristics of the carcinogenic action of methyl(acetoxymethyl)nitrosamine and DNA repair in rats of different ages].
A pattern of DNA methylation and carcinogenesis has been studied in young (3 month-old) and old (14 month-old) female rats following a single intravenous injection (13 mg/kg) of methyl(acetoxymethyl)nitrosamine (DMN-OAc). The incidence of various tumours as well as the incidence of tumours in some peculiar sites were found to be similar in young and old DMN-OAc-treated rats. The life time of old rats was less than that in young animals; the average period of tumour detection was also shorter in old rats. In both young and old animals the highest concentrations of methylated purines were found in lung and kidney DNA. However, the level of DNA methylation in old rats was higher than in corresponding tissues of young animals. Efficiency of O6-meG repair in methylated template DNA was found to be the highest in liver extracts of 1- and 12-month-old rats. Further, by the age of 2 years, the activity of O6-meGT decreased. The findings suggest that different age periods could be characterized by different efficiency of DNA alkylation, synthesis and repair.


Changes in Children's Oral Health Related Quality of Life Following Dental Treatment under General Anesthesia.
Children's oral health related quality of life (OHRQoL) evaluates the impacts of oral daily activities of children and family on quality of life. Oral health related quality of life as outcome can be used to evaluate the dental health services. This study aimed to assess the extent to which dental treatment under general anesthesia affects quality of life of children and their families. One hundred parents of 3-10 year-old children who needed dental treatment under general anesthesia completed a parent-children perception questionnaire (P-CPQ) and family impact scale (FIS) before, and 4 weeks after dental treatment under general anesthesia. The questionnaire had statements related to oral health, functional limitation, emotional state and well being social well-being and family issues. Data were analyzed using SPSS version 11.5. The mean scores and standard deviations of oral health quality of life of the children before and after dental treatment were 43.3 ± 7.14 and 39.24 ± 5.47 respectively. The mean scores of FIS before and after dental treatment were 8.00 ± 3.21 and 3.66 ± 2.62, respectively. The effect size of mean differences in P-CPQ and FIS scores were 1.84 ± 1.64 and 1.35 ± 4.34, respectively. Provision of dental treatment under general anesthesia for uncooperative, young children with extensive dental problems had significant effects on quality of life of both children and their families.


[Halitosis: a multidisciplinary problem].
Bad breath, or halitosis, affects between 50 and 65% of the population. Despite its frequency, this problem is often unaccepted and declared taboo. In about 8% of the cases, bad breath is related to an ENT pathology (sinusitis, tonsillitis, ...). More rarely it is caused by a metabolic (diabetes, trimethylaminuremia, ...) or gastric dysfunction. Ninety percent of the cases however, are associated to an oral disease: either gingivitis due to an inadequate removal of dental plaque, especially from interdental spaces, or periodontitis (alveolar bone destruction), or bacterial accumulation on the dorsum of the tongue. In most cases, an intensive disinfection of the mouth by scaling and root planing and/or instruction of a perfect oral hygiene will be sufficient to solve the problem. Perfumed mouthwashes or toothpastes will only give a short-term masking effect. An effective collaboration between a dentist or a periodontist and an ENT specialist is of great importance to dealt with bad breath.


Stages of change for adherence to antiretroviral medications.
Providers do not predict reliably which of their HIV-positive patients are having difficulty adhering to antiretroviral therapy (ART). The transtheoretical, or stages of change model, may be a useful tool to help providers identify patients who are having difficulty with ART adherence. The objective of the current study was to determine the relationship between stages of change and ART adherence among patients who were actively taking ART. Data from a randomized trial of a provider-focused intervention were used to examine the relationship between the stages of change and adherence, measured using electronic monitoring devices in the 30 days following the stages of change assessment. Individuals were eligible for inclusion if they were taking ART and had detectable plasma viral load (HIV-RNA). Repeated measures analysis of covariance was used to determine the impact of stages of change on adherence after controlling for potential confounders. The sample of 137 participants was 22% female, 48% white, 28% African-American, with a mean age of 42 years. Fifty-eight percent reported sex with a man as an HIV risk factor, while 13% reported sex with a woman, 14% reported injecting drugs and 15% reported other risk factors. In adjusted models, those in earlier stages of change (i.e., contemplation and preparation) had significantly lower adherence (-9.8%, p=0.04) compared to those in the action and maintenance phases. No demographic characteristics predicted adherence. The stages of change model may function as a screening tool for clinicians to discover patients at-risk of lower adherence.


Short-term antidepressant administration reduces default mode and task-positive network connectivity in healthy individuals during rest.
Resting-state studies in depressed patients have revealed increased connectivity within the default mode network (DMN) and task-positive network (TPN). This has been associated with heightened rumination, which is the tendency to repetitively think about symptoms of distress. Here, we performed a pharmacological neuroimaging study in healthy volunteers to investigate whether short-term antidepressant administration could reduce DMN connectivity. We recorded resting-state functional magnetic resonance imaging (fMRI) scans in twenty-three healthy volunteers after two week intake of the combined serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine in a double-blind, placebo-controlled, crossover study. Duloxetine improved mood in part as a result of increased resilience to the mood-worsening effects of scanning and reduced DMN and TPN connectivity. Within the DMN, duloxetine reduced connectivity between the medial prefrontal cortex (MPFC) and the lateral parietal cortex (LPC) and uncoupled the MPFC from the dorsolateral prefrontal cortex (DLPFC). Within the TPN, duloxetine uncoupled the intraparietal sulcus (IPS) from the inferior occipital gyrus. These results show that two-week antidepressant administration reduces DMN and TPN connectivity in healthy volunteers, which may contribute to their antidepressant effects in depression.


Retroperitoneoscopic live-donor right nephrectomy: a Chinese single center.
To evaluate our right-retro- peritoneoscopic live-donor nephrectomy by comparing the left side with the right side, and reporting our single-center experience for rightretroperitoneoscopic live-donor nephrectomy. In China, live-kidney transplant is limited. It is even more essential now, because the deceased-donor kidney has become fewer after enacting the Chinese Regulation on Human Organ Transplantation. Therefore, there is a continued need to use the limited live-donor population. We chose 103 consecutive cases (84 left and 19 right) that underwent retroperitoneoscopic live-donor nephrectomy between December 2005 and December 2009, to compare the intraoperative and postoperative characteristics between the left and right sides, and report our experiences for 19 right-retroperitoneoscopic live-donor nephrectomies. All 84 left and 19 right-retro peritoneoscopic live-donor nephrectomies were accomplished successfully without open conversion and transfusion. No significant differences were observed between the 2 groups regarding operative time, warm ischemia time, estimated blood loss, length of hospital stay, and serum creatinine level at discharge (Table 1). Eight of the donors and 3 of the grafts had minor complications that were all resolved with conservative treatment. The recipient's serum creatinine levels at 1 day and 1 month after surgery were the same in both groups. No acute renal tubule necrosis or delayed graft function was observed in the recipients. Our right-retroperitoneoscopic live-donor nephrectomy achieves comparable outcomes with the left side and proves to be a feasible, cost-effective, safe, and minimally invasive alternative for live-kidney donation. This maximally uses the innately limited donors and potentially increases the donor pool in China.


Creating a pipeline of talent for informatics: STEM initiative for high school students in computer science, biology, and biomedical informatics.
This editorial provides insights into how informatics can attract highly trained students by involving them in science, technology, engineering, and math (STEM) training at the high school level and continuing to provide mentorship and research opportunities through the formative years of their education. Our central premise is that the trajectory necessary to be expert in the emergent fields in front of them requires acceleration at an early time point. Both pathology (and biomedical) informatics are new disciplines which would benefit from involvement by students at an early stage of their education. In 2009, Michael T Lotze MD, Kirsten Livesey (then a medical student, now a medical resident at University of Pittsburgh Medical Center (UPMC)), Richard Hersheberger, PhD (Currently, Dean at Roswell Park), and Megan Seippel, MS (the administrator) launched the University of Pittsburgh Cancer Institute (UPCI) Summer Academy to bring high school students for an 8 week summer academy focused on Cancer Biology. Initially, pathology and biomedical informatics were involved only in the classroom component of the UPCI Summer Academy. In 2011, due to popular interest, an informatics track called Computer Science, Biology and Biomedical Informatics (CoSBBI) was launched. CoSBBI currently acts as a feeder program for the undergraduate degree program in bioinformatics at the University of Pittsburgh, which is a joint degree offered by the Departments of Biology and Computer Science. We believe training in bioinformatics is the best foundation for students interested in future careers in pathology informatics or biomedical informatics. We describe our approach to the recruitment, training and research mentoring of high school students to create a pipeline of exceptionally well-trained applicants for both the disciplines of pathology informatics and biomedical informatics. We emphasize here how mentoring of high school students in pathology informatics and biomedical informatics will be critical to assuring their success as leaders in the era of big data and personalized medicine.


Fine structural localization of a blood-brain barrier to exogenous peroxidase.
Horseradish peroxidase was administered to mice by intravenous injection, and its distribution in cerebral cortex studied with a recently available technique for localizing peroxidase with the electron microscope. Brains were fixed by either immersion or vascular perfusion 10-60 min after administration of various doses of peroxidase. Exogenous peroxidase was localized in the lumina of blood vessels and in some micropinocytotic vesicles within endothelial cells; none was found beyond the vascular endothelium. Micropinocytotic vesicles were few in number and did not appear to transport peroxidase while tight junctions between endothelial cells were probably responsible for preventing its intercellular passage. Our findings therefore localize, at a fine structural level, a "barrier" to the passage of peroxidase at the endothelium of vessels in the cerebral cortex. The significance of these findings is discussed, particularly with reference to a recent study in which similar techniques were applied to capillaries in heart and skeletal muscle.


Patterns of neighborhood environment attributes related to physical activity across 11 countries: a latent class analysis.
Neighborhood environment studies of physical activity (PA) have been mainly single-country focused. The International Prevalence Study (IPS) presented a rare opportunity to examine neighborhood features across countries. The purpose of this analysis was to: 1) detect international neighborhood typologies based on participants' response patterns to an environment survey and 2) to estimate associations between neighborhood environment patterns and PA. A Latent Class Analysis (LCA) was conducted on pooled IPS adults (N=11,541) aged 18 to 64 years old (mean=37.5±12.8 yrs; 55.6% women) from 11 countries including Belgium, Brazil, Canada, Colombia, Hong Kong, Japan, Lithuania, New Zealand, Norway, Sweden, and the U.S. This subset used the Physical Activity Neighborhood Environment Survey (PANES) that briefly assessed 7 attributes within 10-15 minutes walk of participants' residences, including residential density, access to shops/services, recreational facilities, public transit facilities, presence of sidewalks and bike paths, and personal safety. LCA derived meaningful subgroups from participants' response patterns to PANES items, and participants were assigned to neighborhood types. The validated short-form International Physical Activity Questionnaire (IPAQ) measured likelihood of meeting the 150 minutes/week PA guideline. To validate derived classes, meeting the guideline either by walking or total PA was regressed on neighborhood types using a weighted generalized linear regression model, adjusting for gender, age and country. A 5-subgroup solution fitted the dataset and was interpretable. Neighborhood types were labeled, "Overall Activity Supportive (52% of sample)", "High Walkable and Unsafe with Few Recreation Facilities (16%)", "Safe with Active Transport Facilities (12%)", "Transit and Shops Dense with Few Amenities (15%)", and "Safe but Activity Unsupportive (5%)". Country representation differed by type (e.g., U.S. disproportionally represented "Safe but Activity Unsupportive"). Compared to the Safe but Activity Unsupportive, two types showed greater odds of meeting PA guideline for walking outcome (High Walkable and Unsafe with Few Recreation Facilities, OR=2.26 (95% CI 1.18-4.31); Overall Activity Supportive, OR=1.90 (95% CI 1.13-3.21). Significant but smaller odds ratios were also found for total PA. Meaningful neighborhood patterns generalized across countries and explained practical differences in PA. These observational results support WHO/UN recommendations for programs and policies targeted to improve features of the neighborhood environment for PA.


Composites of Platinum-Iridium Alloy Nanoparticles and Graphene Oxide for the Dimethyl Amine Borane (DMAB) dehydrogenation at ambient conditions: An Experimental and Density Functional Theory Study.
In this paper, we present the synthesis, characterization, catalytic and computational studies of Composites of Platinum-Iridium Alloy Nanoparticles and Graphene Oxide (PtIr@GO) for dimethylamine borane (DMAB) dehydrogenation. The prepared PtIr@GO nanocatalysts were synthesized using an ethanol super-hydride method, and the characterization procedures for PtIr@GO alloy nanoparticles were carried out by various advanced spectroscopic methods like X-ray Diffraction (XRD), X-ray photoelectron spectroscopy (XPS), Transmission Electron Microscopy(TEM) and high-resolution transmission electron microscopy (HRTEM). Additionally, catalytic activity, reusability, substrate concentration, and catalyst concentration experiments were performed for DMAB dehydrogenation catalyzed by PtIr@GO alloy nanomaterials. According to the results obtained in this study, PtIr@GO NPs catalyst was found to be active and reusable for the DMAB even at ambient conditions. Besides, DFT-B3LYP calculations have been utilized on PtIr@GO cluster to reveal the prepared catalyst activity. The calculated findings based on DFT was found to be a good agreement with experimental results.


Genetic variation in Pythium myriotylum based on SNP typing and development of a PCR-RFLP detection of isolates recovered from Pythium soft rot ginger.
Pythium myriotylum is responsible for severe losses in both capsicum and ginger crops in Australia under different regimes. Intraspecific genomic variation within the pathogen might explain the differences in aggressiveness and pathogenicity on diverse hosts. In this study, whole genome data of four P. myriotylum isolates recovered from three hosts and one Pythium zingiberis isolate were derived and analysed for sequence diversity based on single nucleotide polymorphisms (SNPs). A higher number of true and unique SNPs occurred in P. myriotylum isolates obtained from ginger with symptoms of Pythium soft rot (PSR) in Australia compared to other P. myriotylum isolates. Overall, SNPs were discovered more in the mitochondrial genome than those in the nuclear genome. Among the SNPs, a single substitution from the cytosine (C) to the thymine (T) in the partially sequenced CoxII gene of 14 representatives of PSR P. myriotylum isolates was within a restriction site of HinP1I enzyme which was used in the PCR-RFLP for detection and identification of the isolates without sequencing. The PCR-RFLP was also sensitive to detect PSR P. myriotylum strains from artificially infected ginger without the need for isolation for pure cultures. This is the first study of intraspecific variants of Pythium myriotylum isolates recovered from different hosts and origins based on single nucleotide polymorphism (SNP) genotyping of multiple genes. The SNPs discovered provide valuable makers for detection and identification of P. myriotylum strains initially isolated from Pythium soft rot (PSR) ginger by using PCR-RFLP of the CoxII locus. The PCR-RFLP was also sensitive to detect P. myriotylum directly from PSR ginger sampled from pot trials without the need of isolation for pure cultures.


Interplay between oxygen and Fe-S cluster biogenesis: insights from the Suf pathway.
Iron-sulfur (Fe-S) cluster metalloproteins conduct essential functions in nearly all contemporary forms of life. The nearly ubiquitous presence of Fe-S clusters and the fundamental requirement for Fe-S clusters in both aerobic and anaerobic Archaea, Bacteria, and Eukarya suggest that these clusters were likely integrated into central metabolic pathways early in the evolution of life prior to the widespread oxidation of Earth's atmosphere. Intriguingly, Fe-S cluster-dependent metabolism is sensitive to disruption by oxygen because of the decreased bioavailability of ferric iron as well as direct oxidation of sulfur trafficking intermediates and Fe-S clusters by reactive oxygen species. This fact, coupled with the ubiquity of Fe-S clusters in aerobic organisms, suggests that organisms evolved with mechanisms that facilitate the biogenesis and use of these essential cofactors in the presence of oxygen, which gradually began to accumulate around 2.5 billion years ago as oxygenic photosynthesis proliferated and reduced minerals that buffered against oxidation were depleted. This review highlights the most ancient of the Fe-S cluster biogenesis pathways, the Suf system, which likely was present in early anaerobic forms of life. Herein, we use the evolution of the Suf pathway to assess the relationships between the biochemical functions and physiological roles of Suf proteins, with an emphasis on the selective pressure of oxygen toxicity. Our analysis suggests that diversification into oxygen-containing environments disrupted iron and sulfur metabolism and was a main driving force in the acquisition of accessory Suf proteins (such as SufD, SufE, and SufS) by the core SufB-SufC scaffold complex. This analysis provides a new framework for the study of Fe-S cluster biogenesis pathways and Fe-S cluster-containing metalloenzymes and their complicated patterns of divergence in response to oxygen.


The Mitochondrial Contribution to Animal Performance, Adaptation, and Life-History Variation.
Animals display tremendous variation in their rates of growth, reproductive output, and longevity. While the physiological and molecular mechanisms that underlie this variation remain poorly understood, the performance of the mitochondrion has emerged as a key player. Mitochondria not only impact the performance of eukaryotes via their capacity to produce ATP, but they also play a role in producing heat and reactive oxygen species and function as a major signaling hub for the cell. The papers included in this special issue emerged from a symposium titled "Inside the Black Box: The Mitochondrial Basis of Life-history Variation and Animal Performance." Based on studies of diverse animal taxa, three distinct themes emerged from these papers. (1) When linking mitochondrial function to components of fitness, it is crucial that mitochondrial assays are performed in conditions as close as the intracellular conditions experienced by the mitochondria in vivo. (2) Functional plasticity allows mitochondria to retain their performance, as well as that of their host, over a range of exogenous conditions, and selection on mitochondrial and nuclear-derived proteins can optimize the match between the environment and the bioenergetic capacity of the mitochondrion. Finally, (3) studies of wild and wild-derived animals suggest that mitochondria play a central role in animal performance and life history strategy. Taken as a whole, we hope that these papers will foster discussion and inspire new hypotheses and innovations that will further our understanding of the mitochondrial processes that underlie variation in life history traits and animal performance.


Prasinons A and B: potent insecticides from Streptomyces prasinus.
Two metabolites which have high activity against sheep blowfly larvae (Lucilia sericata and L. cuprina) were found to be produced by Streptomyces prasinus NCIB 10719. These substances were isolated from culture filtrate by solvent extraction and chromatography and named prasinons A and B. Fermentation factors affecting the formation of these substances are described together with their physical, chemical, and biological properties.


Using Situs for the integration of multi-resolution structures.
Situs is a modular and widely used software package for the integration of biophysical data across the spatial resolution scales. It has been developed over the last decade with a focus on bridging the resolution gap between atomic structures, coarse-grained models, and volumetric data from low-resolution biophysical origins, such as electron microscopy, tomography, or small-angle scattering. Structural models can be created and refined with various flexible and rigid body docking strategies. The software consists of multiple, stand-alone programs for the format conversion, analysis, visualization, manipulation, and assembly of 3D data sets. The programs have been ported to numerous platforms in both serial and shared memory parallel architectures and can be combined in various ways for specific modeling applications. The modular design facilitates the updating of individual programs and the development of novel application workflows. This review provides an overview of the Situs package as it exists today with an emphasis on functionality and workflows supported by version 2.5. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12551-009-0026-3) contains supplementary material, which is available to authorized users.


Improving occupational health care for construction workers: a process evaluation.
To evaluate the process of a job-specific workers' health surveillance (WHS) in improving occupational health care for construction workers. From January to July 2012 were 899 bricklayers and supervisors invited for the job-specific WHS at three locations of one occupational health service throughout the Netherlands. The intervention aimed at detecting signs of work-related health problems, reduced work capacity and/or reduced work functioning. Measurements were obtained using a recruitment record and questionnaires at baseline and follow-up. The process evaluation included the following: reach (attendance rate), intervention dose delivered (provision of written recommendations and follow-up appointments), intervention dose received (intention to follow-up on advice directly after WHS and remembrance of advice three months later), and fidelity (protocol adherence). The workers scored their increase in knowledge from 0-10 with regard to health status and work ability, their satisfaction with the intervention and the perceived (future) effect of such an intervention. Program implementation was defined as the mean score of reach, fidelity, and intervention dose delivered and received. Reach was 9% (77 workers participated), fidelity was 67%, the intervention dose delivered was 92 and 63%, and the intervention dose received was 68 and 49%. The total programme implementation was 58%. The increases in knowledge regarding the health status and work ability of the workers after the WHS were graded as 7.0 and 5.9, respectively. The satisfaction of the workers with the entire intervention was graded as 7.5. The perceived (future) effects on health status were graded as 6.3, and the effects on work ability were graded with a 5.2. The economic recession affected the workers as well as the occupational health service that enacted the implementation. Programme implementation was acceptable. Low reach, limited protocol adherence and modest engagement of the workers with respect to the intervention were the most prominent aspects that influenced the intervention process. The increase in the workers' knowledge about their health status and work ability was substantial, and the workers' satisfaction with the intervention was good. The perceived effect of the advised preventive actions on health status was sufficient. Netherlands Trial Register: http://NTR3012.