Mapping the naloxone binding sites on the mu-opioid receptor using cell-based photocrosslinkers.
Naloxone is an alkaloid antagonist that acts as an antidote to opioids through the mu-opioid receptor (MOR), a G protein-coupled receptor. However, its binding site on the MOR remains unknown. To investigate the binding interfaces necessary for naloxone and MOR, available structural information was combined with a cell-based photocrosslinking approach. Computer prediction revealed that four binding sites on MOR were required for naloxone binding. In addition, in the photocrosslinking approach, an amber stop codon was used to replace the sense codon of the MOR at 266 selected individual positions, in order to introduce the photoreactive amino acid p-benzoyl-l-phenylalanine (BzF) into MOR to evaluate the results of the computer analysis. The BzF-incorporated MOR mutant genes were expressed in CHO cells, in which MOR retained the ability to interact with its ligands, such as morphine, and exhibited MOR-dependent activation of ERK signaling following morphine stimulation. Notably, after treatment with tritium-labeled naloxone and exposure to UV light, we observed naloxone crosslinking with BzF replacement at hydrophobic residues and some polar/uncharged residues in the computer-predicted sites 1 and 3, indicating that these two sites in the MOR interact with naloxone. In conclusion, these results indicate that MOR has two naloxone binding sites and that the hydrophobic and polar/uncharged residues within these sites are important for naloxone binding.


Depression in patients with chronic hepatitis B: an experience on individual solution- focused therapy.
Hepatitis B, as a chronic disorder that may be associated with several psychiatric disorders, such as depression, and decrease quality of life of affected patients. One of the most important consequences of psychiatric problems is reduced patient compliance with prolonged therapeutic regimens. Psychotherapy, such as solution- focused therapy, may help these patients to resolve psychiatric problems, increase quality of life and completion of therapeutic regimens. Solution-focused therapy is effective for patients when developing effective coping responses to the stressors associated with chronic diseases. In this study, the process and effects of solution-focused therapy on depression of 2 patients with chronic hepatitis B have been described. They received solution focused therapy for 5 sessions, each session 1 hour once a week. This technique was helpful to decrease symptoms and signs of depression within 5 weeks.


Creeping attachment after 10 years of treatment of a gingival recession with acellular dermal matrix: a case report.
Acellular dermal matrix grafts have become a good alternative to autogenous soft tissue grafts in root coverage. Until now, the literature has reported short- or medium-term data regarding the stability of the gingival margin after the use of acellular dermal matrix on root coverage. The aim of this article is to describe a case report with 10 years of evolution with creeping attachment that developed bucally on a moderate recession of a maxillary canine with an old composite restoration subsequent to an acellular dermal matrix. Long-term creeping attachment and complete root coverage on a restored tooth treated with acellular dermal matrix has not been previously reported in the dental literature.


Hedgehog/Ras interactions regulate early stages of pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDA) constitutes a lethal disease that affects >30,000 people annually in the United States. Deregulation of Hedgehog signaling has been implicated in the pathogenesis of PDA. To gain insights into the role of the pathway during the distinct stages of pancreatic carcinogenesis, we established a mouse model in which Hedgehog signaling is activated specifically in the pancreatic epithelium. Transgenic mice survived to adulthood and developed undifferentiated carcinoma, indicating that epithelium-specific Hedgehog signaling is sufficient to drive pancreatic neoplasia but does not recapitulate human pancreatic carcinogenesis. In contrast, simultaneous activation of Ras and Hedgehog signaling caused extensive formation of pancreatic intraepithelial neoplasias, the earliest stages of human PDA tumorigenesis, and accelerated lethality. These results indicate the cooperation of Hedgehog and Ras signaling during the earliest stages of PDA formation. They also mark Hedgehog pathway components as relevant therapeutic targets for both early and advanced stages of pancreatic ductal neoplasia.


Pooled analysis of rofecoxib placebo-controlled clinical trial data: lessons for postmarket pharmaceutical safety surveillance.
In September 2004, rofecoxib was voluntarily withdrawn from the worldwide market. Our objective was to determine whether and when analysis of published and unpublished placebo-controlled trials could have revealed cardiovascular risk associated with rofecoxib before its withdrawal as an example to inform future postmarket pharmaceutical safety surveillance efforts. We conducted a cumulative subject-level pooled analysis of data from all randomized, placebo-controlled trials of rofecoxib conducted by the manufacturer before September 2004. Our main outcome measurement was incidence of any investigator-reported death from any cause or cardiovascular thromboembolic (CVT) adverse event. We identified 30 randomized, placebo-controlled trials of rofecoxib that enrolled a combined 20 152 subjects. Trial duration ranged from 4 weeks to 4 years; enrollment ranged from 17 to 2586 subjects prescribed either rofecoxib or placebo; and rofecoxib dose ranged from 12.5 mg to 50 mg. As of December 2000, 21 of these trials had been completed (70%), and the risk of a CVT adverse event or death was greater among subjects assigned to the rofecoxib group (rate ratio [RR], 2.18; 95% confidence interval [CI], 0.93-5.81) (P = .07), raising concerns from a safety standpoint. Subsequently collected data through June 2001 showed that rofecoxib was associated with a 35% increased risk of a CVT adverse event or death (RR, 1.35; 95% CI, 1.00-1.96) (P = .05). Analyzing data available as of April 2002, we found a 39% increased risk (RR, 1.39; 95% CI, 1.07-1.80) (P = .02), and using data available as of September 2004, we found a 43% increased risk (RR,1.43; 95% CI, 1.16-1.76) (P < .001). Cumulative pooled analysis of all randomized, placebo-controlled trials demonstrates a trend toward increased cardiovascular risk associated with rofecoxib compared with placebo as early as December 2000, the comparison reaching a P value of .05 by June 2001, nearly 3(1/2) years before the manufacturer's voluntary market withdrawal.


Prognostic models in acute pulmonary embolism: a systematic review and meta-analysis.
To review the evidence for existing prognostic models in acute pulmonary embolism (PE) and determine how valid and useful they are for predicting patient outcomes. Systematic review and meta-analysis. OVID MEDLINE and EMBASE, and The Cochrane Library from inception to July 2014, and sources of grey literature. Studies aiming at constructing, validating, updating or studying the impact of prognostic models to predict all-cause death, PE-related death or venous thromboembolic events up to a 3-month follow-up in patients with an acute symptomatic PE. Study characteristics and study quality using prognostic criteria. Studies were selected and data extracted by 2 reviewers. Summary estimates (95% CI) for proportion of risk groups and event rates within risk groups, and accuracy. We included 71 studies (44,298 patients). Among them, 17 were model construction studies specific to PE prognosis. The most validated models were the PE Severity Index (PESI) and its simplified version (sPESI). The overall 30-day mortality rate was 2.3% (1.7% to 2.9%) in the low-risk group and 11.4% (9.9% to 13.1%) in the high-risk group for PESI (9 studies), and 1.5% (0.9% to 2.5%) in the low-risk group and 10.7% (8.8% to12.9%) in the high-risk group for sPESI (11 studies). PESI has proved clinically useful in an impact study. Shifting the cut-off or using novel and updated models specifically developed for normotensive PE improves the ability for identifying patients at lower risk for early death or adverse outcome (0.5-1%) and those at higher risk (up to 20-29% of event rate). We provide evidence-based information about the validity and utility of the existing prognostic models in acute PE that may be helpful for identifying patients at low risk. Novel models seem attractive for the high-risk normotensive PE but need to be externally validated then be assessed in impact studies.


Synthesis and Spectroscopic Investigation of a Series of Push-Pull Boron Dipyrromethenes (BODIPYs).
A series of push-pull BODIPYs bearing multiple electron-donating and electron-acceptor groups were synthesized regioselectively from 2,3,5,6,8-pentachloro-BODIPY, and characterized by NMR spectroscopy, HRMS, and X-ray crystallography. The influence of the push-pull substituents on the spectroscopic and electrochemical properties of BODIPYs was investigated. Bathochromic shifts were observed for both absorbance (up to 37 nm) and emission (up to 60 nm) in different solvents upon introduction of the push-pull moieties. DFT calculations, consistent with the spectroscopic and cyclic voltammetry studies, show decreased HOMO-LUMO energy gaps upon the installation of the push-pull moieties. BODIPY 7 bearing thienyl groups on the 2 and 6 positions showed the largest λmax for both absorption (635-653 nm) and emission (706-707 nm), but also the lowest fluorescence quantum yields. All BODIPYs were nontoxic in the dark (IC50 > 200 μM) and showed low phototoxicity (IC50 > 100 μM, 1.5 J/cm2) toward human HEp2 cells. Despite the relatively low fluorescence quantum yields, the push-pull BODIPYS were effective for cell imaging, readily accumulating within cells and localizing mainly in the ER and Golgi. Our structure-property studies can guide future design of functionalized BODIPYs for various applications, including bioimaging and in dye-sensitized solar cells.


Social determinants of children's health in urban areas in India.
Children of the urban poor in India suffer a much poorer health status than the urban non-poor, influenced to a large extent by social determinants. In this paper, National Family Health Survey-3 (2005-06) data were analyzed to assess the health status of urban poor children vis-à-vis the non-poor, and to identify the social determinants precipitating disparities. The analysis shows sharp disparity between child health indicators between urban poor and non-poor. Key findings include under-five mortality per thousand (urban poor 72.7 and non-poor 41.8) and children under-five underweight for age (urban poor 47% and non-poor 26.2%). Significant demographic and social correlates of child health in urban areas included poverty, gender, caste status, religion, mother's educational attainment, occupational status of parents, and women's autonomy in the household. They influenced different facets of child health, such as nutritional status and access to immunization.


Clinical audit on "evaluation of special issues in adolescents with cancer treated in an adult cancer setting": an Indian experience.
Adolescents with cancer form a distinct group with special care needs. These patients are often cared in an adult supportive care setting where the special needs of adolescents are not met. To identify special issues in adolescents with cancer and to determine whether special needs of adolescents are met in an adult cancer setting 10 adolescents with cancer were randomly chosen and retrospectively studied for physical, psychoscocial and emotional issues using an internally validated tool. Pain was the most common physical symptom seen in all 10 patients. 3 out of 10 patients were involved in decision making, 3 out of 10 patients had identity issues and 4 out of 10 patients had peer group isolation issues. Only 3 were aware of diagnosis and none were aware of treatment outcomes and mortality. 4 out of 10 had anxiety and depression and 3 out of 10 had body image issues. Sexuality, spiritual and existential issues were not explored in any of the patients studied. The outcomes of the study were in an adult oncology setting there was a poor recognition of key adolescent issues such as sexuality, body image, identity and peer group isolation. The psychosocial supports to these adolescents were minimal and spiritual and existential issues were not explored. The inferences drawn from this study suggested a need for multidisciplinary team approach oriented in handling adolescent care needs and preferably to have a dedicated space that will help the peer group to interact, bond and cope better with the illness.


Differentiating Operator Skill during Routine Fetal Ultrasound Scanning using Probe Motion Tracking.
In this paper, we consider differentiating operator skill during fetal ultrasound scanning using probe motion tracking. We present a novel convolutional neural network-based deep learning framework to model ultrasound probe motion in order to classify operator skill levels, that is invariant to operators' personal scanning styles. In this study, probe motion data during routine second-trimester fetal ultrasound scanning was acquired by operators of known experience levels (2 newly-qualified operators and 10 expert operators). The results demonstrate that the proposed model can successfully learn underlying probe motion features that distinguish operator skill levels during routine fetal ultrasound with 95% accuracy.


Nurses on the Front Lines: Improving Adolescent Sexual and Reproductive Health Across Health Care Settings.
: Nurses care for adolescents in a variety of settings, including communities, schools, and public health and acute care clinics, which affords them many opportunities to improve adolescents' sexual and reproductive health and reduce the rates of unplanned pregnancy and sexually transmitted infections. To ensure that adolescents have access to sexual and reproductive health care (which includes both preventive counseling and treatment) in all nursing practice sites, nurses need to gain the knowledge and hone the skills required to deliver evidence-based counseling and services to adolescents and parents. Collectively, nurses can use their unique combination of knowledge and skills to make a positive impact on adolescent sexual and reproductive outcomes. Nurses have the capacity and opportunity to disseminate information about sexual and reproductive health to adolescents and their parents in communities, schools, public health clinics, and acute care settings. This article discusses the Society for Adolescent Health and Medicine's goals and recommendations, which address adolescent sexual and reproductive health as both a health care and a human rights issue.


Ultrasound Guided Therapeutic Excisional Vacuum Assisted Biopsy in Breast Fibroadenomas.
The aim of this study was to evaluate the performance of ultrasound (US) guided Vacuum Assisted Biopsy (VAB) in the therapeutic excision of breast fibroadenomas. Patients who underwent excisional US guided VAB of their fibroadenomas between December 1999-May 2001 were retrospectively evaluated. Seventy-eight patients with BI-RADS category 3 and 4a lesions (one lesion per patient) with a maximum diameter smaller than 3 cm were enrolled in the study. Fifty-one of those were diagnosed with fibroadenoma. Biopsies were performed with a 11G needle using the Mammotome (Johnson & Johnson, New Jersey, USA) vacuum biopsy device. Patients were followed up with US for three years. Follow-ups were done semiannually in the first year and annually afterwards. Ten patients (19%) were found to have residual lesions in the first week after the biopsy. Additional eight patients (15%) were found to have residual-recurrent lesions in their annual follow up. However, none of these eight lesions demonstrated growth during the three year follow-up. The initial size of the FA was not found to be significantly different between the lesions which were completely excised with no residue or recurrence and those which were not (p>0.05). The VAB method for the therapeutic excision of small FAs or other benign lesions is practical and easily tolerated by patients. Lesions smaller than 3 cm should be preferred for VAB. A multidisciplinary clinical environment is necessary for each step of the treatment.


Transcriptomic and life history responses of the mayfly Neocloeon triangulifer to chronic diel thermal challenge.
To better understand the effects of transient thermal stress in an aquatic insect, we first identified static temperatures associated with fitness deficits, and then reared larvae from egg hatch to adulthood under diurnally variable regimens including daily forays into deleterious temperatures. We sampled mature larvae at the coolest and warmest portions of their respective regimens for RNA-seq analysis. Few transcripts (28) were differentially expressed when larvae oscillated between favorable temperatures, while 614 transcripts were differentially expressed when experiencing daily transient thermal stress. Transcripts associated with N-glycan processing were downregulated while those associated with lipid catabolism and chitin turnover were significantly upregulated in heat stressed larvae. An across-regimen comparison of differentially expressed transcripts among organisms sampled at comparable temperatures demonstrated that the effects of daily thermal stress persisted even when larvae were sampled at a more optimal temperature (806 differentially expressed transcripts). The chronically stressed population had reduced expression of transcripts related to ATP synthesis, mitochondrial electron chain functions, gluconeogenesis and glycolytic processes while transcripts associated with cell adhesion, synaptic vesicle transport, regulation of membrane potential and lipid biosynthesis increased. Comparisons of constant vs. variable temperatures revealed that the negative consequences of time spent at stressful temperatures were not offset by more time spent at optimal temperatures.


Association of Alcohol Consumption After Development of Heart Failure With Survival Among Older Adults in the Cardiovascular Health Study.
More than 1 million older adults develop heart failure annually. The association of alcohol consumption with survival among these individuals after diagnosis is unknown. To determine whether alcohol use is associated with increased survival among older adults with incident heart failure. This prospective cohort study included 5888 community-dwelling adults aged 65 years or older who were recruited to participate in the Cardiovascular Health Study between June 12, 1989, and June 1993, from 4 US sites. Of the total participants, 393 individuals had a new diagnosis of heart failure within the first 9 years of follow-up through June 2013. The study analysis was performed between January 19, 2016, and September 22, 2016. Alcohol consumption was divided into 4 categories: abstainers (never drinkers), former drinkers, 7 or fewer alcoholic drinks per week, and more than 7 drinks per week. Participant survival after the diagnosis of incident heart failure. Among the 393 adults diagnosed with incident heart failure, 213 (54.2%) were female, 339 (86.3%) were white, and the mean (SD) age was 78.7 (6.0) years. Alcohol consumption after diagnosis was reported in 129 (32.8%) of the participants. Across alcohol consumption categories of long-term abstainers, former drinkers, consumers of 1-7 drinks weekly and consumers of more than 7 drinks weekly, the percentage of men (32.1%, 49.0%, 58.0%, and 82.4%, respectively; P < .001 for trend), white individuals (78.0%, 92.7%, 92.0%, and 94.1%, respectively, P <. 001 for trend), and high-income participants (22.0%, 43.8%, 47.3%, and 64.7%, respectively; P < .001 for trend) increased with increasing alcohol consumption. Across the 4 categories, participants who consumed more alcohol had more years of education (mean, 12 years [interquartile range (IQR), 8.0-10.0 years], 12 years [IQR, 11.0-14.0 years], 13 years [IQR, 12.0-15.0 years], and 13 years [IQR, 12.0-14.0 years]; P < .001 for trend). Diabetes was less common across the alcohol consumption categories (32.1%, 26.0%, 22.3%, and 5.9%, respectively; P = .01 for trend). Across alcohol consumption categories, there were fewer never smokers (58.3%, 44.8%, 35.7%, and 29.4%, respectively; P < .001 for trend) and more former smokers (34.5%, 38.5%, 50.0%, and 52.9%, respectively; P = .006 for trend). After controlling for other factors, consumption of 7 or fewer alcoholic drinks per week was associated with additional mean survival of 383 days (95% CI, 17-748 days; P = .04) compared with abstinence from alcohol. Although the robustness was limited by the small number of individuals who consumed more than 7 drinks per week, a significant inverted U-shaped association between alcohol consumption and survival was observed. Multivariable model estimates of mean time from heart failure diagnosis to death were 2640 days (95% CI, 1967-3313 days) for never drinkers, 3046 days (95% CI, 2372-3719 days) for consumers of 0 to 7 drinks per week, and 2806 (95% CI, 1879-3734 days) for consumers of more than 7 drinks per week (P = .02). Consumption of 10 drinks per week was associated with the longest survival, a mean of 3381 days (95% CI, 2806-3956 days) after heart failure diagnosis. These findings suggest that limited alcohol consumption among older adults with incident heart failure is associated with survival benefit compared with long-term abstinence. These findings suggest that older adults who develop heart failure may not need to abstain from moderate levels of alcohol consumption.


Racial disparities in HIV prevalence and risk behaviors among injection drug users and members of their risk networks.
In the United States, racial differences in the prevalence and incidence of HIV infection and AIDS diagnoses are dramatic. These differences are large, have been recognized for nearly 20 years, and are as yet not well investigated. These disparities show no signs of diminishing and, in fact, are widening, particularly among drug users and women. Most observers of the racial disparities in prevalence and incidence of HIV infections and AIDS diagnoses in the United States have concluded that these disparities exist because prevention messages, supplies, and/or interventions do not effectively reach those at greatest risk of infection. In essence, such interpretations suggest that Blacks and Latinos continue to practice more risk behaviors than Whites. There are much data to suggest that this is, in fact, not true. Evidence from 232 'index' injection drug users and 465 of their drug and sexual network members participating in HIV Prevention Trials Network 037 is presented. These data describe lower use and/or access to drug treatment and needle exchange programs by Black injectors. In addition, data indicate the coexistence of increased prevalence of HIV in the networks of uninfected Black drug users and fewer associated risk behaviors in the networks of Black and Latino indices compared with networks of White indices. Understanding racial disparities in HIV is a critical challenge; yet, risk behaviors alone do not explain observed disparities in infection rates.


Age-related changes in static accommodation and accommodative miosis.
An attempt was made to explore the validity of the Hess-Gullstrand and Duane-Fincham models of presbyopia development, on the assumption that accommodative miosis could be used as an indicator of ciliary muscle effort. Monocular accommodation response and pupil size were measured as a function of accommodation demand over the range 0-4 D, in 48 normal subjects with ages between 17 and 56 years. The slope of the response/stimulus curve was found to decrease only slowly with age up to about 35 years and then to decline more rapidly. Accommodative miosis per dioptre of accommodation response did not change systematically with age up to about 35 years, this being apparently more in accord with the Hess-Gullstrand model. However, accommodative miosis varied very widely between younger subjects of similar age and accommodative amplitude (from zero to around 1 mm per dioptre of accommodation response for subjects in their twenties). It is concluded that miosis does not necessarily accompany accommodation and that its magnitude is not related in any simple general way to ciliary muscle contraction. Hence it cannot be used to support or refute particular theories of presbyopia.


Adenocarcinoma of the duodenum: factors influencing long-term survival.
This single-institution retrospective analysis reviews the management and outcome of patients with surgically treated adenocarcinoma of the duodenum. Between February 1984 and August 1996, fifty-five patients with adenocarcinoma of the duodenum underwent surgery at The Johns Hopkins Hospital. Univariate analysis was performed to identify possible prognostic indicators. Curative resection was performed in 48 patients (87%): 35 of these patients (73%) underwent a pancreaticoduodenectomy (PD), whereas 27% (n = 13) underwent a pancreas-sparing duodenectomy (PSD). Patients undergoing PD were comparable to those undergoing PSD with respect to demographic factors, presenting symptoms, and tumor pathology. The remaining 13% of patients (n = 7) were deemed unresectable at the time of surgery and underwent biopsy and/or palliative bypass. PD was associated with an increase in postoperative complications when compared to PSD (57% vs. 30%), but this difference was not statistically significant. One perioperative death occurred following PD (mortality 2.9%). The overall 5-year survival rate for the 48 patients undergoing potentially curative resection was 53%. Negative resection margins (P <0.001), PD (P <0.005), and tumors in the first and second portions of the duodenum (P <0.05) were favorable predictors of long-term survival by univariate analysis. Nodal status, tumor diameter, degree of differentiation, and the use of adjuvant chemoradiation therapy did not influence survival. These data support an aggressive role for resection in patients with adenocarcinoma of the dueodenum


A sense of security: Spouses' experiences of participating in an orthopaedic case management intervention (the SICAM-trial).
The aim of the study was to explore and describe spouses' experiences of participating in a case management intervention during older patients' fast-track programme having total hip replacement as well as which intervention elements they found useful. Data were collected through qualitative interviews with 10 spouses from the intervention group of the SICAM-trial, directed by predetermined codes based on elements of the intervention. Data were analysed by both authors using directed content analysis. The results showed that the spouses were very pleased about being a part of the case management intervention. They enjoyed being active participants even though problems sometimes occurred such as coordination difficulties between the case manager and other healthcare professionals and their feeling of being burdened. The spouses experienced the contact with the case manager as the most meaningful part of their participation and the telephone contact with her as the most useful element of the intervention. The fact that not all spouses participated in all the available intervention elements could be explained by their feeling of being burdened and that they were not fully aware of what the intervention elements were.


They "miss more than anything their normal life back home": masculinity and extramarital sex among Mexican migrants in Atlanta.
Gender has been recognized as a significant influence on sexual health behaviors. Labor migration presents an important context of vulnerability for sexual health. To understand how the context of migration affects risk-related practices, both cultural and social aspects of gender need to be explored. In the quantitative part of a mixed-methods study conducted in 1999 in Atlanta, 187 Mexican migrant men were asked about their demographic characteristics; sexual history; migration motivations; substance use; social support; leisure-time activities; and ideas about masculinity, sexuality and marriage. Multivariate regression analyses were conducted to test the association between these domains and men's number of partners since their arrival in Atlanta. Number of partners was positively associated with owning a home in Mexico; number of trips back to Mexico; social network size; having had a sex worker as a partner; and going out dancing and to strip clubs on weekends (coefficients, 0.3-4.1). It was negatively associated with age, education, contact with social network members and feeling that sex is tied to emotional intimacy (-0.4 to -1.0). Programs must acknowledge and target migrant men's social networks and the spaces in which they may encounter risky sexual situations. Multilevel strategies, such as the development of more health-enhancing community spaces and the promotion of safer sexual practices should form part of comprehensive efforts to reduce sexual risk among migrant men.


Current evidence and future perspectives of immune-checkpoint inhibitors in unresectable malignant pleural mesothelioma.
Platinum-based chemotherapy is commonly used as the standard first-line treatment for unresectable malignant pleural mesothelioma (MPM). However, in recent times, immune-checkpoint inhibitors (ICIs) have led to a paradigm shift. Herein, we review relevant literature and ongoing trials of ICIs used as both first-line and salvage therapies. Specifically, in the Japanese single-arm, phase II trial, the MERIT trial, nivolumab, an antiprogrammed cell death 1 (PD-1) antibody showed favorable efficacy when used as a salvage therapy. Currently, multiple ICI monotherapy or combination therapy trials have been conducted, which could provide further evidence. Among available ICIs, the anti-PD-1 antibody is promising for unresectable MPM, despite the limited efficacy of anti-CTLA4 monotherapy. Ongoing studies will further confirm the potential efficacy of ICIs for MPM, as observed across other malignancies. It is also crucial to identify any clinically useful predictive biomarkers that could reveal ICIs with maximal effects in MPM.


Antibacterial activity of cationic proteins from human granulocytes.
Human granulocytes contain several cationic proteins with a molecular weight of approximately 25,000, almost identical amino acid composition, and complete immunologic identity. These proteins possess a chymotrypsin-like protease activity at a neutral pH. The antibacterial activity of the cationic proteins has been studied. Bactericidal activities are found against both Gram-positive (Streptococcus faecalis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Pseudomonas aeruginosa) organisms. Gram-positive bacteria are, however, the most sensitive. The pH-optimum is near neutrality, and the microbicidal activity shows an inverse relationship to the ionic strength, indicating an ionic interaction between the cationic proteins and the bacterial surface. The microbicidal effect of the cationic proteins is generally independent of the chymotrypsin-like activity of the same proteins since the activity against several bacterial species is heat stable while the chymotrypsin-like activity is heat labile. The surface properties of S. aureus that are determined by protein A do not seem to influence the susceptibility to cationic proteins. The properties of the Gram-negative envelope of E. coli that determine the susceptibility to the lytic action of serum do not influence the sensitivity to the action of cationic proteins. The present study shows that cationic proteins of human granulocytes represent one potential microbicidal mechanism that is independent of hydrogen peroxide and myeloperoxidase.


Algebraic iterative algorithm for deflection tomography and its application to density flow fields in a hypersonic wind tunnel.
A novel algebraic iterative algorithm based on deflection tomography is presented. This algorithm is derived from the essentials of deflection tomography with a linear expansion of the local basis functions. By use of this algorithm the tomographic problem is finally reduced to the solution of a set of linear equations. The algorithm is demonstrated by mapping a three-peak Gaussian simulative temperature field. Compared with reconstruction results obtained by other traditional deflection algorithms, its reconstruction results provide a significant improvement in reconstruction accuracy, especially in cases with noisy data added. In the density diagnosis of a hypersonic wind tunnel, this algorithm is adopted to reconstruct density distributions of an axial symmetry flow field. One cross section of the reconstruction results is selected to be compared with the inverse Abel transform algorithm. Results show that the novel algorithm can achieve an accuracy equivalent to the inverse Abel transform algorithm. However, the novel algorithm is more versatile because it is applicable to arbitrary kinds of distribution.


Androgen inhibition of MAP kinase pathway and Elk-1 activation in proliferating osteoblasts.
Non-aromatizable androgens have significant beneficial effects on skeletal homeostasis independently of conversion to estradiol, but the effects of androgens on bone cell metabolism and cell proliferation are still poorly understood. Using an osteoblastic model with enhanced androgen responsiveness, MC3T3-E1 cells stably transfected with androgen receptor (AR) under the control of the type I collagen promoter (colAR-MC3T3), the effects of androgens on mitogenic signaling were characterized. Cultures were treated with the non-aromatizable androgen 5alpha-dihydrotestosterone (DHT) and the effects on osteoblast viability were determined as measured by an MTT assay. A complex response was observed in that continuous short-term DHT treatment enhanced osteoblast viability, but with longer-term DHT treatment inhibition was observed. The inhibition by DHT was prevented by the specific AR antagonist hydroxyflutamide, and was also observed in primary cultures of normal rat calvarial osteoblasts. In order to identify potential mediators of this effect, mitogenic pathway-specific cDNA microarrays were interrogated. Reduced hybridization of several genes important in MAP kinase-mediated signaling was observed, with the most dramatic effect on Elk-1 expression. Analysis of phosphorylation cascades demonstrated that DHT treatment inhibited phosphoERK1/2 levels, MAP kinase activation of Elk-1, Elk-1 protein and phosphoElk-1 levels, and downstream AP-1/luciferase reporter activity. Together, these data provide the first evidence that androgen inhibition of the MAP kinase signaling pathway is a potential mediator of osteoblast growth, and are consistent with the hypothesis that the MAP cascade may be a specific downstream target of DHT.


MRI-guided radiofrequency ablation of breast cancer: preliminary clinical experience.
This study was designed to demonstrate the feasibility of MRI-guided radiofrequency ablation (RFA) of breast cancer. A total of three women diagnosed with invasive ductal breast cancer were treated with percutaneous MRI-guided RFA, according to a treat and resect protocol, in our hospital. RFA procedures were performed in an open 0.5T Signa-SP imager allowing direct patient access and real-time monitoring of the procedure. In all patients ablation was performed with a 15-gauge insulated MRI-compatible multiple needle probe. MRI thermometry and contrast-enhanced postablation MRI were used to evaluate the ablation process. Patients underwent lumpectomy within a week of the RFA procedure. Histopathology confirmed successful (100%) tumor ablation in one patient, and partial tumor destruction (33% and 50%, respectively) in two patients. Challenges of MRI-guided breast RFA that need to be solved to facilitate progress of the technique toward clinical practice are discussed.


Predicting personalized multiple birth risks after in vitro fertilization-double embryo transfer.
To report and evaluate the performance and utility of an approach to predicting IVF-double embryo transfer (DET) multiple birth risks that is evidence-based, clinic-specific, and considers each patient's clinical profile. Retrospective prediction modeling. An outpatient university-affiliated IVF clinic. We used boosted tree methods to analyze 2,413 independent IVF-DET treatment cycles that resulted in live births. The IVF cycles were retrieved from a database that comprised more than 33,000 IVF cycles. None. The performance of this prediction model, MBP-BIVF, was validated by an independent data set, to evaluate predictive power, discrimination, dynamic range, and reclassification. Multiple birth probabilities ranging from 11.8% to 54.8% were predicted by the model and were significantly different from control predictions in more than half of the patients. The prediction model showed an improvement of 146% in predictive power and 16.0% in discrimination over control. The population standard error was 1.8%. We showed that IVF patients have inherently different risks of multiple birth, even when DET is specified, and this risk can be predicted before ET. The use of clinic-specific prediction models provides an evidence-based and personalized method to counsel patients.


Polymerized bovine hemoglobin solution as a replacement for allogeneic red blood cell transfusion after cardiac surgery: results of a randomized, double-blind trial.
Blood loss leading to reduced oxygen-carrying capacity is usually treated with red blood cell transfusions. This study examined the hypothesis that a hemoglobin-based oxygen-carrying solution can serve as an initial alternative to red blood cell transfusion. In a randomized, double-blind efficacy trial of HBOC-201, a total of 98 patients undergoing cardiac surgery and requiring transfusion were randomly assigned to receive either red blood cell units or HBOC-201 (Hemopure; Biopure Corporation, Cambridge, Mass) for the first three postoperative transfusions. Patients were monitored before and after transfusion, at discharge, and at 3 to 4 weeks after the operation for subsequent red blood cell use, hemodynamics, and clinical laboratory parameters. The use of HBOC-201 eliminated the need for red blood cell transfusions in 34% of cases (95% confidence interval 21%-49%). Patients in the HBOC group received a mean of 1.72 subsequent units of red blood cells; those who received red blood cells only received a mean of 2.19 subsequent units (P =.05). Hematocrit values were transiently lower in the HBOC group but were similar in the two groups at discharge and follow-up. Oxygen extraction was greater in the HBOC group (P =.05). Mean increases in blood pressure were greater in the HBOC group, but not significantly so. HBOC-201 may be an initial alternative to red blood cell transfusions for patients with moderate anemia after cardiac surgery. In a third of cases, HBOC-201 eliminated the need for red blood cell transfusion, although substantial doses were needed to produce this modest degree of blood conservation.


Family-group names of Recent fishes.
The family-group names of animals (superfamily, family, subfamily, supertribe, tribe and subtribe) are regulated by the International Code of Zoological Nomenclature. Family names are particularly important because they are among the most widely used of all technical animal names. Apart from using the correct family-group name according to the Code, it is also important to use one unique universal name (with a fixed spelling) to avoid confusion. We have compiled a list of family-group names for Recent fishes, applied the rules of the Code and, if possible, tried to conserve the names in prevailing recent practice. We list all of the family-group names found to date for Recent fishes (N=2625), together with their author(s) and year of publication. This list can be used in assigning the correct family-group name to a genus or a group of genera. With this publication we contribute to the usage of correct, universal family-group names in the classification of, and for communication about, Recent fishes.


Postoperative Delirium in Patients after Pancreaticoduodenectomy.
Postoperative delirium (POD) is one of the most common complications after various types of surgery. The aim of this study was to investigate the incidence and risk factors for delirium after pancreaticoduodenectomy (PD). This was a retrospective study of 146 consecutive patients who underwent PD between April 2007 and June 2015 at Saiseikai Yokohamashi Tobu Hospital. Twenty-nine patients (19.9%) were diagnosed with delirium. Patients who were >70 years were divided into a delirium group (n = 24) and a non-delirium group (n = 41). Multivariate analysis showed that only the Charlson Age Comorbidity Index (CACI) (OR 1.8; 95% CI 1.067-3.036; p = 0.028) was an independent risk factor of delirium for patients >70 years. The receiver operating characteristic curve revealed an optimal cutoff value of 4.5 for the CACI score in all patients (sensitivity 62.1%; specificity 82.9%; area under the curve 0.782). The higher CACI score (≥5) is significantly different from the lower CACI score (p < 0.0001) with respect to POD occurrence. The CACI, especially in elderly patients, was associated with the incidence of POD. Therefore, utilizing this validated and practical tool preoperatively might be useful for POD.


Family-Centered Communication and Acute Stress in Israeli Intensive Care Units.
Intensive care unit stays can be stressful for patients' family members. Family-centered communication has 6 components: fostering relationships, exchanging information, responding to emotions, managing uncertainty, making decisions, and enabling patient self-management. Whether these communication components decrease family members' stress is unknown. To describe levels of family-centered communication and associations with acute stress while patients are in the intensive care unit. A convenience sample of 130 family members of patients in 2 intensive care units in a Jerusalem, Israel, tertiary medical center received a family-centered communication questionnaire, the Perceived Stress Scale, and a personal characteristics questionnaire. Most respondents were women (n = 79, 60.8%), children of the patient (n = 67, 51.9%), and familiar with the patient's diagnosis (n = 111, 85.4%). Mean (SD) participant age was 45.7 (13.6) years. Most considered the patient medically stable (n = 75, 57.7%). Mean (SD) intensive care unit stay was 7.45 (5.8) days. Mean (SD) total and item scores for family-centered communication were 98.75 (18.21) and 3.80 (0.70), respectively; for the Perceived Stress Scale, 19.63 (5.92) and 1.96 (0.59), respectively. Relationship building (r = -0.31, P = .002), participation in care management (r = -0.32, P = .001), and emotional support (r = -0.29, P = .003), and were significantly related to stress. Stress levels were mild to moderate and communication scores were moderate to high. Better nurse communication with family members was associated with decreased acute stress, irrespective of personal characteristics or perceptions of the patient's medical status.


Fibronectin promotes survival and migration of primary neural stem cells transplanted into the traumatically injured mouse brain.
Multipotential stem cells are an attractive choice for cell therapy after traumatic brain injury (TBI), as replacement of multiple cell types may be required for functional recovery. In the present study, neural stem cells (NSCs) derived from the germinal zone of E14.5 GFP-expressing mouse brains were cultured as neurospheres in FGF2-enhanced medium. When FGF2 was removed in vitro, NSCs expressed phenotypic markers for neurons. astrocytes, and oligodendrocytes and exhibited migratory behavior in the presence of adsorbed fibronectin (FN). NSCs (10(5) cells) were transplanted into mouse brains 1 week after a unilateral, controlled, cortical contusion (depth = 1 mm, velocity = 6 m/s, duration = 150 ms) (n = 19). NSCs were injected either directly into the injury cavity with or without an injectable FN-based scaffold [collagen I (CnI)/FN gel; n = 14] or into the striatum below the injury cavity (n = 5). At all time points examined (1 week to 3 months posttransplant), GFP+ cells were confined to the ipsilateral host brain tissue. At 1 week, cells injected into the injury cavity lined the injury penumbra while cells inserted directly into the striatum remained in or around the needle track. Striatal transplants had a lower number of surviving GFP+ cells relative to cavity injections at the 1 week time point (p < 0.01). At the longer survival times (3 weeks-3 months), 63-76% of transplanted cells migrated into the fimbria hippocampus regardless of injection site, perhaps due to cues from the degenerating hippocampus. Furthermore, cells injected into the cavity within a FN-containing matrix showed increased survival and migration at 3 weeks (p < 0.05 for both) relative to injections of cells alone. These results suggest that FGF2-responsive NSCs present a promising approach for cellular therapy following trauma and that the transplant location and environment may play an important role in graft survival and integration.


[Role of nuclear factor of kB in tumor necrosis factor alpha-mediated INS-1 cell apoptosis].
To investigate the effect of cytokine tumor necrosis factor alpha(TNFalpha) on pancreatic beta cells apoptosis and the effect of transcription factor nuclear factor of kappa B (NF-kB) on TNFalpha-mediated apoptosis. INS-1 cells, a pancreatic beta cell line, were cultured,and recombinant DNA technique, transfection and reinfection technology were used to obtain INS-1/IkBDeltaN cells expressing inhibitor of kB (IkB)alphaDeltaN, mutant IkBalpha (inhibitor of NF-kB). DNA fragmentation assay and fluorescence analysis using a kB-luc reporter gene were applied to observe the NF-kB activity and beta cell apoptosis. NF-kB activity induced by IL-Ibeta was detectable in INS-1 cells but not in INS-1/IkBDeltaN cells. After incubation of the cells with IL-1beta (10 micro g/L), TNFalpha (100 micro g/L) and interferon (IFN)gamma (100 000 U/L) for 48 hours, the combination of TNFalpha and IFNgamma induced apoptosis in INS-1 cells but not in INS-1/IkBDeltaN cells. No apoptosis was observed after incubation of INS-1 cells with IL-1beta or IFNgamma or IL-1beta plus IFNgamma. Apoptosis is one of the TNFalpha-induced beta-cell death forms. NF-kB may play an important role in the TNFalpha-mediated beta-cell apoptosis. Inhibition of NF-kB activation protects beta-cells from TNFalpha-induced apoptosis.


Human challenge trials in vaccine development, Rockville, MD, USA, September 28-30, 2017.
The International Alliance for Biological Standardization organized the second workshop on human challenge trials (HCT) in Rockville, MD, in September 2017. The objective of this meeting was to examine the use of HCT, in response to the continuing human suffering caused by infectious diseases, preventable by the development of new and improved vaccines. For this, the approach of HCT could be valuable, as HCT can provide key safety, tolerability, immunogenicity, and efficacy data, and can be used to study host-pathogen biology. HCT can generate these data with speed, efficiency and minimal expense, albeit not with the same level of robustness as clinical trials. Incorporated wisely into a clinical development plan, HCT can support optimization or down-selection of new vaccine candidates, assuring that only the worthiest candidates progress to field testing. HCT may also provide pivotal efficacy data in support of licensure, particularly when field efficacy studies are not feasible. Many aspects of HCT were discussed by the participants, including new and existing models, standardization and ethics. A consensus was achieved that HCT, if ethically justified and performed with careful attention to safety and informed consent, should be pursued to promote and accelerate vaccine development.


Prevalence of frequent headache in a population sample.
Patients with daily or near-daily headaches are commonly seen in neurology practices and in headache subspecialty centers, but there is little information on the prevalence of this condition in the general population. We present the first US-based study describing the prevalence and characteristics of frequent headache in the general population. In Baltimore County, Maryland, 13 343 individuals 18 to 65 years of age were selected by random-digit dialing and interviewed by telephone about their headaches. Subjects reporting 180 or more headaches per year were classified as having frequent headache. Three mutually exclusive subtypes of frequent headache were identified: frequent headache with migrainous features, chronic tension-type headache, and unclassified frequent headache. The overall prevalence of frequent headache was 4.1% (5.0% female, 2.8% male; 1.8:1 female to male ratio). Frequent headache was 33% more common in Caucasians (4.4%) than in African Americans (3.3%). In both males and females, prevalence was highest in the lowest educational category. Among frequent headache sufferers, more than half (52% female, 56% male) met criteria for chronic tension-type headache, almost one third (33% female, 25% male) met criteria for frequent headache with migrainous features, and the remainder (15% female, 19% male) were unclassified. Overall, 30% of female and 25% of male frequent headache sufferers met International Headache Society (IHS) criteria for migraine (with or without aura). Frequent headache is common in the general population and is more prevalent in Caucasians and in those with less than a high school education. Chronic tension-type headache is more common than frequent headache with migrainous features, though the latter is more disabling. Although more common in females than males, the female preponderance of frequent headache is less marked than in migraine. The sex ratio varies by frequent headache subtype.


Synthetic biology, patenting, health and global justice.
The legal and moral issues that synthetic biology (SB) and its medical applications are likely to raise with regard to intellectual property (IP) and patenting are best approached through the lens of a theoretical framework highlighting the "co-construction" or "co-evolution" of patent law and technology. The current situation is characterized by a major contest between the so-called IP frame and the access-to-knowledge frame. In SB this contest is found in the contrasting approaches of Craig Venter's chassis school and the BioBricks school. The stakes in this contest are high as issues of global health and global justice are implied. Patents are not simply to be seen as neutral incentives, but must also be judged on their effects for access to essential medicines, a more balanced pattern of innovation and the widest possible social participation in innovative activity. We need moral imagination to design new institutional systems and new ways of practising SB that meet the new demands of global justice.


Findings from a comprehensive diarrhoea prevention and treatment programme in Lusaka, Zambia.
The Programme for the Awareness and Elimination of Diarrhoea (PAED) was a pilot comprehensive diarrhoea prevention and control programme aimed to reduce post-neonatal, all-cause under-five mortality by 15 % in Lusaka Province. Interventions included introduction of the rotavirus vaccine, improved clinical case management of diarrhoea, and a comprehensive community prevention and advocacy campaign on hand washing with soap, exclusive breastfeeding up to 6 months of age, and the use of ORS and Zinc. This study aimed to assess the impact of PAED on under-5 mortality. The study was a pre-post evaluation design. The Demographic and Health Survey style population-based two-stage approach was used to collect data at the beginning of the intervention and 3 years following the start of intervention implementation in Lusaka province. The primary outcome of interest was an all-cause, post-neonatal under-five mortality rate defined as the probability of dying after the 28th day and before the fifth birthday among children aged 1-59 months. The Kaplan-Meier time to event analysis was used to estimate the probability of death; multiplying this probability by 1000 to yield the post-neonatal mortality rate. Survival-time inverse probability weighting model was used to estimate Average Treatment Effect (ATE). The percentage of children under age 5 who had diarrhoea in the last 2 weeks preceding the survey declined from 15.8 % (95 % CI: 15.2 %, 16.4 %) in 2012 to 12.7 % (95 % CI: 12.3 %, 13.2 %) in 2015. Over the same period, mortality in post-neonatal children under 5 years of age declined by 34 %, from an estimated rate of 29 deaths per 1000 live births (95 % CI: (26, 32) death per 1000 live births) to 19 deaths per 1000 live births (95 % CI: (16, 21) death per 1000 live births). When every child in the population of children aged 1-59 months is exposed to the intervention, the average time-to-death was estimated to be about 8 months more than when no child is exposed (ATE = 7.9; 95 % CI: 4.4,11.5; P < 0.001). Well-packaged diarrhoea preventive and treatment interventions delivered at the clinic and community-level could potentially reduce probability of death among children aged 1-59 months.


DNA methylation screening of primary prostate tumors identifies SRD5A2 and CYP11A1 as candidate markers for assessing risk of biochemical recurrence.
Altered DNA methylation in CpG islands of gene promoters has been implicated in prostate cancer (PCa) progression and can be used to predict disease outcome. In this study, we determine whether methylation changes of androgen biosynthesis pathway (ABP)-related genes in patients' plasma cell-free DNA (cfDNA) can serve as prognostic markers for biochemical recurrence (BCR). Methyl-binding domain capture sequencing (MBDCap-seq) was used to identify differentially methylated regions (DMRs) in primary tumors of patients who subsequently developed BCR or not, respectively. Methylation pyrosequencing of candidate loci was validated in cfDNA samples of 86 PCa patients taken at and/or post-radical prostatectomy (RP) using univariate and multivariate prediction analyses. Putative DMRs in 13 of 30 ABP-related genes were found between tumors of BCR (n = 12) versus no evidence of disease (NED) (n = 15). In silico analysis of The Cancer Genome Atlas data confirmed increased DNA methylation of two loci-SRD5A2 and CYP11A1, which also correlated with their decreased expression, in tumors with subsequent BCR development. Their aberrant cfDNA methylation was also associated with detectable levels of PSA taken after patients' post-RP. Multivariate analysis of the change in cfDNA methylation at all of CpG sites measured along with patient's treatment history predicted if a patient will develop BCR with 77.5% overall accuracy. Overall, increased DNA methylation of SRD5A2 and CYP11A1 related to androgen biosynthesis functions may play a role in BCR after patients' RP. The correlation between aberrant cfDNA methylation and detectable PSA in post-RP further suggests their utility as predictive markers for PCa recurrence. .


Single amino acid chelates (SAAC): a strategy for the design of technetium and rhenium radiopharmaceuticals.
Radiolabeled biomolecules can be used to visualize a variety of diseases through interaction with specific cell receptors. A key step is the introduction of a molecular entity that allows facile labeling with the medically useful radionuclide (99m)Tc without significant alteration of the structure and function of the biomolecule. One strategy focuses on the design of single amino acid chelates (SAACs), novel bifunctional chelators constructed from derivatized amino acids or amino acid analogues. The chelating terminus of the SAAC has been designed for effective coordination to the {(99m)Tc(CO)(3)}(+) core, while the other terminus allows incorporation into any position along a peptide sequence or into a variety of biomolecules. In applications to peptidic materials, the approach affords significant flexibility in the choice of donors for (99m)Tc coordination combined with the considerable advantages of routine solid phase synthetic techniques. The methodology allows libraries of peptide-based (99m)Tc(i) and (186,188)Re(i) radiopharmaceuticals to prepared using conventional automated peptides synthesis. Other biomolecules, including nucleosides, carbohydrates, folic acid and vitamin B12 are also readily modified using analogous methods. The approach also allows the preparation of isostructural (99m)Tc and Re complexes for the correlation of in vivo and in vitro imaging studies.


Treatment of Dyslipidemias to Prevent Cardiovascular Disease in Patients with Type 2 Diabetes.
Current preventive and treatment guidelines for type 2 diabetes have failed to decrease the incidence of comorbidities, such as dyslipidemia and ultimately heart disease. The goal of this review is to describe the physiological and metabolic lipid alterations that develop in patients with type 2 diabetes mellitus. Questions addressed include the differences in lipid and lipoprotein metabolism that characterize the dyslipidemia of insulin resistance and type 2 diabetes mellitus. We also examine the relevance of the new AHA/ADA treatment guidelines to dyslipidemic individuals. In this review, we provide an update on the pathophysiology of diabetic dyslipidemia, including the role of several apolipoproteins such as apoC-III. We also point to new studies and new agents for the treatment of individuals with type 2 diabetes mellitus who need lipid therapies. Type 2 diabetes mellitus causes cardiovascular disease via several pathways, including dyslipidemia characterized by increased plasma levels of apoB-lipoproteins and triglycerides, and low plasma concentrations of HDL cholesterol. Treatments to normalize the dyslipidemia and reduce the risk for cardiovascular events include the following: lifestyle and medication, particularly statins, and if necessary, ezetimibe, to significantly lower LDL cholesterol. Other treatments, more focused on triglycerides and HDL cholesterol, are less well supported by randomized clinical trials and should be used on an individual basis. Newer agents, particularly the PCSK9 inhibitors, show a great promise for even greater lowering of LDL cholesterol, but we await the results of ongoing clinical trials.


First Report of Iris yellow spot virus Infecting Onion in Pakistan.
Onion (Allium cepa L.) is an important vegetable crop in Pakistan. According to the Food and Agricultural Organization (FAO), Pakistan is the world's fifth largest onion producer. The area and production is 127.8 thousand hectares and 1.7 million tons, respectively, with a yield of 13.8 tons per hectare during 2012. The agro-ecological diversity in the country enables onion production almost year round. Iris yellow spot virus (IYSV; family Bunyaviridae, genus Tospovirus), transmitted principally by Thrips tabaci, is an economically important viral pathogen of bulb and seed onion crops in many onion-growing areas of the world (1,3). In Asia, IYSV has been reported in India and Sri Lanka (2,4). During March to May 2012, as part of a survey for tospoviruses in vegetables, symptoms suspected to be caused by IYSV were observed on bulb and seed onions grown in farmers' fields in Faisalabad, Nankana, Sheikhupura, and Sialkot districts of Punjab. Symptoms consisted of spindle-shaped, straw colored, irregular chlorotic lesions with occasional green islands on the leaves. Approximately 60% of the fields surveyed had about 30% of the plants with these symptoms. The presence of the virus was confirmed with an IYSV-specific ELISA kit (Bioreba). IYSV infection was verified by RT-PCR with primers IYSV-F (TAAAACAAACATTCAAACAA) and IYSV-R (CTCTTAAACACATTTAACAAGCA) as forward and reverse primers, respectively. Amplicons of approximately 1,100 bp were obtained from the symptomatic samples, but not from healthy and water controls. The amplicons were cloned and sequenced. The IYSV-Pakistan isolates (GenBank Accession Nos. KF171103, KF171104, and KF171105) had the highest nucleotide sequence identity of 99% with the corresponding region of an IYSV isolate from Chile (DQ150107). To our knowledge, this is the first report of IYSV infecting onion in Pakistan. The relatively widespread occurrence of IYSV underscores the need for systematic surveys to assess its incidence and impact on onion bulb and seed crops so that appropriate management tactics can be developed. References: (1) D. H. Gent et al. Plant Dis. 88:446, 2004. (2) B. Mandal et al. Plant Dis. 94:468, 2012. (3) H. R. Pappu et al. Virus Res. 141:219, 2009. (4) K. S. Ravi et al. Plant Pathol. 55:288, 2006.


OprK and OprM define two genetically distinct multidrug efflux systems in Pseudomonas aeruginosa.
Multidrug-resistant derivatives of Pseudomonas aeruginosa PAO1 were obtained after stepwise selection on tetracycline or erythromycin. Two phenotypes were generated. The tetracycline-resistant mutant (TETR) was phenotypically similar to OprM-overexpressing strains. This group displayed cross-resistance to quinolones, chloramphenicol, and all beta-lactams tested except imipenem, with no changes in the erythromycin MICs for the strains. Sodium dodecyl sulfate-polyacrylamide gels showed the overproduction of an outer membrane protein in the range of 50 kDa and a 46-kDa inner membrane protein. The erythromycin-resistant mutant (ERYR) kept its susceptibility to all beta-lactams tested with the exception of cefpirome, but it was resistant to chloramphenicol, quinolones, and tetracycline and was hypersusceptible to imipenem. This mutant also exhibited overexpression of a 50-kDa outer membrane protein that was different from OprM and of a 43-kDa inner membrane protein. The phenotype of ERYR was comparable to those of OprK- and OprJ-overexpressing strains. These strains were therefore classified as the OprK-like group. Transduction of the oprK::omega-Hg mutation of strain K613 (K. Poole, K. Krebes, C. McNally, and S. Neshat, J. Bacteriol. 175:7363-7372, 1993) into the multidrug-resistant strains resulted in the loss of multidrug resistance and the acquisition of hypersusceptibility in the OprM group, while the phenotype of the OprK-like group was unaffected. These experiments demonstrated the existence of two genetically distinct efflux systems in P. aeruginosa. The identities of the operons encoding the two efflux systems and their physiological roles are discussed.


The impact of vaporized nanoemulsions on ultrasound-mediated ablation.
The clinical feasibility of using high-intensity focused ultrasound (HIFU) for ablation of solid tumors is limited by the high acoustic pressures and long treatment times required. The presence of microbubbles during sonication can increase the absorption of acoustic energy and accelerate heating. However, formation of microbubbles within the tumor tissue remains a challenge. Phase-shift nanoemulsions (PSNE) have been developed as a means for producing microbubbles within tumors. PSNE are emulsions of submicron-sized, lipid-coated, and liquid perfluorocarbon droplets that can be vaporized into microbubbles using short (<1 ms), high-amplitude (>5 MPa) acoustic pulses. In this study, the impact of vaporized phase-shift nanoemulsions on the time and acoustic power required for HIFU-mediated thermal lesion formation was investigated in vitro. PSNE containing dodecafluoropentane were produced with narrow size distributions and mean diameters below 200 nm using a combination of sonication and extrusion. PSNE was dispersed in albumin-containing polyacrylamide gel phantoms for experimental tests. Albumin denatures and becomes opaque at temperatures above 58°C, enabling visual detection of lesions formed from denatured albumin. PSNE were vaporized using a 30-cycle, 3.2-MHz, at an acoustic power of 6.4 W (free-field intensity of 4,586 W/cm(2)) pulse from a single-element, focused high-power transducer. The vaporization pulse was immediately followed by a 15-s continuous wave, 3.2-MHz signal to induce ultrasound-mediated heating. Control experiments were conducted using an identical procedure without the vaporization pulse. Lesion formation was detected by acquiring video frames during sonication and post-processing the images for analysis. Broadband emissions from inertial cavitation (IC) were passively detected with a focused, 2-MHz transducer. Temperature measurements were acquired using a needle thermocouple. Bubbles formed at the HIFU focus via PSNE vaporization enhanced HIFU-mediated heating. Broadband emissions detected during HIFU exposure coincided in time with measured accelerated heating, which suggested that IC played an important role in bubble-enhanced heating. In the presence of bubbles, the acoustic power required for the formation of a 9-mm(3) lesion was reduced by 72% and the exposure time required for the onset of albumin denaturation was significantly reduced (by 4 s), provided that the PSNE volume fraction in the polyacrylamide gel was at least 0.008%. The time or acoustic power required for lesion formation in gel phantoms was dramatically reduced by vaporizing PSNE into bubbles. These results suggest that PSNE may improve the efficiency of HIFU-mediated thermal ablation of solid tumors; thus, further investigation is warranted to determine whether bubble-enhanced HIFU may potentially become a viable option for cancer therapy.


Simultaneous evaluation of paternal and maternal immigrant gene flow and the implications for the overall genetic composition of Pinus densiflora dispersed seeds.
When considering the genetic implications of immigrant gene flow, it is important to evaluate both the proportions of immigrant gametes and their genetic composition. We simultaneously investigated paternal and maternal gene flow in dispersed seeds in a natural population of Pinus densiflora located along a ridge. The paternity and maternity of a total of 454 dispersed seeds (in 2004 and 2005) were accurately and separately assigned to 454 candidate adult trees, by analyzing the nuclear DNA of both diploid biparentally derived embryos and haploid maternally derived megagametophytes of the seeds. The relative genetic diversities and differences between within-population and immigrant groups of both paternally and maternally derived gametes (4 groups) that formed the genotypes of the seeds were evaluated. Using 8 microsatellite markers, we found that 64.0-72.6% of paternally derived gametes, and 17.8-20.2% of maternally derived gametes, were from other populations. Principal coordinate analysis showed that the 4 gamete groups tended to be plotted at different locations on the scattergram, indicating that they each have different genetic compositions. Substantial paternal and maternal immigrant gene flow occurred in this population, and therefore, the overall genetic variation of dispersed seeds is enhanced by both paternally and maternally derived immigrant gametes.


Memory enhancement in elderly humans: effects of glucose ingestion.
Recent findings demonstrate that, in rats, posttraining injections of glucose can enhance subsequent memory performance. The purpose of this study was to extend these findings to an elderly human population by testing the hypothesis that acute increases in peripheral blood glucose levels would enhance performance on memory tasks. Eleven subjects ranging in age from 58 to 76 years participated in the study. A within-subject, repeated-measures design was used in which each subject was tested under two different glycemic conditions: with fasting blood glucose levels and with increased blood glucose levels. Blood glucose was manipulated via consumption of beverages sweetened with either saccharin or glucose powder. After beverage consumption, subjects took four tests from the Wechsler Memory Scale. Comparisons of performance under the two glycemic conditions showed that scores were higher after the glucose beverage on narrative memory tests and the total Wechsler Scale. Nine of the eleven subjects had higher total Wechsler Scale scores. These results contribute to the growing evidence that glucose metabolism should be considered in the study of memory processes. The implications of such relationships for age-related memory deficits are discussed.


Production of interleukin-10 by combining a granulocyte and monocyte adsorption carrier with ulinastatin.
Interleukin (IL)-10 is an anti-inflammatory cytokine mainly produced by monocytes and is essential for the induction of anti-inflammatory intestinal macrophages with macrophage colony-stimulating factor (M-CSF). Thus, IL-10- and M-CSF-rich conditions in colonic tissues seem to contribute to the improvement of pathological conditions in patients with inflammatory bowel diseases (IBD). We have already reported that ulinastatin, a serine protease inhibitor, increases M-CSF production during granulocyte/monocyte (GM) adsorption to cellulose acetate (CA) beads (carriers for Adacolumn therapy). However, the effects of ulinastatin on IL-10 production have not been clarified. The aim of the present study was to clarify the effects of ulinastatin on IL-10 production during GM adsorption by in vitro experiments. Peripheral blood was divided into four groups: (Control) no ulinastatin added, no contact with CA beads; (1) no ulinastatin added, contact with CA beads; (2) ulinastatin added, no contact with CA beads; and (3) ulinastatin added, contact with CA beads. After incubation, IL-10 in the plasma was measured. Compared with the level in the Control group, plasma IL-10 was significantly higher only in group 3, in which ulinastatin was added in the presence of CA beads, but did not increase in the absence of CA beads. These results suggest that ulinastatin synergistically increases IL-10 production with monocyte adsorption stimuli. By increasing not only M-CSF but also IL-10, a combination of ulinastatin and Adacolumn therapy may improve clinical efficacy for the treatment of IBD in terms of the induction of anti-inflammatory intestinal macrophages.


A noisy linear map underlies oscillations in cell size and gene expression in bacteria.
During bacterial growth, a cell approximately doubles in size before division, after which it splits into two daughter cells. This process is subjected to the inherent perturbations of cellular noise and thus requires regulation for cell-size homeostasis. The mechanisms underlying the control and dynamics of cell size remain poorly understood owing to the difficulty in sizing individual bacteria over long periods of time in a high-throughput manner. Here we measure and analyse long-term, single-cell growth and division across different Escherichia coli strains and growth conditions. We show that a subset of cells in a population exhibit transient oscillations in cell size with periods that stretch across several (more than ten) generations. Our analysis reveals that a simple law governing cell-size control-a noisy linear map-explains the origins of these cell-size oscillations across all strains. This noisy linear map implements a negative feedback on cell-size control: a cell with a larger initial size tends to divide earlier, whereas one with a smaller initial size tends to divide later. Combining simulations of cell growth and division with experimental data, we demonstrate that this noisy linear map generates transient oscillations, not just in cell size, but also in constitutive gene expression. Our work provides new insights into the dynamics of bacterial cell-size regulation with implications for the physiological processes involved.


Obtaining blood cultures by venipuncture versus from central lines: impact on blood culture contamination rates and potential effect on central line-associated bloodstream infection reporting.
Reduce the frequency of contaminated blood cultures that meet National Healthcare Safety Network definitions for a central line-associated bloodstream infection (CLABSI). An observational study. A 500-bed university-affiliated hospital. A new blood culture policy discouraged drawing blood samples from central lines. Phlebotomists were reeducated regarding aseptic technique when obtaining blood samples by venipuncture. The intravenous therapy team was taught how to draw blood samples by venipuncture and served as a backup when phlebotomists were unable to obtain blood samples. A 2-nurse protocol and a special supply kit for obtaining blood samples from catheters were developed. Rates of blood culture contamination were monitored by the microbiology laboratory. The proportion of blood samples obtained for culture from central lines decreased from 10.9% during January-June 2010 to 0.4% during July-December 2012 (P < .001). The proportion of blood cultures that were contaminated decreased from 84 (1.6%) of 5,274 during January-June 2010 to 21 (0.5%) of 4,245 during January-June 2012 (P < .001). Based on estimated excess hospital costs of $3,000 per contaminated blood culture, the reduction in blood culture contaminants yielded an estimated annualized savings of $378,000 in 2012 when compared to 2010. In mid-2010, 3 (30%) of 10 reported CLABSIs were suspected to represent blood culture contamination compared with none of 6 CLABSIs reported from mid-November 2010 through June 2012 (P = 0.25). Multiple interventions resulted in a reduction in blood culture contamination rates and substantial cost savings to the hospital, and they may have reduced the number of reportable CLABSIs.


OH concentration and temperature measurements by use of near-resonant holographic interferometry.
Near-resonant holographic interferometry is demonstrated to measure temperature and species concentration in a two-dimensional steady premixed air-acetylene flame. A peak temperature of (2600 +/- 100) K and a peak OH number density of (9.6 +/- 0.3) x 10(22) m(-3) are obtained, consistent with the expected values for such a flame. These values are determined by recording interferograms with a laser assumed sufficiently detuned from line center so that pressure and temperature broadening can be ignored. The results are thus obtained without making prior assumptions on the temperature or pressure of the flame beyond the existence of thermal equilibrium.


High-resolution MEA platform for in-vitro electrogenic cell networks imaging.
A platform based on an active-pixel-sensor electrode array (APS-MEA) for high-resolution imaging of in-vitro electrogenic cell cultures is presented, characterized and validated under culture conditions. The system enables full frame acquisition at 8 kHz from 4096 microelectrodes integrated with separations of 21 microm and zoomed area acquisition with temporal resolutions down to 8 micros. This bi-modal acquisition feature opens new perspectives in particular for neuronal activity analysis and for the correlation of micro-scale and macro-scale behaviors. The low-noise performances of the integrated amplifier (11 microVRMS) combined with a hardware implementation reflecting image-/video-concepts enable high-resolution acquisitions with real-time processing capabilities adapted to the handling of the large amount of acquired data.


Sugar-sweetened soft drinks and obesity: a systematic review of the evidence from observational studies and interventions.
Sugar-sweetened soft drinks (SSD) are a special target of many obesity-prevention strategies, yet critical reviews tend to be more cautious regarding the aetiological role of SSD in promoting excess body weight. Since ongoing evaluation of this issue is important, the present systematic review re-examined the evidence from epidemiological studies and interventions, up to July 2008. Database searches of Medline, Cochrane reviews, Google scholar and a hand search of cross-references identified forty-four original studies (twenty-three cross-sectional, seventeen prospective and four intervention) in adults and children, as well as six reviews. These were critically examined for methodology, results and interpretation. Approximately half the cross-sectional and prospective studies found a statistically significant association between SSD consumption and BMI, weight, adiposity or weight gain in at least one subgroup. The totality of evidence is dominated by American studies where SSD consumption tends to be higher and formulations different. Most studies suggest that the effect of SSD is small except in susceptible individuals or at high levels of intake. Methodological weaknesses mean that many studies cannot detect whether soft drinks or other aspects of diet and lifestyle have contributed to excess body weight. Progress in reaching a definitive conclusion on the role of SSD in obesity is hampered by the paucity of good-quality interventions which reliably monitor diet and lifestyle and adequately report effect sizes. Of the three long-term (>6 months) interventions, one reported a decrease in obesity prevalence but no change in mean BMI and two found a significant impact only among children already overweight at baseline. Of the six reviews, two concluded that the evidence was strong, one that an association was probable, while three described it as inconclusive, equivocal or near zero. Reasons for some discrepancies are presented.


Neuromuscular Training Improves Lower Extremity Biomechanics Associated with Knee Injury during Landing in 11-13 Year Old Female Netball Athletes: A Randomized Control Study.
The purpose of this study was to examine the effects of a neuromuscular training (NMT) program on lower-extremity biomechanics in youth female netball athletes. The hypothesis was that significant improvements would be found in landing biomechanics of the lower-extremities, commonly associated with anterior cruciate ligament (ACL) injury, following NMT. Twenty-three athletes (age = 12.2 ± 0.9 years; height = 1.63 ± 0.08 m; mass = 51.8 ± 8.5 kg) completed two testing sessions separated by 7-weeks and were randomly assigned to either a experimental or control group. Thirteen athletes underwent 6-weeks of NMT, while the remaining 10 served as controls and continued their regular netball training. Three-dimensional lower-extremity kinematics and vertical ground reaction force (VGRF) were measured during two landing tasks, a drop vertical jump and a double leg broad jump with a single leg landing. The experimental group significantly increased bilateral knee marker distance during the bilateral landing task at maximum knee-flexion range of motion. Knee internal rotation angle during the unilateral landing task at maximum knee flexion-extension range of motion was significantly reduced (p ≤ 0.05, g > 1.00). The experimental group showed large, significant decreases in peak vertical ground reaction force in both landing tasks (p ≤ 0.05, g > -1.30). Control participants did not demonstrate any significant pre-to-post-test changes in response to the 6-week study period. Results of the study affirm the hypothesis that a 6-week NMT program can enhance landing biomechanics associated with ACL injury in 11-13 year old female netball athletes.


Tailoring the pore sizes of microporous pillared interlayered clays through layer charge reduction.
A F-rich potassium hectorite, [K(0.48(2))](inter)[Mg(2.54(8))Li(0.43)](oct)[Si(4)](tet)O(10)F(2), with a layer charge of x = 0.48 per formula unit (pfu) was synthesized by high temperature melt synthesis. After Mg-exchange, the layer charge could be reduced significantly post synthesis by annealing (250 °C) as confirmed by alkylammonium exchange and cation exchange capacity. By pillaring this new low charge material with Me(2)DABCO(2+) (N,N-dimethyl-1,1-diazabicyclo [2.2.2]octane dication) and Rh(bpy)(3)(3+) (rhodium-tris-2,2'-bipyridin trication), we observed a remarkable increase in micropore volume and pore diameter by Ar/Ar(l) physisorption measurements. This method allows the tailoring of pore sizes of pillared clays by reducing the layer charge and consequently the pillar density.


The thermodynamics of formation of a three-strand, DNA three-way junction complex.
Isothermal titration calorimetry (ITC) is used to study the thermodynamics of assembly of the three DNA oligonucleotides S1 (5'-GCCTGCCACCGC), S2 (5'-GCGGTGCGTCCG), and S3AA (5'-CGGACGAAGCAGGC) to form a three-way junction (TWJ) complex consisting of three double-helical arms radiating from a junction region having two unpaired adenosines in one strand (S3AA). The thermodynamics of assembly were measured for three different orders of addition of the component oligonucleotides at four temperatures between 10 and 25 degrees C. At each temperature studied, the overall values of delta H, delta S degrees, and delta G degrees for assembly of the complex from the component single strands were found to be independent of the order of addition. The enthalpy of binding, delta H, was found to be linearly dependent on temperature. From the temperature dependence of delta H, the change in heat capacity delta Cp, for the overall assembly of three strands to form the junction complex was calculated and found to be -1.6 kcal mol-1K-1. This work represents the first attempt to evaluate the thermodynamics of DNA TWJ formation by ITC.


Determination of the α-conotoxin Vc1.1 binding site on the α9α10 nicotinic acetylcholine receptor.
α-Conotoxin Vc1.1 specifically and potently inhibits the nicotinic acetylcholine receptor subtype α9α10 (α9α10 nAChR) and is a potential novel treatment for neuropathic pain. Here, we used a combination of computational modeling and electrophysiology experiments to determine the Vc1.1 binding site on the α9α10 nAChR. Interactions of Vc1.1 with two probable binding sites, α9α10 and α10α9, were modeled. Mutational energies calculated by assuming specific interactions in the α10α9 binding site correlated better with electrophysiological recordings than those assuming interactions with the α9α10 binding site. Two novel Vc1.1 analogues, [N9F]Vc1.1 and [N9W]Vc1.1, were predicted to have large differences in affinity between the two binding sites. Data from functional studies were consistent with computational predictions that assumed preferred binding of Vc1.1 to the α10α9 pocket. Moreover, our modeling study suggested that a single hydrogen bond formed between Vc1.1 and position 59 of the α10α9 pocket confers specificity to rat versus human α9α10 nAChRs.


Long-term follow-up of a high school alcohol misuse prevention program's effect on students' subsequent driving.
Alcohol-related injuries, particularly motor vehicle, are an important cause of adolescent mortality. School-based alcohol prevention programs have not been evaluated in terms of driving outcomes. This study examined the effects on subsequent driving of a high school-based alcohol prevention program. The Alcohol Misuse Prevention Study included a randomized test of the effectiveness of an alcohol misuse prevention curriculum conducted among 4,635 10th-grade students. Students were assigned to intervention (n = 1,820) or control (n = 2,815) groups and were followed for an average of 7.6 years after licensure, which typically occurred during or shortly after 10th grade. Outcomes examined included alcohol-related and other serious offenses, and at-fault, single-vehicle, and alcohol-related crashes. Only serious offenses (which included alcohol-related) had a significant treatment effect (statistically marginal) after we adjusted for sex, age, race, alcohol use/misuse, family structure, presence of prelicense offenses, age of driver licensure, and parental attitudes toward teen drinking. The effect was found only during the first year of licensure (estimated adjusted relative risk = 0.80, confidence interval = 0.63-1.01). Two first-year serious offense interactions were found. The positive effect was strongest among the largest subgroup of students, those who were drinking less than one drink per week on average before the curriculum, compared with those who drank more than one drink per week (p = 0.009). The effect was also stronger for the small subgroup of students whose parents had not expressed disapproval of teens' drinking, compared with those whose parents had disapproved (p = 0.004). These findings suggest that a high school-based alcohol prevention program can positively affect subsequent driving, particularly that of students who do not use alcohol regularly. The results highlight the need to start prevention efforts early and extend them beyond the initial exposure to driving. Programs should incorporate the differing backgrounds of the students.


Superbugs causing ventilator associated pneumonia in a tertiary care hospital and the return of pre-antibiotic era!
The rise in super bugs causing Ventilator-Associated Pneumonia (VAP) is a major cause of mortality and morbidity despite recent advances in management owing to the looming 'antibiotic apocalypse'. The aetiology and susceptibility pattern of the VAP isolates varies with patient population, type of intensive care unit (ICU) and is an urgent diagnostic challenge. The present study carried out for a period of one year in a tertiary care hospital, enrolled patients on mechanical ventilation (MV) for ≥48 hrs. Endotracheal aspirates (ETA) from suspected VAP patients were processed by semi quantitative method. Staphylococus aureus, members of Enterobacteriaceae were more common in early onset VAP (EOVAP), while Nonfermenting Gram negative bacilli (NFGNB) were significantly associated with late onset VAP (LOVAP). Most of the isolates were multi drug resistant (MDR) super bugs. With limited treatment options left for this crisis situation like the pre-antibiotic era; it is an alarm for rational antibiotic therapy usage and intensive education programs.


Survival Benefit in Older Patients Associated With Earlier Transplant With High KDPI Kidneys.
Given high dialysis mortality rates for patients older than 60 years, accepting a kidney with a high Kidney Donor Profile Index (KDPI) score could enable earlier and potentially preemptive transplantation (preKT). However, evidence regarding the risks of high KDPI allografts in older patients is limited. Our objective was to determine the relative benefit for older patients of KDPI greater than 85% transplant either preemptively or not compared with remaining on the waitlist. United Network of Organ Sharing data from 2003 to 2012 for adult deceased donor kidney transplant candidates was analyzed to evaluate patient survival in patients older than 60 years for preKT and non-preKT KDPI greater than 85% transplants compared with candidates remaining on the waitlist including patients who received KDPI 0% to 85% transplants according to multivariate Cox regression models. In the first year posttransplant for KDPI greater than 85% of transplants in recipients older than 60 years, preKT had a reduced mortality hazard (hazards ratio [HR], 0.61; 95% confidence interval [95% CI], 0.41-0.90) and non-preKT an increased mortality hazard (HR, 1.15; 95% CI, 1.03-1.27) compared with the waitlist including KDPI 0% to 85% transplant recipients. At 1 to 2 years and after 2 years, both KDPI greater than 85% groups had significant reductions in mortality (1-2 years: preKT HR, 0.38; 95% CI, [0.23-0.60] and non-preKT HR, 0.52; 95% CI, 0.45-0.61; and 2+ years: preKT HR, 0.50; 95% CI, 0.38-0.66 and non-preKT HR, 0.64; 95% CI, 0.58-0.70, respectively). PreKT and non-preKT KDPI greater than 85% transplant was associated with lower mortality hazard after the first year compared with the waitlist including KDPI 0% to 85% transplants in patients older than 60 years. Further consideration should be given to increased utilization of high KDPI grafts in older patients with the goal of avoiding or limiting time on dialysis.


Ancient genomic linkage couples metabolism with erythroid development.
Generation of mature cells from progenitors requires tight coupling of differentiation and metabolism. During erythropoiesis, erythroblasts are required to massively upregulate globin synthesis then clear extraneous material and enucleate to produce erythrocytes1-3. Nprl3 has remained in synteny with the α-globin genes for >500 million years4, and harbours the majority of the α-globin enhancers5. Nprl3 is a highly conserved inhibitor of mTORC1, which controls cellular metabolism. However, whether Nprl3 itself serves an erythroid role is unknown. Here, we show that Nprl3 is a key regulator of erythroid metabolism. Using Nprl3-deficient fetal liver and adult competitive bone marrow - fetal liver chimeras, we show that NprI3 is required for sufficient erythropoiesis. Loss of Nprl3 elevates mTORC1 signalling, suppresses autophagy and disrupts erythroblast glycolysis and redox control. Human CD34+ progenitors lacking NPRL3 produce fewer enucleated cells and demonstrate dysregulated mTORC1 signalling in response to nutrient availability and erythropoietin. Finally, we show that the α-globin enhancers upregulate NprI3 expression, and that this activity is necessary for optimal erythropoiesis. Therefore, the anciently conserved linkage of NprI3, α-globin and their associated enhancers has enabled coupling of metabolic and developmental control in erythroid cells. This may enable erythropoiesis to adapt to fluctuating nutritional and environmental conditions.


Rapid Improvement on a Temporal Attention Task within a Single Session of High-frequency Transcranial Random Noise Stimulation.
This study explored the modulatory effects of high-frequency transcranial random noise stimulation (tRNS) on visual sensitivity during a temporal attention task. We measured sensitivity to different onset asynchronies during a temporal order judgment task as a function of active stimulation relative to sham. While completing the task, participants were stimulated bilaterally for 20 min over either the TPJ or the human middle temporal area. We hypothesized that tRNS over the TPJ, which is critical to the temporal attention network, would selectively increase cortical excitability and induce cognitive training-like effects on performance, perhaps more so in the left visual field [Matthews, N., & Welch, L. Left visual field attentional advantage in judging simultaneity and temporal order. Journal of Vision, 15, 1-13, 2015; Romanska, A., Rezlescu, C., Susilo, T., Duchaine, B., & Banissy, M. J. High-frequency transcranial random noise stimulation enhances perception of facial identity. Cerebral Cortex, 25, 4334-4340, 2015]. In Experiment 1, we measured the performance of participants who judged the order of Gabors temporally imbedded in flickering discs, presented with onset asynchronies ranging from -75 msec (left disc first) to +75 msec (right disc first). In Experiment 2, we measured whether each participant's temporal sensitivity increased with stimulation by using temporal offsets that the participant initially perceived as simultaneous. We found that parietal cortex stimulation temporarily increased sensitivity on the temporal order judgment task, especially in the left visual field. Stimulation over human middle temporal area did not alter cortical excitability in a way that affected performance. The effects were cumulative across blocks of trials for tRNS over parietal cortex but dissipated when stimulation ended. We conclude that single-session tRNS can induce temporary improvements in behavioral sensitivity and that this shows promising insight into the relationship between cortical stimulation and neural plasticity.


International genetic evaluations for feed intake in dairy cattle through the collation of data from multiple sources.
Feed represents a large proportion of the variable costs in dairy production systems. The omission of feed intake measures explicitly from national dairy cow breeding objectives is predominantly due to a lack of information from which to make selection decisions. However, individual cow feed intake data are available in different countries, mostly from research or nucleus herds. None of these data sets are sufficiently large enough on their own to generate accurate genetic evaluations. In the current study, we collate data from 10 populations in 9 countries and estimate genetic parameters for dry matter intake (DMI). A total of 224,174 test-day records from 10,068 parity 1 to 5 records of 6,957 cows were available, as well as records from 1,784 growing heifers. Random regression models were fit to the lactating cow test-day records and predicted feed intake at 70 d postcalving was extracted from these fitted profiles. The random regression model included a fixed polynomial regression for each lactation separately, as well as herd-year-season of calving and experimental treatment as fixed effects; random effects fit in the model included individual animal deviation from the fixed regression for each parity as well as mean herd-specific deviations from the fixed regression. Predicted DMI at 70 d postcalving was used as the phenotype for the subsequent genetic analyses undertaken using an animal repeatability model. Heritability estimates of predicted cow feed intake 70 d postcalving was 0.34 across the entire data set and varied, within population, from 0.08 to 0.52. Repeatability of feed intake across lactations was 0.66. Heritability of feed intake in the growing heifers was 0.20 to 0.34 in the 2 populations with heifer data. The genetic correlation between feed intake in lactating cows and growing heifers was 0.67. A combined pedigree and genomic relationship matrix was used to improve linkages between populations for the estimation of genetic correlations of DMI in lactating cows; genotype information was available on 5,429 of the animals. Populations were categorized as North America, grazing, other low input, and high input European Union. Albeit associated with large standard errors, genetic correlation estimates for DMI between populations varied from 0.14 to 0.84 but were stronger (0.76 to 0.84) between the populations representative of high-input production systems. Genetic correlations with the grazing populations were weak to moderate, varying from 0.14 to 0.57. Genetic evaluations for DMI can be undertaken using data collated from international populations; however, genotype-by-environment interactions with grazing production systems need to be considered.


Molecular rotors confined at an ordered 2D interface.
Intramolecular rotation of molecules contained in a two-dimensional monolayer or a three-dimensional collapsed film at an air-water interface was investigated by in situ fluorescence spectroscopy of twisted intramolecular charge transfer (TICT) type 9-(2-carboxy-2-cyanovinyl)julolidine (CCVJ) derivatives. The TICT type molecules, CCVJ-C12 and CCVJ-Chol, that contain a linear alkyl dodecyl chain or a cholesteryl group, respectively, as their hydrophobic group, were designed and synthesized to manipulate them at the air-water interface. These lipophilized molecular rotors showed the general properties of TICT molecules in solutions that the fluorescence intensity increases with increasing viscosity of the solvent, which is induced by inhibition of internal molecular rotations. The molecular rotors CCVJ-C12 and CCVJ-Chol formed monolayers at the air-water interface and in situ fluorescence spectroscopy was performed during the in-plane compression of the monolayers. It was revealed that the monomer emissions were suppressed and only after the collapse of monolayers, excimer emission from both layers consisting of CCVJ-C12 or CCVJ-Chol was observed. Suppressed monomer emission from monolayers suggests that intramolecular rotation is not inhibited in dense ordered monolayers. Furthermore, fluorescence spectroscopy of Langmuir-Blodgett (LB) films indicated that molecular rotations are not inhibited in the monolayer transferred on the solid substrates.


Use of anticoagulants in elderly patients: practical recommendations.
Elderly people represent a patient population at high thromboembolic risk, but also at high hemorrhagic risk. There is a general tendency among physicians to underuse anticoagulants in the elderly, probably both because of underestimation of thromboembolic risk and overestimation of bleeding risk. The main indications for anticoagulation are venous thromboembolism (VTE) prophylaxis in medical and surgical settings, VTE treatment, atrial fibrillation (AF) and valvular heart disease. Available anticoagulants for VTE prophylaxis and initial treatment of VTE are low molecular weight heparins (LMWH), unfractionated heparin (UFH) or synthetic anti-factor Xa pentasaccharide fondaparinux. For long-term anticoagulation vitamin K antagonists (VKA) are the first choice and only available oral anticoagulants nowadays. Assessing the benefit-risk ratio of anticoagulation is one of the most challenging issues in the individual elderly patient, patients at highest hemorrhagic risk often being those who would have the greatest benefit from anticoagulants. Some specific considerations are of utmost importance when using anticoagulants in the elderly to maximize safety of these treatments, including decreased renal function, co-morbidities and risk of falls, altered pharmacodynamics of anticoagulants especially VKAs, association with antiplatelet agents, patient education. Newer anticoagulants that are currently under study could simplify the management and increase the safety of anticoagulation in the future.