Multidimensional MRI-CT atlas of the naked mole-rat brain (Heterocephalus glaber).
Naked mole-rats have a variety of distinctive features such as the organization of a hierarchical society (known as eusociality), extraordinary longevity, and cancer resistance; thus, it would be worthwhile investigating these animals in detail. One important task is the preparation of a brain atlas database that provide comprehensive information containing multidimensional data with various image contrasts, which can be achievable using a magnetic resonance imaging (MRI). Advanced MRI techniques such as diffusion tensor imaging (DTI), which generates high contrast images of fiber structures, can characterize unique morphological properties in addition to conventional MRI. To obtain high spatial resolution images, MR histology, DTI, and X-ray computed tomography were performed on the fixed adult brain. Skull and brain structures were segmented as well as reconstructed in stereotaxic coordinates. Data were also acquired for the neonatal brain to allow developmental changes to be observed. Moreover, in vivo imaging of naked mole-rats was established as an evaluation tool of live animals. The data obtained comprised three-dimensional (3D) images with high tissue contrast as well as stereotaxic coordinates. Developmental differences in the visual system were highlighted in particular by DTI. Although it was difficult to delineate optic nerves in the mature adult brain, parts of them could be distinguished in the immature neonatal brain. From observation of cortical thickness, possibility of high somatosensory system development replaced to the visual system was indicated. 3D visualization of brain structures in the atlas as well as the establishment of in vivo imaging would promote neuroimaging researches towards detection of novel characteristics of eusocial naked mole-rats.


Tuning the extraordinary transmission in a metallic/dielectric CDC hole array by changing the temperature.
Tunable extraordinary transmission via changing temperature of a porous metallic layer on top of a thin layer of dielectric strontium titanate (STO) was studied. The metallic layer has a through-hole array and each hole has a circular converging-diverging channel (CDC) shape, which induces the excitation of surface plasmon polaritons (SPPs) and then results in a controllable extraordinary optical transmission in the terahertz (THz) frequency range. We used a three-dimensional (3D) finite element method to analyze the transmission characteristics of the structure. Location and magnitude of the transmission peaks can be adjusted by hole size, converging angle, and thicknesses of metal and STO layers. Remarkably, the suggested structure presents a strong transmission dependency on temperature, which offers a new approach to actively and externally tune the transmission. This new design could lead to a family of temperature-sensitive devices working in the THz frequency range, promising in many applications including photonics, nanolithography, imaging, and sensing.


Effects of increasing atmospheric CO2 on the marine phytoplankton and bacterial metabolism during a bloom: A coastal mesocosm study.
Increases of atmospheric CO2 concentrations due to human activity and associated effects on aquatic ecosystems are recognized as an environmental issue at a global scale. Growing attention is being paid to CO2 enrichment effects under multiple stresses or fluctuating environmental conditions in order to extrapolate from laboratory-scale experiments to natural systems. We carried out a mesocosm experiment in coastal water with an assemblage of three model phytoplankton species and their associated bacteria under the influence of elevated CO2 concentrations. Net community production and the metabolic characteristics of the phytoplankton and bacteria were monitored to elucidate how these organisms responded to CO2 enrichment during the course of the algal bloom. We found that CO2 enrichment (1000μatm) significantly enhanced gross primary production and the ratio of photosynthesis to chlorophyll a by approximately 38% and 39%, respectively, during the early stationary phase of the algal bloom. Although there were few effects on bulk bacterial production, a significant decrease of bulk bacterial respiration (up to 31%) at elevated CO2 resulted in an increase of bacterial growth efficiency. The implication is that an elevation of CO2 concentrations leads to a reduction of bacterial carbon demand and enhances carbon transfer efficiency through the microbial loop, with a greater proportion of fixed carbon being allocated to bacterial biomass and less being lost as CO2. The contemporaneous responses of phytoplankton and bacterial metabolism to CO2 enrichment increased net community production by about 45%, an increase that would have profound implications for the carbon cycle in coastal marine ecosystems.


A Multi-Node Energy Prediction Approach Combined with Optimum Prediction Interval for RF Powered WSNs.
Energy prediction plays a vital role in designing an efficient power management system for any environmentally powered Wireless Sensor Networks (WSNs). Most of the Moving Average (MA)-based energy prediction methods depend on past energy readings of the concerned node to predict its future energy availability. However, in case of RF powered WSNs the harvesting history of the main node along with neighbouring nodes can also be used to develop a more robust prediction technique. In this paper, we propose a Multi-Node energy prediction method for Radio Frequency Energy Harvesting (RF-EH) WSNs, which predicts the future energy availability by taking into account harvesting history of all nodes surrounding the main node. We analyse the effective distance for prediction and also develop a mathematical model to compute the optimum value of prediction interval, which has a major effect in prediction accuracy and system design, considering energy neutrality. Results show that Multi-Node prediction is less sensitive to prediction interval while inheriting the advantages of MA techniques. Also, nodes located at a larger distance were utilized less for prediction, and as the prediction interval increased, the utilization of more distant nodes decreased. Furthermore, we also establish a linear relation between the prediction interval and the energy threshold limit.


Blood lead levels in Mexico and pediatric burden of disease implications.
Although there has been success in reducing lead exposure with the phase-out of leaded gasoline, exposure to lead in Mexico continues to threaten the health of millions, much of which is from lead-based glazes used in pottery that leaches into food. An extensive historical review and analysis of available data on blood lead levels in Mexican populations was conducted. We used a calculated geometric mean to evaluate the effect of lead on the pediatric burden of disease. An extensive bibliographic search identified 83 published articles from 1978 to 2010 with blood lead level (BLL) data in Mexican populations representing 150 data points from more than 50,000 study participants. Values from these publications were categorized into various groupings. We then calculated the incidence of disease and disability-adjusted life-years resulting from these BLLs using the World Health Organization's burden of disease spreadsheets for mild mental retardation. Reviewing all relevant studies, the geometric means of Mexican BLLs in urban and rural areas were found to be 8.85 and 22.24 ug/dL, respectively. Since the phase-out of leaded gasoline, the mean in urban areas was found to be 5.36 ug/dL and the average in rural areas is expected to be much higher. The U.S. Centers for Disease Control and Prevention's (CDC) upper limit of blood lead in children under the age of 6 years is 5 ug/dL and the current U.S. average is 1.2 ug/dL. Our results indicate that more than 15% of the population will experience a decrement of more than 5 IQ points from lead exposure. The analysis also leads us to believe that lead is responsible for 820,000 disability-adjusted life-years for lead-induced mild mental retardation for children aged 0 to 4 years. Lead continues to threaten the health of millions and remains a significant cause of disability in Mexico. Additional interventions in reducing or managing lead-based ceramic glazes are necessary to protect the public health.


Nix is a selective autophagy receptor for mitochondrial clearance.
Autophagy is the cellular homeostatic pathway that delivers large cytosolic materials for degradation in the lysosome. Recent evidence indicates that autophagy mediates selective removal of protein aggregates, organelles and microbes in cells. Yet, the specificity in targeting a particular substrate to the autophagy pathway remains poorly understood. Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins, ubiquitin-like modifiers that are required for the growth of autophagosomal membranes. In cultured cells, Nix recruits GABARAP-L1 to damaged mitochondria through its amino-terminal LC3-interacting region. Furthermore, ablation of the Nix:LC3/GABARAP interaction retards mitochondrial clearance in maturing murine reticulocytes. Thus, Nix functions as an autophagy receptor, which mediates mitochondrial clearance after mitochondrial damage and during erythrocyte differentiation.


Factors Impacting Range Hood Use in California Houses and Low-Income Apartments.
Venting range hoods can control indoor air pollutants emitted during residential cooktop and oven cooking. To quantify their potential benefits, it is important to know how frequently and under what conditions range hoods are operated during cooking. We analyzed data from 54 single family houses and 17 low-income apartments in California in which cooking activities, range hood use, and fine particulate matter (PM2.5) were monitored for one week per home. Range hoods were used for 36% of cooking events in houses and 28% in apartments. The frequency of hood use increased with cooking frequency across homes. In both houses and apartments, the likelihood of hood use during a cooking event increased with the duration of cooktop burner use, but not with the duration of oven use. Actual hood use rates were higher in the homes of participants who self-reported more frequent use in a pre-study survey, but actual use was far lower than self-reported frequency. Residents in single family houses used range hoods more often when cooking caused a discernible increase in PM2.5. In apartments, residents used their range hood more often only when high concentrations of PM2.5 were generated during cooking.


Meeting report: 4th ISIRV antiviral group conference: Novel antiviral therapies for influenza and other respiratory viruses.
The International Society for Influenza and other Respiratory Virus Diseases (isirv) held its 4th Antiviral Group Conference at the University of Texas on 2-4 June, 2015. With emerging resistance to the drugs currently licensed for treatment and prophylaxis of influenza viruses, primarily the neuraminidase inhibitor oseltamivir phosphate (Tamiflu) and the M2 inhibitors amantadine and rimantadine, and the lack of effective interventions against other respiratory viruses, the 3-day programme focused on the discovery and development of inhibitors of several virus targets and key host cell factors involved in virus replication or mediating the inflammatory response. Virus targets included the influenza haemagglutinin, neuraminidase and M2 proteins, and both the respiratory syncytial virus and influenza polymerases and nucleoproteins. Therapies for rhinoviruses and MERS and SARS coronaviruses were also discussed. With the emerging development of monoclonal antibodies as therapeutics, the potential implications of antibody-dependent enhancement of disease were also addressed. Topics covered all aspects from structural and molecular biology to preclinical and clinical studies. The importance of suitable clinical trial endpoints and regulatory issues were also discussed from the perspectives of both industry and government. This meeting summary provides an overview, not only for the conference participants, but also for those interested in the current status of antivirals for respiratory viruses.


Serological proteome analysis reveals new specific biases in the IgM and IgG autoantibody repertoires in autoimmune polyendocrine syndrome type 1.
Autoimmune polyendocrine syndrome type 1 (APS 1) is caused by mutations in the AIRE gene that induce intrathymic T-cell tolerance breakdown, which results in tissue-specific autoimmune diseases. To evaluate the effect of a well-defined T-cell repertoire impairment on humoral self-reactive fingerprints, comparative serum self-IgG and self-IgM reactivities were analyzed using both one- and two-dimensional western blotting approaches against a broad spectrum of peripheral tissue antigens. Autoantibody patterns of APS 1 patients were compared with those of subjects affected by other autoimmune endocrinopathies (OAE) and healthy controls. Using a Chi-square test, significant changes in the Ab repertoire were found when intergroup patterns were compared. A singular distortion of both serum self-IgG and self-IgM repertoires was noted in APS 1 patients. The molecular characterization of these antigenic targets was conducted using a proteomic approach. In this context, autoantibodies recognized more significantly either tissue-specific antigens, such as pancreatic amylase, pancreatic triacylglycerol lipase and pancreatic regenerating protein 1α, or widely distributed antigens, such as peroxiredoxin-2, heat shock cognate 71-kDa protein and aldose reductase. As expected, a well-defined self-reactive T-cell repertoire impairment, as described in APS 1 patients, affected the tissue-specific self-IgG repertoire. Interestingly, discriminant IgM reactivities targeting both tissue-specific and more widely expressed antigens were also specifically observed in APS 1 patients. Using recombinant targets, we observed that post translational modifications of these specific antigens impacted upon their recognition. The data suggest that T-cell-dependent but also T-cell-independent mechanisms are involved in the dynamic evolution of autoimmunity in APS 1.


Regulation by calcium of arachidonic acid metabolism in the isolated perfused rabbit heart.
Activation of beta-adrenergic receptors with isoproterenol fails to stimulate prostaglandin synthesis in the isolated rabbit heart perfused with Ca2+-free Krebs-Henseleit buffer. This lack of response could be due to reduced isoproterenol-stimulated liberation of arachidonic acid, reduced cyclooxygenase activity during Ca2+-free perfusion, or both. To test these hypotheses, we have examined the effect of isoproterenol and exogenous arachidonic acid on prostaglandin output in hearts perfused with Ca2+-containing and nominally Ca2+-free Krebs-Henseleit buffer. In hearts prelabelled with [3H]arachidonic acid and perfused with nominally Ca2+-free buffer, the release of radioactivity following isoproterenol was about 90% less than when Ca2+ was included in the perfusion buffer. When exogenous arachidonic acid was administered to hearts perfused with Ca2+-depleted buffer, the output of both 6-keto-prostaglandin F1 alpha and prostaglandin E2 was about threefold greater than when Ca2+ was present in the perfusion medium. In the absence of Ca2+, the dose response curve for arachidonic acid-induced 6-keto-prostaglandin F1 alpha synthesis underwent a parallel shift to the left, with no change in maximal synthesis levels, and a tenfold reduction in the ED50 of arachidonic acid. The cyclooxygenase activities of cell-free homogenates prepared from hearts perfused with and without Ca2+ were not different from each other and were both insensitive to added Ca2+. Reduction of the Na+ concentration of the perfusion medium to 35 mM resulted in increases in arachidonic acid-induced 6-keto-prostaglandin F1 alpha less than those obtained during Ca2+-free perfusion, but greater than that observed during perfusion with normal Na+ (139 mM) and Ca2+ (2.5 mM). Arachidonic acid induced 6-keto-prostaglandin F1 alpha output was inversely correlated with tissue Ca2+ but not Na+ content. These data suggest that in the absence of perfusate Ca2+, the availability of exogenous arachidonic acid to cyclooxygenase is increased, possibly by reduced incorporation into tissue phospholipids.


siRNA applications in nanomedicine.
The ability to specifically silence genes using RNA interference (RNAi) has wide therapeutic applications for the treatment of disease or the augmentation of tissue formation. RNAi is the sequence-specific gene silencing mediated by a 21-25 nucleotide double-stranded small interfering RNA (siRNA) molecule. siRNAs are incorporated into the RNA-induced silencing complex (RISC), which mediates mRNA sequence-specific binding and cleavage. Although RNAi has the potential to be a powerful therapeutic drug, its delivery remains a major limitation. The generation of nanosized particles is being investigated to enhance the delivery of siRNA-based drugs. These nanoparticles are generally designed to overcome one or more of the barriers encountered by the siRNA when trafficked to the cytosol. In this review, we will discuss recent advances in the design of delivery strategies for siRNA, focusing our attention to those strategies that have had in vivo success or have introduced novel functionality that allowed enhanced intracellular trafficking and/or cellular targeting. First, we will discuss the different barriers that must be overcome for efficient siRNA delivery. Second, we will discuss the approaches for siRNA delivery by size including direct modification of siRNAs (less than 10 nm), self-assembled particles based on cationic polymers and cationic lipids (100-300 nm), neutral liposomes (<200 nm), and macroscale matrices that contain naked siRNA or siRNA loaded nanoparticles (>100 microm). Finally, we will briefly discuss recent in vivo therapeutic success.


Phase diagram of the spin Hall effect.
We obtain analytic formulas for the frequency-dependent spin-Hall conductivity of a two-dimensional electron gas (2DEG) in the presence of impurities, linear spin-orbit Rashba interaction, and external magnetic field perpendicular to the 2DEG. We show how different mechanisms (skew scattering, side jump, and spin precession) can be brought in or out of focus by changing controllable parameters such as frequency, magnetic field, and temperature. We find, in particular, that the dc spin-Hall conductivity vanishes in the absence of a magnetic field, while a magnetic field restores the skew-scattering and side jump contributions proportionally to the ratio of magnetic and Rashba fields.


Success Of An Expedited Emergency Department Triage Evaluation System For Geriatric Trauma Patients Not Meeting Trauma Activation Criteria.
Geriatric patients are at increased risk of injury following low-energy mechanisms and are less tolerant of injury. Current criteria for trauma team activation (TTA) often miss these injuries. We evaluated a novel triage process for an expedited Emergency Medicine Physician evaluation protocol (T3) for at-risk geriatric sub-populations not meeting trauma team activation (TTA) criteria. Retrospective review of injured patients (≥65 years) from a Level II Trauma Center with an Injury Severity Score (ISS < 16), prior to (Pre-T3, Jan 2007-Oct 2009), and after (Post-T3, Jan 2010-Oct 2012), implementation of T3, as well as a contemporary period (CP, Jan 2013-Oct 2015). Demographics, physiologic variables, and timeliness of care were measured. Rates of ICU admission, operative procedures and lengths of stay and in-hospital mortality were compared for all periods. Logistic regression analysis determined variables independently associated with mortality. Post-T3, 49.2% of geriatric registry patients underwent T3 with a reduction in key time intervals. Median time to evaluation (42.1 mins vs 61.7 min, p<0.001), median time to CT (161.3 mins vs 212.9 mins, p<0.001) and EDLOS (364.6 mins vs 451.5 mins, p=0.023) were all reduced compared to non-expedited evaluations. There was no change in mortality after the implementation of the protocol. The T3 protocol expedited patient evaluation of at-risk geriatric patients that would not otherwise meet TTA criteria. The new process met the goals of the American College of Surgeons Trauma Quality Improvement Program while conserving resources.


Problems and barriers of pain management in the emergency department: Are we ever going to get better?
Pain is the most common reason people visit emergency rooms. Pain does not discriminate on the basis of gender, race or age. The state of pain management in the emergency department (ED) is disturbing. ED physicians often do not provide adequate analgesia to their patients, do not meet patients' expectations in treating their pain, and struggle to change their practice regarding analgesia. A review of multiple publications has identified the following causes of poor management of painful conditions in the ED: failure to acknowledge pain, failure to assess initial pain, failure to have pain management guidelines in ED, failure to document pain and to assess treatment adequacy, and failure to meet patient's expectations. The barriers that preclude emergency physicians from proper pain management include ethnic and racial bias, gender bias, age bias, inadequate knowledge and formal training in acute pain management, opiophobia, the ED, and the ED culture. ED physicians must realize that pain is a true emergency and treat it as such.


Diarrheal disease risk in rural Bangladesh decreases as tubewell density increases: a zero-inflated and geographically weighted analysis.
This study investigates the impact of tubewell user density on cholera and shigellosis events in Matlab, Bangladesh between 2002 and 2004. Household-level demographic, health, and water infrastructure data were incorporated into a local geographic information systems (GIS) database. Geographically-weighted regression (GWR) models were constructed to identify spatial variation of relationships across the study area. Zero-inflated negative binomial regression models were run to simultaneously measure the likelihood of increased magnitude of disease events and the likelihood of zero cholera or shigellosis events. The aim of this study was to examine the effect of tubewell density on both the occurrence of diarrheal disease and the magnitude of diarrheal disease incidence. In Matlab, households with greater tubewell density were more likely to report zero cholera or shigellosis events. Results for both cholera and shigellosis GWR models suggest that tubewell density effects are spatially stationary and the use of non-spatial statistical methods is appropriate. Increasing the amount of drinking water available to households through increased density of tubewells contributed to lower reports of cholera and shigellosis events in rural Bangladesh. Our findings demonstrate the importance of tubewell installation and access to groundwater in reducing diarrheal disease events in the developing world.


Health cognitions mediate physical (in)activity and walking in midlife women.
This study sought to identify which of the many facilitators and barriers to physical activity (PA) and walking are most significant to changing midlife women's exercise behaviour, with a view to informing future interventions. A cross-sectional survey explored associations of PA and sedentary time with self-reported health value, health locus of control (HLOC) and physical and mental health. Open-ended questions were included to elicit barriers and facilitators to walking. A sample of 295 women, aged 35-55, was recruited via women's groups, social media, online forums, and posters in doctors' surgeries, and completed the survey online. Quantitative data were analysed using descriptive statistics, t-test, analysis of variance and regression analyses. The low activity levels reported underline the urgency of developing interventions for this population. Results suggest that the key factors associated with higher activity levels are having a more internal HLOC, better mental health and placing greater value on health. While health cognitions may therefore be one important factor to target, these must be tackled in the context of women's other barriers to and facilitators of exercise. Thematic analysis of the open-ended questions revealed that the key barrier to walking was women's busy lives and their many competing priorities and that the most important facilitators were mental health and social connection. Overall, results suggest that, rather than emphasizing physical health and activity targets, practitioners should seek to make walking more relevant to women by emphasizing mental wellbeing and self-care, and more enjoyable by focusing on social and family-based walking interventions.


Searching the evidence: the clinically-effective nutritionist.
As a clinically-effective nutritionist faced with needing to find the answer to a clinical question quickly it is necessary to search the best evidence efficiently. The requirements are to: (1) avoid having lots of papers to read; (2) be able to access this information at one's place of work; (3) restrict reading to trials and systematic reviews of trials. If a decision has to be made while on the ward, the best resource is probably an easy-to-use book, Clinical Evidence. This resource is also available on-line, but there may not be access to the Internet on the ward. If a little more time is available, and access to the Internet, the following plan is suggested: (1) work out what the question is and highlight the search terms; (2) using the best search engine available, search MEDLiNE from 1990 for titles and abstracts of papers containing the search terms, this is the search strategy (limit the search by publication type by requesting randomised controlled trials only, English language only and human only); (3) if more or less than approximately ten hits are obtained, alter the limits of the search (not the search strategy); (4) read the abstract, or full paper where available, of the relevant hits and appraise this evidence.


Alpha terpineol: a potential anticancer agent which acts through suppressing NF-kappaB signalling.
Alpha terpineol is a bioactive component of Salvia libanotica essential oil extract and has shown antitumour activity. The cytotoxicity of alpha terpineol towards different tumour cell lines was evaluated in vitro. Mechanistic characterization was performed using analysis of drug activity in a cell line panel and drug-induced gene expression perturbation using the connectivity map approach. The small cell lung carcinoma was the cell line most sensitive to alpha terpineol. The results proposed alpha terpineol as an NF-kappaB inhibitor, which was confirmed by the observed dose-dependent inhibition of NF-kappaB translocation and activity using two NF-kappaB assays, and by the down-regulation of the expression of several NF-kappaB-related genes such as IL-1 beta and IL1R1. The results suggest that alpha terpineol inhibits the growth of tumour cells through a mechanism that involves inhibition of the NF-kappaB pathway.


A protective role for the A1 adenosine receptor in adenosine-dependent pulmonary injury.
Adenosine is a signaling nucleoside that has been implicated in the regulation of asthma and chronic obstructive pulmonary disease. Adenosine signaling can serve both pro- and anti-inflammatory functions in tissues and cells. In this study we examined the contribution of A(1) adenosine receptor (A(1)AR) signaling to the pulmonary inflammation and injury seen in adenosine deaminase-deficient (ADA-deficient) mice, which exhibit elevated adenosine levels. Experiments revealed that transcript levels for the A(1)AR were elevated in the lungs of ADA-deficient mice, in which expression was localized predominantly to alveolar macrophages. Genetic removal of the A(1)AR from ADA-deficient mice resulted in enhanced pulmonary inflammation along with increased mucus metaplasia and alveolar destruction. These changes were associated with the exaggerated expression of the Th2 cytokines IL-4 and IL-13 in the lungs, together with increased expression of chemokines and matrix metalloproteinases. These findings demonstrate that the A(1)AR plays an anti-inflammatory and/or protective role in the pulmonary phenotype seen in ADA-deficient mice, which suggests that A(1)AR signaling may serve to regulate the severity of pulmonary inflammation and remodeling seen in chronic lung diseases by controlling the levels of important mediators of pulmonary inflammation and damage.


Grading criteria for disease severity by pemphigus disease area index.
Pemphigus is a group of autoimmune blistering diseases that affect the skin and mucous membranes. A reliable and accurate disease severity tool to assess pemphigus severity is crucial for managing pemphigus and for clinical trials. The purpose of this study was to compare the pemphigus disease area index activity score (PDAI), the Japanese pemphigus disease severity score (JPDSS) and the physician's subjective impression, and also to find appropriate severity grading cut-offs for the PDAI. We also evaluated the correlation between PDAI activity score and the JPDSS. Thirty-seven pemphigus patients and 110 assessments were analyzed in this study. The optimal points of pemphigus disease severity score in PDAI were: mild (0-8), moderate (9-24) and severe (≥25). In mild or moderate cases, the JPDSS was well correlated with the PDAI, but in severe cases the JPDSS reached a plateau at a PDAI score of approximately 30. The PDAI evaluates disease severity more accurately than the JPDSS, particularly in severe cases. The PDAI is not only a useful tool to measure the extent of cutaneous lesions, but also an excellent scoring system for evaluating pemphigus disease severity.


Chronic obstructive pulmonary disease and lung cancer incidence in never smokers: a cohort study.
There has been limited evidence for the association between chronic obstructive pulmonary disease (COPD) and the incidence of lung cancer among never smokers. We aimed to estimate the risk of lung cancer incidence in never smokers with COPD, and to compare it with the risk associated with smoking. This cohort study involved 338 548 subjects, 40 to 84 years of age with no history of lung cancer at baseline, enrolled in the National Health Insurance Service National Sample Cohort. During 2 355 005 person-years of follow-up (median follow-up 7.0 years), 1834 participants developed lung cancer. Compared with never smokers without COPD, the fully-adjusted hazard ratios (95% CI) for lung cancer in never smokers with COPD, ever smokers without COPD, and ever smokers with COPD were 2.67 (2.09 to 3.40), 1.97 (1.75 to 2.21), and 6.19 (5.04 to 7.61), respectively. In this large national cohort study, COPD was also a strong independent risk factor for lung cancer incidence in never smokers, implying that COPD patients are at high risk of lung cancer, irrespective of smoking status.


ASH: A Modern Framework for Parallel Spatial Hashing in 3D Perception.
We present ASH, a modern and high-performance framework for parallel spatial hashing on GPU. Compared to existing GPU hash map implementations, ASH achieves higher performance, supports richer functionality, and requires fewer lines of code (LoC) when used for implementing spatially varying operations from volumetric geometry reconstruction to differentiable appearance reconstruction. Unlike existing GPU hash maps, the ASH framework provides a versatile tensor interface, hiding low-level details from the users. In addition, by decoupling the internal hashing data structures and key-value data in buffers, we offer direct access to spatially varying data via indices, enabling seamless integration to modern libraries such as PyTorch. To achieve this, we 1) detach stored key-value data from the low-level hash map implementation; 2) bridge the pointer-first low level data structures to index-first high-level tensor interfaces via an index heap; 3) adapt both generic and non-generic integer-only hash map implementations as backends to operate on multi-dimensional keys. We first profile our hash map against state-of-the-art hash maps on synthetic data to show the performance gain from this architecture. We then show that ASH can consistently achieve higher performance on various large-scale 3D perception tasks with fewer LoC by showcasing several applications, including 1) point cloud voxelization, 2) retargetable volumetric scene reconstruction, 3) non-rigid point cloud registration and volumetric deformation, and 4) spatially varying geometry and appearance refinement. ASH and its example applications are open sourced in Open3D (http://www.open3d.org).


Infectious diseases in allogeneic haematopoietic stem cell transplantation: prevention and prophylaxis strategy guidelines 2016.
Infectious complications after allogeneic haematopoietic stem cell transplantation (allo-HCT) remain a clinical challenge. This is a guideline provided by the AGIHO (Infectious Diseases Working Group) of the DGHO (German Society for Hematology and Medical Oncology). A core group of experts prepared a preliminary guideline, which was discussed, reviewed, and approved by the entire working group. The guideline provides clinical recommendations for the preventive management including prophylactic treatment of viral, bacterial, parasitic, and fungal diseases. The guideline focuses on antimicrobial agents but includes recommendations on the use of vaccinations. This is the updated version of the AGHIO guideline in the field of allogeneic haematopoietic stem cell transplantation utilizing methods according to evidence-based medicine criteria.


Staminal evolution in the genus Salvia (Lamiaceae): molecular phylogenetic evidence for multiple origins of the staminal lever.
The genus Salvia has traditionally included any member of the tribe Mentheae (Lamiaceae) with only two stamens and with each stamen expressing an elongate connective. The recent demonstration of the non-monophyly of the genus presents interesting implications for staminal evolution in the tribe Mentheae. In the context of a molecular phylogeny, the staminal morphology of the various lineages of Salvia and related genera is characterized and an evolutionary interpretation of staminal variation within the tribe Mentheae is presented. Two molecular analyses are presented in order to investigate phylogenetic relationships in the tribe Mentheae and the genus Salvia. The first presents a tribal survey of the Mentheae and the second concentrates on Salvia and related genera. Schematic sketches are presented for the staminal morphology of each major lineage of Salvia and related genera. These analyses suggest an independent origin of the staminal elongate connective on at least three different occasions within the tribe Mentheae, each time with a distinct morphology. Each independent origin of the lever mechanism shows a similar progression of staminal change from slight elongation of the connective tissue separating two fertile thecae to abortion of the posterior thecae and fusion of adjacent posterior thecae. A monophyletic lineage within the Mentheae is characterized consisting of the genera Lepechinia, Melissa, Salvia, Dorystaechas, Meriandra, Zhumeria, Perovskia and Rosmarinus. Based on these results the following are characterized: (1) the independent origin of the staminal lever mechanism on at least three different occasions in Salvia, (2) that Salvia is clearly polyphyletic, with five other genera intercalated within it, and (3) staminal evolution has proceeded in different ways in each of the three lineages of Salvia but has resulted in remarkably similar staminal morphologies.


Symptoms of ocular surface disease in construction workers: comparative study with office workers.
To investigate and contrast the prevalence of dry eye symptoms in construction workers and office workers using the OSDI questionnaire. A cross-sectional, observational study was conducted using the OSDI questionnaire to evaluate dry eye symptoms and associated risk factors. Sampled size calculation with a power of 80% and a 95% degree of confidence suggested the inclusion of 298 participants. We studied 304 subjects (149 construction workers and 155 office workers). More than half (55%) of the participants presented dry eye symptoms (OSDI > 12). The average OSDI score was 21.30 ± 22.20 points, being lower in the group of construction workers (12.45 ± 17.50) than in-office workers (28.51 ± 22.99) (p < 0.001). Considering participants who had moderate and severe symptoms (23 to 100 points in OSDI), office workers presented dry eye symptoms 4.15 times more frequently than construction workers (OR 4.15, 95% CI 2.52, 6.85). Women presented statistical evidence of higher OSDI scores than men (32.47 ± 23.72 vs. 14.87 ± 18.48, respectively). construction workers have four times less risk of presenting dry eye symptoms than people working in the average office space. This highlights the pernicious effects on the ocular surface of the office environment, which poses a significant risk for the development or worsening of dry eye symptoms.


A 3-dimensional extracellular matrix as a delivery system for the transplantation of glioma-targeting neural stem/progenitor cells.
Neural stem/progenitor cells (NSPCs) display inherent pathotropic properties that can be exploited for targeted delivery of therapeutic genes to invasive malignancies in the central nervous system. Optimizing transplantation efficiency will be essential for developing relevant NSPC-based brain tumor therapies. To date, the real-world issue of handling and affixing NSPCs in the context of the neurosurgical resection cavity has not been addressed. Stem cell transplantation using biocompatible devices is a promising approach to counteract poor NSPC graft survival and integration in various types of neurological disorders. Here, we report the development of a 3-dimensional substrate that is based on extracellular matrix purified from tissue-engineered skin cultures (3DECM). 3DECM enables the expansion of embedded NSPCs in vitro while retaining their uncommitted differentiation status. When implanted in intracerebral glioma models, NSPCs were able to migrate out of the 3DECM to targeted glioma growing in the contralateral hemisphere, and this was more efficient than the delivery of NSPC by intracerebral injection of cell suspensions. Direct application of a 3DECM implant into a tumor resection cavity led to a marked NSPC infiltration of recurrent glioma. The semisolid consistency of the 3DECM implants allowed simple handling during the surgical procedure of intracerebral and intracavitary application and ensured continuous contact with the surrounding brain parenchyma. Here, we demonstrate proof-of-concept of a matrix-supported transplantation of tumor-targeting NSPC. The semisolid 3DECM as a delivery system for NSPC has the potential to increase transplantation efficiency by reducing metabolic stress and providing mechanical support, especially when administered to the surgical resection cavity after brain tumor removal.


Disability and HIV: a systematic review and a meta-analysis of the risk of HIV infection among adults with disabilities in Sub-Saharan Africa.
More than one billion people worldwide are estimated to be living with a disability. A significant proportion of them lives in Sub-Saharan Africa where they are reported to be at increased risk of HIV. However, quantitative evidence on this remains scarce. A systematic review and a meta-analysis of the risk of HIV infection among people with disabilities living in Sub-Saharan Africa were undertaken. We searched all published or unpublished studies and national surveys reporting HIV prevalence among adults with disabilities living in Sub-Saharan Africa between 2000 and 2013. The risk ratio (RR) of HIV infection in people with disabilities versus people without disabilities was estimated through a random-effects meta-analysis. Of the 12,252 references screened, 13 studies were selected. HIV prevalence varied widely across studies from 1.1% to 29%. Pooled RRs of HIV infection in people with disabilities compared to the general population were 1.31 (1.02-1.69) overall; 1.16 (0.71-1.87) among people with mental illness or intellectual disabilities and 1.07 (0.58-1.95) among people with hearing disabilities. This meta-analysis provides evidence that people with disabilities do not have a lower risk of HIV when compared to the general population, and that women with disabilities are especially affected. A clear increasing gradient in the risk of HIV according to gender and disability status was also observed. The important heterogeneity across studies and their varying quality warrant a closer look at the intersection between disability and HIV. Additional studies with more systematic approaches and with higher-quality methodologies are required to further address this knowledge gap.


Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation.
ATP-dependent nucleosome remodeling and core histone acetylation and deacetylation represent mechanisms to alter nucleosome structure. NuRD is a multisubunit complex containing nucleosome remodeling and histone deacetylase activities. The histone deacetylases HDAC1 and HDAC2 and the histone binding proteins RbAp48 and RbAp46 form a core complex shared between NuRD and Sin3-histone deacetylase complexes. The histone deacetylase activity of the core complex is severely compromised. A novel polypeptide highly related to the metastasis-associated protein 1, MTA2, and the methyl-CpG-binding domain-containing protein, MBD3, were found to be subunits of the NuRD complex. MTA2 modulates the enzymatic activity of the histone deacetylase core complex. MBD3 mediates the association of MTA2 with the core histone deacetylase complex. MBD3 does not directly bind methylated DNA but is highly related to MBD2, a polypeptide that binds to methylated DNA and has been reported to possess demethylase activity. MBD2 interacts with the NuRD complex and directs the complex to methylated DNA. NuRD may provide a means of gene silencing by DNA methylation.


Rearrangement and expression of the antigen receptor alpha, beta and gamma genes in suppressor antigen-specific T cell lines.
The rearrangement and transcription of the antigen receptor alpha, beta and gamma genes were investigated in murine antigen-specific suppressor T cell lines, to establish whether the suppressor T cell subset expresses the same antigen receptor transcripts previously found in helper and cytotoxic T lymphocytes. The genomic organization of the alpha, beta and gamma chain loci was investigated using probes representative of the entire gene or fragments from variable, joining and constant regions. The present results show that in functional suppressor T cells the three antigen receptor genes are all rearranged. The beta gene is expressed in all the tested cell lines, while the expression of the alpha and gamma genes is variable. In one cell line (LH8) alpha and gamma genes are not efficiently transcribed; in the other cell line (LA41) the gamma mRNA is found in amounts similar to beta mRNA, whereas the alpha gene is expressed at low levels. These data suggest that in suppressor T cells no direct correlation exists between the expression of alpha, beta and gamma antigen receptor genes and the effector function.


Strategy of total synthesis based on the use of Rh-catalyzed stereoselective 1,4-addition.
In 1998, Hayashi and Miyaura reported the first asymmetric conjugate addition of aryl- and alkenyl-boronic acids to α,β-unsaturated ketones using chiral rhodium complexes as catalysts. During the last decade, this reaction has been developed quickly and the enantioselectivity was significantly improved with the emergence of new phosphine ligands. In addition to the methodological work, this reaction was applied as a key step in the total synthesis of natural compounds. The purpose of this paper focuses on examples of the use of this reaction to prepare elaborated chiral molecules with high diastereoselectivies and/or enantioselectivities.


Parents who use drugs: accounting for damage and its limitation.
Parents who use drugs parent in a context of heightened concern regarding the damaging effects of parental drug use on child welfare and family life. Yet there is little research exploring how parents who use drugs account for such damage and its limitation. We draw here upon analyses of audio-recorded depth qualitative interviews, conducted in south-east England between 2008 and 2009, with 29 parents who use drugs. Our approach to thematic analysis treated accounts as co-produced and socially situated. An over-arching theme of accounts was 'damage limitation'. Most damage limitation work centred on efforts to create a sense of normalcy of family life, involving keeping drug use secret from children, and investing heavily in strategies to maintain ambiguity regarding children's awareness. Our analysis highlights that damage limitation strategies double-up in accounts as resources of child protection as well as self protection. This illuminates tensions in the multiple functions that accounts of damage limitation can serve. We draw a distinction between accounts in which damage is qualified and those in which damage is accepted. Accounts of damage qualification highlight a theme of 'good enough' parenting. Accounts of damage acceptance highlight a theme of 'recovery'. We find that the interview accounts operate in response to a regulative norm of 'good parenting' in which one strives to deflect damaged identity through narratives of damage qualification and to seek understanding and acceptance through narratives of recovery. Noting the absence of space for parents who use drugs to openly reflect or talk about the challenges they face, we identify the need for social change interventions to create enabling environments for earlier help seeking and talking.


Mycobacterium tuberculosis-specific cytokine biomarkers to differentiate active TB and LTBI: A systematic review.
New tests are needed to overcome the limitations of existing immunodiagnostic tests for tuberculosis (TB) infection, including their inability to differentiate between active TB and latent TB infection (LTBI). This review aimed to identify the most promising cytokine biomarkers for use as stage-specific markers of TB infection. A systematic review was done using electronic databases to identify studies that have investigated Mycobacterium tuberculosis (MTB)-specific cytokine responses as diagnostic tools to differentiate between LTBI and active TB. The 56 studies included in this systematic review measured the MTB-specific responses of 100 cytokines, the most frequently studied of which were IFN-γ, IL-2, TNF-α, IP-10, IL-10 and IL-13. Ten studies assessed combinations of cytokines, most commonly IL-2 and IFN-γ. For most cytokines, findings were heterogenous between studies. The variation in results likely relates to differences in the study design and laboratory methods, as well as participant and environmental factors. Although several cytokines show promise as stage-specific markers of TB infection, this review highlights the need for further well-designed studies, in both adult and paediatric populations, to establish which cytokine(s) will be of most use in a new generation of immunodiagnostic tests.


Long-term outcome of unilateral deep brain stimulation of the subthalamic nucleus for a patient with drug-resistant focal myoclonic seizure.
It remains an unsolved problem in the treatment of patients with refractory focal epilepsy originating from the motor cortex since resection surgery can result in significant morbidity. Neurostimulation has emerged as an effective method for treating patients who are not suitable for conventional surgical procedures due to its relative safety, reversibility, and lower risk of complications. The subthalamic nucleus (STN) has been shown to be a potential target for treating refractory motor seizures. Here, we report a favorable outcome of unilateral deep brain stimulation (DBS) of the STN for a patient with drug-resistant focal myoclonic seizures during a 5-year follow-up period.


Effect of suckling on gastric motility in lactating rats.
Recent reports indicate that in male rats dehydration, LiCl, and cholecystokinin (CCK) each stimulate pituitary oxytocin (OT) secretion and also decrease gastric emptying and motility. In contrast, the present experiments demonstrate that nipple attachment and sucking by pups, a well-known stimulus for neurohypophysial secretion of OT, did not decrease gastric motility in lactating rats. Moreover, systemic injection of naloxone, which is known to potentiate the inhibitory effects of LiCl and CCK on gastric motility in male rats, had no effect on gastric motility of lactating rats while nursing. These data indicate that pituitary OT secretion from magnocellular neurons is not invariably linked to decreased gastric motility in rats. As such, our results support previous findings that inhibition of gastric motility is not secondary to the pituitary secretion of OT but allow a possible role for parvocellular oxytocinergic neurons that project from the hypothalamic paraventricular nucleus to the brain stem in the control of gastric function.


Contribution of the multi-echo approach in accelerated functional magnetic resonance imaging multiband acquisition.
We wanted to verify the effect of combining multi-echo (ME) functional magnetic resonance imaging (fMRI) with slice acceleration in simultaneous multi-slice acquisition. The aim was to shed light on the benefits of multiple echoes for various acquisition settings, especially for levels of slice acceleration and flip angle. Whole-brain ME fMRI data were obtained from 26 healthy volunteers (using three echoes; seven runs with slice acceleration 1, 4, 6, and 8; and two different flip angles for each of the first three acceleration factors) and processed as single-echo (SE) data and ME data based on optimal combinations weighted by the contrast-to-noise ratio. Global metrics (temporal signal-to-noise ratio, signal-to-noise separation, number of active voxels, etc.) and local characteristics in regions of interest were used to evaluate SE and ME data. ME results outperformed SE results in all runs; the differences became more apparent for higher acceleration, where a significant decrease in data quality is observed. ME fMRI can improve the observed data quality metrics over SE fMRI for a wide range of accelerated fMRI acquisitions.


Kinetic Simulations of Magnetic Reconnection in Partially Ionized Plasmas.
Fast magnetic reconnection occurs in nearly all natural and laboratory plasmas and rapidly releases stored magnetic energy. Although commonly studied in fully ionized plasmas, if and when fast reconnection can occur in partially ionized plasmas, such as the interstellar medium or solar chromosphere, is not well understood. This Letter presents the first fully kinetic particle-in-cell simulations of partially ionized reconnection and demonstrates that fast reconnection can occur in partially ionized systems. In the simulations, the transition to fast reconnection occurs when the current sheet width thins below the ion-inertial length in contrast to previous analytic predictions. The peak reconnection rate is ≥0.08 when normalized to the bulk Alfvén speed (including both ion and neutral mass), consistent with previous experimental results. However, when the bulk Alfvén speed falls below the neutral sound speed, the rate becomes system size dependent. The normalized inflow velocity is ionization fraction dependent, which is shown to be a result of neutral momentum transport. A model for the inflow is developed which agrees well with the simulation results.


Palbociclib (PD0332991)-a Selective and Potent Cyclin-Dependent Kinase Inhibitor: A Review of Pharmacodynamics and Clinical Development.
Palbociclib (PD0332991) is a newly developed drug that received breakthrough designation and recent US Food and Drug Administration approval in combination with endocrine therapy in the treatment of hormone receptor positive, ERBB2-negative (formerly HER2 or HER2/neu) breast cancer in the first-line metastatic setting. Herein we describe the preclinical and translational data and early- and late-phase clinical trials in which palbociclib has been investigated in a broad array of tumor types. We discuss the pharmacodynamics, pharmacokinetics, toxic effects, and clinical response rates. On March 1, 2015, we conducted a review of the literature describing the development of palbociclib. We used the PubMed search terms "PD0332991," "palbociclib," and "CDK4/6 inhibitor" to find all published articles of interest, without limitation as to publication date. Palbociclib is a potent and specific oral cyclin-dependent kinase (CDK) 4/6 inhibitor that has strong preclinical data to support its activity in retinoblastoma protein-expressing tumors. Phase 1 trials have demonstrated safety, and phase 2 trials have shown single-agent activity in mantle-cell lymphoma, breast cancer, liposarcoma, and teratoma with reversible neutropenia as the main toxic effect. Addition of palbociclib to endocrine therapy improves progression-free survival in endocrine therapy-naïve and endocrine therapy-resistant metastatic settings. Palbociclib is well tolerated and has therapeutic potential for multiple cancers, including breast cancer, where its efficacy has been demonstrated alone and in combination with endocrine therapy. Additional combinations of palbociclib with endocrine therapy, chemotherapy, and targeted therapy have potential in various tumors, and phase 3 trials are under way.


Phase I trial of the cyclin-dependent kinase inhibitor and protein kinase C inhibitor 7-hydroxystaurosporine in combination with Fluorouracil in patients with advanced solid tumors.
Preclinical studies indicate that the cyclin-dependent kinase and protein kinase C inhibitor 7-hydroxystaurosporine (UCN-01) potentiates the cytotoxic effects of fluorouracil (FU). We designed a phase I clinical trial of FU in combination with UCN-01. FU was administered as a weekly 24-hour infusion. Doses were escalated in successive cohorts according to a modified Fibonacci design. UCN-01 was administered once every 4 weeks, immediately after disconnection from FU, at a dose of 135 mg/m(2) over 72 hours in cycle 1 and 67.5 mg/m(2) over 36 hours in subsequent cycles. FU and UCN-01 pharmacokinetics were obtained on all patients, and thymidylate synthetase (TS) activity was measured in peripheral-blood mononuclear cells by reverse-transcriptase polymerase chain reaction. We escalated the weekly FU dose to 2,600 mg/m(2) in combination with once a month infusions of UCN-01. Dose-limiting toxicity included arrhythmia and syncope. Other toxicities included hyperglycemia, headache, and nausea and vomiting. The mean maximal plasma concentration of UCN-01 was 33.5 micromol/L. There was significant interpatient variability, which correlated with plasma concentrations of alpha-1 acid glycoprotein. FU was rapidly cleared and the dose had no effect on the area under the curve of UCN-01. Changes in TS expression were detectable in peripheral-blood mononuclear cells after administration of UCN-01 but did not correlate with toxicity or activity. We observed no objective response, although seven patients had stable disease, six of whom had received prior fluoropyrimidines. The combination of weekly infusions of FU and monthly UCN-01 can be administered safely and warrants further study in phase II trials. The recommended phase II dose of FU in combination with monthly UCN-01 is 2,600 mg/m(2).


Risk factors for chronic rejection in renal allograft recipients.
Chronic rejection is a major barrier to long-term renal allograft survival. Cyclosporine, though effective at reducing graft loss to acute rejection, has had little impact on the incidence of chronic rejection. Between June 2, 1986 and January 22, 1991, 587 kidney-alone transplants (566 patients) were performed, and had been entered into our renal transplant database and had at least 1 year of follow-up: 103 with biopsy-proven chronic rejection (37 living-related donor, 66 cadaver) and 484 without chronic rejection (236 LRD 248 CAD). The 5-year patient survival was 84% for recipients with biopsy-proven chronic rejection vs. 89% without (P = .08). The 5-year graft survival was 31% for recipients with biopsy-proven chronic rejection vs. 81% without (P < .0001). Using multivariate analysis, we determined the impact on the incidence of chronic rejection of these variables: transplant number, age at transplant (< 18 years, 18 to 50 years, > 50 years), gender, human leukocyte antigen matching, peak and transplant panel-reactive antibody, acute rejection episodes, infections (including cytomegalovirus, viral, and bacterial), donor age, and CsA dosage at 1 year (< 5 mg/kg vs. > or = 5 mg/kg). Logistic regression models were fit to the data using a forward stepwise selection procedure. In this analysis, risk factors included an acute rejection episode (P < .001), CsA dosage < 5 mg/kg/day at 1 year (P = .007), infection (P = .023), female gender (P = .042), and retransplant (P = .103). Individual analyses were done for CAD and LRD recipients. For both groups, important variables were acute rejection, infection, CsA dosage at 1 year, and age at transplant. In conclusion, acute rejection, CsA dosage < 5 mg/kg/day at 1 year, and infection are the major risk factors for the development of chronic rejection, suggesting that chronic rejection may be the result of inadequate immunosuppression (acute rejection episodes and low CsA dosage) or the production of inflammatory cytokines (infections).


Evaluating effectiveness of screening house eaves as a potential intervention for reducing indoor vector densities and malaria prevalence in Nyabondo, western Kenya.
Mosquito-proofing of houses using wire mesh screens is gaining greater recognition as a practical intervention for reducing exposure to malaria transmitting mosquitoes. Screening potentially protects all persons sleeping inside the house against transmission of mosquito-borne diseases indoors. The study assessed the effectiveness of house eaves screening in reducing indoor vector densities and malaria prevalence in Nyabondo, western Kenya. 160 houses were selected for the study, with half of them randomly chosen for eaves screening with fibre-glass coated wire mesh (experimental group) and the other half left without screening (control group). Randomization was carried out by use of computer-generated list in permuted blocks of ten houses and 16 village blocks, with half of them allocated treatment in a ratio of 1:1. Cross-sectional baseline entomological and parasitological data were collected before eave screening. After baseline data collection, series of sampling of indoor adult mosquitoes were conducted once a month in each village using CDC light traps. Three cross-sectional malaria parasitological surveys were conducted at three month intervals after installation of the screens. The primary outcome measures were indoor Anopheles mosquito density and malaria parasite prevalence. A total of 15,286 mosquitoes were collected over the two year period using CDC light traps in 160 houses distributed over 16 study villages (mean mosquitoes = 4.35, SD = 11.48). Of all mosquitoes collected, 2,872 (18.8%) were anophelines (2,869 Anopheles gambiae sensu lato, 1 Anopheles funestus and 2 other Anopheles spp). Overall, among An. gambiae collected, 92.6% were non-blood fed, 3.57% were blood fed and the remaining 0.47% were composed of gravid and half gravid females. More indoor adult mosquitoes were collected in the control than experimental arms of the study. Results from cross-sectional parasitological surveys showed that screened houses recorded relatively low malaria parasite prevalence rates compared to the control houses. Overall, malaria prevalence was 5.6% (95% CI: 4.2-7.5) n = 1,918, with baseline prevalence rate of 6.1% (95% CI: 3.9-9.4), n = 481 and 3rd follow-up survey prevalence of 3.6% (95% CI: 2.0-6.8) n = 494. At all the three parasitological follow-up survey points, house screening significantly reduced the malaria prevalence by 100% (p < 0.001), 63.6% (p = 0.026), and 100% (p < 0.001) in the 1st, 2nd and 3rd follow-up surveys respectively. The study demonstrated that house eave screening has potential to reduce indoor vector densities and malaria prevalence in high transmission areas.


Current knowledge in lentil genomics and its application for crop improvement.
Most of the lentil growing countries face a certain set of abiotic and biotic stresses causing substantial reduction in crop growth, yield, and production. Until-to date, lentil breeders have used conventional plant breeding techniques of selection-recombination-selection cycle to develop improved cultivars.These techniques have been successful in mainstreaming some of the easy-to-manage monogenic traits. However, in case of complex quantitative traits, these conventional techniques are less precise. As most of the economic traits are complex, quantitative, and often influenced by environments and genotype-environment interaction, the genetic improvement of these traits becomes difficult. Genomics assisted breeding is relatively powerful and fast approach to develop high yielding varieties more suitable to adverse environmental conditions. New tools such as molecular markers and bioinformatics are expected to generate new knowledge and improve our understanding on the genetics of complex traits. In the past, the limited availability of genomic resources in lentil could not allow breeders to employ these tools in mainstream breeding program.The recent application of the next generation sequencing and genotyping by sequencing technologies has facilitated to speed up the lentil genome sequencing project and large discovery of genome-wide single nucleotide polymorphism (SNP) markers. Currently, several linkage maps have been developed in lentil through the use of expressed sequenced tag (EST) derived simple sequence repeat (SSR) and SNP markers.These maps have emerged as useful genomic resources to identify quantitative trait loci imparting tolerance to biotic and abiotic stresses in lentil. In this review, the current knowledge on available genomic resources and its application in lentil breeding program are discussed.


A core avenue for transcultural research on dementia: on the cross-linguistic generalization of language-related effects in Alzheimer's disease and Parkinson's disease.
Language is a key source of cross-cultural variability, which may have both subtle and major effects on neurocognition. However, this issue has been largely overlooked in two flourishing lines of research assessing the relationship between language-related neural systems and dementia. This paper assesses the limitations of the evidence on (i) the neuroprotective effects of bilingualism in Alzheimer's disease and (ii) specific language deficits as markers of Parkinson's disease. First, we outline the rationale behind each line of research. Second, we review available evidence and discuss the potential impact of cross-linguistic factors. Third, we outline ideas to foster progress in both fields and, with it, in cross-cultural neuroscience at large. On the one hand, studies on bilingualism suggest that sustained use of more than one language may protect against Alzheimer's disease symptoms. On the other hand, insights from the embodied cognition framework point to syntactic and action-verb deficits as early (and even preclinical) markers of Parkinson's disease. However, both fields share a key limitation that lies at the heart of cultural neuroscience: the issue of cross-linguistic generalizability. Relevant evidence for both research trends comes from only a handful of (mostly Indo-European) languages, which are far from capturing the full scope of structural and typological diversity of the linguistic landscape worldwide. This raises questions on the external validity of reported findings. Greater collaboration between linguistic typology and cognitive neuroscience seems crucial as a first step to assess the impact of transcultural differences on language-related effects across neurodegenerative diseases. Copyright © 2017 John Wiley & Sons, Ltd.


Phenformin-associated metabolic acidosis.
We report 18 consecutive phenformin-treated diabetic patients admitted to this Medical Service acutely ill with metabolic acidosis. Lactic acidosis was anticipated, and documented, in all. Also, however, though most of the patients had only weakly positive, or even negative, serum reactions with the nitroprusside reagent, all were found to have coexisting ketoacidosis, plasma 3-hydroxybutyrate averaging 7.1 mmol/L. +/- 3.9 (S.D.). This finding suggest that treatment of these patients should include insulin, and often also glucose, because most do not have marked hyperglycemia and some have hypoglycemia. The lactic acidosis in the nine patients who survivied was, on average, less severe than in the nine who died, but the difference was not statistically significant. Surivival correlated closely with the absence of shock on arrival. Only eight patients had a identifiable acute illness other than the metabolic acidosis. The other 10 patients had no discernible cause for the acute illness apart from their treatment with phenoformin. This finding raises serious doubts about whether phenformin should be used to treat patients with diabetes.


Performance of the 24-2-5 frequency doubling technology screening test: a prospective case study.
To evaluate the performance of the frequency doubling technology (FDT) 24-2-5 screening test by comparison with the established N-30-5 FDT screening test for detection of glaucoma. A prospective random sample of individuals referred for possible glaucoma were tested with FDT screening tests 24-2-5 and N-30-5 using the Humphrey Matrix perimeter in addition to standard clinical examination relevant to glaucoma detection. Discriminatory power, reliability and test time of these tests were assessed and compared. The case definition for glaucoma was made by patient according to the established clinical diagnosis. Of 63 referred eligible individuals, 53 (84%) were recruited. Sensitivity and specificity for the N-30-5 screening test was 78 and 85% respectively, compared with 83% and 75% for the 24-2-5 with areas under a receiver operator characteristic curve being 0.87 and 0.92. Differences between these indices were not statistically significant. For a specificity of 95%, sensitivity values were 76% and 56% for the 24-2-5 and N-30-5 respectively. Mean (standard deviation) test duration for the FDT 24-2-5 and N-30-5 screening tests were 111 (13) and 39 (10) seconds respectively (p<0.001). A total of 19 subjects (36%) produced unreliable test results in one or both eyes when tested with the 24-2-5 screening test compared with 5 subjects (9%) with the N-30-5 (p<0.0005). Minimal discriminatory power differences existed between the two screening tests evaluated, with both screening tests exhibiting high discriminatory power for detection of individuals with glaucoma. More individuals produced unreliable results on the 24-2-5 screening, which also took longer to perform.


Prevalence of human papillomavirus in men who have sex with men in the era of an effective vaccine; a call to act.
The incidence of human papillomavirus (HPV)-associated anal cancer is increasing. Men who have sex with men (MSM), particularly those coinfected with HIV, are disproportionately affected. Documenting the molecular epidemiology of HPV infection is important in guiding policy makers in formulating universal and/or targeted vaccine guidelines. A prospective cohort study was conducted. HIV-positive and HIV-negative MSM > 18 years old were invited to participate. Provider-performed anal swabs were collected and anal HPV infection was detected using consensus primer solution phase polymerase chain reaction (PCR) followed by type-specific PCR for high-risk (HR)-HPV types 16, 18 and 31. Between-group differences were analysed using χ(2) tests and Wilcoxon rank tests. One hundred and ninety-four MSM [mean (standard deviation (SD)) age 36 (10) years; 51% HIV-positive) were recruited. The median number of sexual contacts in the preceding 12 months was 4 (interquartile range 2-10). HIV-positive subjects had a mean (SD) CD4 count of 557 (217) cells/μL, and 84% were on highly active antiretroviral therapy (HAART). Thirty-one samples were B-globin negative and thus excluded from further analysis. A total of 113 subjects (69%) had detectable HPV DNA. Sixty-eight subjects (42%) had an HR-HPV type detected. HR HPV type 16 was detected in 44 samples (27%), HR-HPV type 18 in 26 samples (16%) and HR-HPV type 31 in 14 samples (23%). Twenty-eight subjects (17%) had more than one type of HR-HPV type detected. When HPV and HR-HPV were stratified by age, those > 35 years had a higher prevalence (P = 0.001 and P = 0.028, respectively). HIV-positive subjects were more likely than HIV-negative subjects to have any detectable HPV (77% vs. 61%, respectively; P = 0.04), to have HR-HPV type 18 or 31 (P = 0.05 and P = 0.006, respectively) and to be infected with more than one HR-HPV type (31% vs. 3%, respectively; P < 0.001). Within the HIV-positive group, the prevalence of HPV was higher in those not on HAART (P = 0.041), although it did not differ when stratified by CD4 count. The identified prevalence of anal HPV infection was high. Emerging patterns of HPV-related disease strengthen the call for universal vaccination of boys and girls with consideration of catch-up and targeted vaccination of high-risk groups such as MSM and those with HIV infection.


C-reactive protein and vulnerability to mental stress-induced myocardial ischemia.
Myocardial ischemia provoked in the laboratory during mental stress (MSI) in patients with stable coronary artery disease (CAD) predicts subsequent clinical events. The pathophysiology of MSI differs from that of exercise ischemia, and the mechanisms tying MSI to poor prognosis are not known. C-reactive protein (CRP) is a risk marker for cardiovascular events in patients with CAD, but little is known regarding the relationship of CRP to MSI. The purpose of this study was to examine the association of CRP to risk of MSI in CAD patients. Eighty-three patients with stable CAD underwent simultaneous single-photon emission computed tomography (SPECT) imaging with technetium-99m tetrofosmin myocardial perfusion imaging (MPI) and transthoracic echocardiography (TTE), at rest and during MS induced by laboratory mental stress. Serum CRP levels were measured 24 h after MS. MSI was defined by the presence of a new perfusion defect on SPECT and/or new regional wall motion abnormality on TTE during MS. Of the 83 patients, 30 (36%) developed MSI. There was no difference in gender, sex, BMI, histories of diabetes, hypertension, smoking, lipid profile, medications used (including statins, beta-blockers, ACE inhibitors, and aspirin), or hemodynamic response during MS between those with and without MSI. In univariate logistic regression analysis, each unit (1 mg/L) increase in CRP level was associated with 20% higher risk of MSI (OR 1.2, 95% CI 1.01-1.39, P=.04). This relationship remained in multivariate models. These data suggest that levels of CRP may be a risk marker for MSI in patients with CAD.


Nonenzymatic sequence-specific methyl transfer to single-stranded DNA.
2'-Deoxyuridine 5'-triphosphate with a methylthioether moiety at the 5 position can be incorporated into a primer-template DNA complex with Klenow enzyme. Activation with CNBr at 25 degrees C, pH 5.5, followed by treatment with piperidine produces sequence-specific cleavage on the template DNA predominantly at a single guanine position. The mechanism involves methyl-group transfer from sulfur on the modified deoxyuridine of the extended primer to N-7 of guanine on the template DNA. This raises the possibility for the design and synthesis of a nonenzymatic class of sequence-specific methyltransferases for DNA.


Increasing physical activity and exercise in lung cancer: reviewing safety, benefits, and application.
Lung cancer continues to be a difficult disease frequently diagnosed in late stages with a high mortality and symptom burden. In part because of frequent lung comorbidity, even lung cancer survivors often remain symptomatic and functionally limited. Though targeted therapy continues to increase treatment options for advanced-stage disease, symptom burden remains high with few therapeutic options. In the last several decades, exercise and physical activity have arisen as therapeutic options for obstructive lung disease and lung cancer. To date, exercise has been shown to reduce symptoms, increase exercise tolerance, improve quality of life, and potentially reduce length of stay and postoperative complications. Multiple small trials have been performed in perioperative non-small-cell lung cancer patients, although fewer studies are available for patients with advanced-stage disease. Despite the increased interest in this subject over the last few years, a validated exercise regimen has not been established for perioperative or advanced-stage disease. Clinicians underutilize exercise and pulmonary rehabilitation as a therapy, in part because of the lack of evidence-based consensus as to how and when to implement increasing physical activity. This review summarizes the existing evidence on exercise in lung cancer patients.


The temporal representation of experience in subjective mood.
Humans refer to their mood state regularly in day-to-day as well as clinical interactions. Theoretical accounts suggest that when reporting on our mood we integrate over the history of our experiences; yet, the temporal structure of this integration remains unexamined. Here, we use a computational approach to quantitatively answer this question and show that early events exert a stronger influence on reported mood (a primacy weighting) compared to recent events. We show that a Primacy model accounts better for mood reports compared to a range of alternative temporal representations across random, consistent, or dynamic reward environments, different age groups, and in both healthy and depressed participants. Moreover, we find evidence for neural encoding of the Primacy, but not the Recency, model in frontal brain regions related to mood regulation. These findings hold implications for the timing of events in experimental or clinical settings and suggest new directions for individualized mood interventions.


Dietary glutamine supplementation increases the activity of peritoneal macrophages and hemopoiesis in early-weaned mice inoculated with Mycobacterium bovis bacillus Calmette-Guérin.
Infants who are breast-fed have been shown to have a lower incidence of certain infectious diseases compared with formula-fed infants. Glutamine is one of the most abundant amino acids found in maternal milk and it is essential for the function of immune system cells such as macrophages. The purpose of this study was to investigate the effect of glutamine supplementation on the function of peritoneal macrophages and on hemopoiesis in early-weaned mice inoculated with Mycobacterium bovis bacillus Calmette-Guérin (BCG). Mice were weaned at 14 d of age and distributed to 2 groups and fed either a glutamine-free diet (n = 16) or a glutamine-supplemented diet (+Gln) (n = 16). Both diets were isonitrogenous (with addition of a mixture of nonessential amino acids) and isocaloric. At d 21, 2 subgroups of mice (n = 16) were intraperitoneally injected with BCG and all mice were killed at d 28. Plasma, muscle and liver glutamine concentrations and muscle glutamine synthetase activity were not affected by diet or inoculation with BCG. The +Gln diet led to increased leukocyte and lymphocyte counts in the peripheral blood (P < 0.05) and granulocyte and lymphocyte counts in the bone marrow and spleen (P < 0.05). The +Gln diet increased spreading and adhesion capacities, hydrogen peroxide, nitric oxide, and tumor necrosis factor-alpha (TNFalpha) syntheses and the phagocytic and fungicidal activity of peritoneal macrophages (P < 0.05). The interaction between the +Gln diet and BCG inoculation increased the area under the curve of interleukin (IL)-1beta and TNFalpha syntheses (P < 0.05). In conclusion, the intake of glutamine increases the function of peritoneal macrophages and hemopoiesis in early-weaned and BCG-inoculated mice. These data have important implications for the design of breast milk substitutes for human infants.


The role of adjuvant surgery in the management of gestational trophoblastic neoplasia.
To evaluate the role of different surgical procedures combined with chemotherapy in the management of gestational trophoblastic neoplasia (GTN). A retrospective descriptive analysis of data was done using charts of diagnosed cases of GTN from 1996 to 2006. The patients were classified according to FIGO staging and WHO prognostic scoring. Surgical procedures were evaluated as to indications, hospital stay, remission rate and number of chemotherapy cycles needed to achieve remission. One hundred thirty-four patients underwent at least 1 major surgery in the form of hysterectomy, with uterine perforation and profuse vaginal bleeding as an indication for surgery. Common indications for adjuvant surgery are completed family size and resistance to chemotherapy. Two patients had excision of liver metastases, and 3 patients had lung resection. With the increasing use of early surgical intervention combined with chemotherapy, we feel that we are maximizing the benefit that can be derived by our patients from our treatment protocol. We are decreasing the number of chemotherapeutic cycles needed to attain remission and in effect decreasing the exposure of the patients to toxicity from the chemotherapy.


Effect of an oral mucositis protocol on quality of life of patients with head and neck cancer treated with radiation therapy.
This study was conducted to determine the effect of an oral mucositis prevention protocol on nutritional status and quality of life for patients undergoing radiation therapy for head and neck cancers. This randomized, controlled, experimental study placed 20 patients in an intervention group where they received an oral care protocol and a nutrition protocol. Thirty patients were placed in the control group. Data were collected through face-to-face interviews using an oral assessment guide, oral evaluation guidelines, an oral toxicity scale, a visual analog scale, a subjective global assessment index, and a quality-of-life scale. As time post-treatment progressed, the prevalence of malnutrition in the intervention group was lower than in the controls group, and the intervention group experienced significantly less pain related to oral mucositis. Similar deteriorations in quality of life were noted in each group.


c-Cbl mediates ubiquitination, degradation, and down-regulation of human protease-activated receptor 2.
Mechanisms that arrest G-protein-coupled receptor (GPCR) signaling prevent uncontrolled stimulation that could cause disease. Although uncoupling from heterotrimeric G-proteins, which transiently arrests signaling, is well described, little is known about the mechanisms that permanently arrest signaling. Here we reported on the mechanisms that terminate signaling by protease-activated receptor 2 (PAR(2)), which mediated the proinflammatory and nociceptive actions of proteases. Given its irreversible mechanism of proteolytic activation, PAR(2) is a model to study the permanent arrest of GPCR signaling. By immunoprecipitation and immunoblotting, we observed that activated PAR(2) was mono-ubiquitinated. Immunofluorescence indicated that activated PAR(2) translocated from the plasma membrane to early endosomes and lysosomes where it was degraded, as determined by immunoblotting. Mutant PAR(2) lacking intracellular lysine residues (PAR(2)Delta14K/R) was expressed at the plasma membrane and signaled normally but was not ubiquitinated. Activated PAR(2) Delta14K/R internalized but was retained in early endosomes and avoided lysosomal degradation. Activation of wild type PAR(2) stimulated tyrosine phosphorylation of the ubiquitin-protein isopeptide ligase c-Cbl and promoted its interaction with PAR(2) at the plasma membrane and in endosomes in an Src-dependent manner. Dominant negative c-Cbl lacking the ring finger domain inhibited PAR(2) ubiquitination and induced retention in early endosomes, thereby impeding lysosomal degradation. Although wild type PAR(2) was degraded, and recovery of agonist responses required synthesis of new receptors, lysine mutation and dominant negative c-Cbl impeded receptor ubiquitination and degradation and allowed PAR(2) to recycle and continue to signal. Thus, c-Cbl mediated ubiquitination and lysosomal degradation of PAR(2) to irrevocably terminate signaling by this and perhaps other GPCRs.


Inclusion of women in nursing research: 1995-2001.
Although the inclusion of women in research has been examined in medical publications, little is known about how federal mandates have influenced the inclusion of women in research published in nursing journals. This study aimed to examine the inclusion of women in published nursing research from 1995 to 2001, with a focus on the leading causes of mortality. All the articles in each journal were reviewed, and all the research articles that focused on the top 10 causes of death were sampled to measure the inclusion of women, the characteristics of the women included, the funding source, and the topic. Of the 1,149 studies reviewed, 139 met the inclusion criteria, and 117 of these studies included women. Only 15 of the studies reported the age of the women in their samples, and 10 of these included women between the ages of 35 and 64 years. The most frequently reported race was White (n = 21), followed by African American (n = 17), Hispanic (n = 6), and Asian (n = 2). There were no associations among year of publication (p =.62), federal funding (p =.30), and inclusion of women. Among the studies including women, heart disease was the most frequent topic (n = 52), followed by Alzheimer's disease (n = 21), cancer (n = 14), respiratory illness (n = 14), and diabetes (n = 8). Although the majority of the research included women, continuing efforts must be made to include sufficient numbers of women.


Dictionary learning for data recovery in positron emission tomography.
Compressed sensing (CS) aims to recover images from fewer measurements than that governed by the Nyquist sampling theorem. Most CS methods use analytical predefined sparsifying domains such as total variation, wavelets, curvelets, and finite transforms to perform this task. In this study, we evaluated the use of dictionary learning (DL) as a sparsifying domain to reconstruct PET images from partially sampled data, and compared the results to the partially and fully sampled image (baseline).A CS model based on learning an adaptive dictionary over image patches was developed to recover missing observations in PET data acquisition. The recovery was done iteratively in two steps: a dictionary learning step and an image reconstruction step. Two experiments were performed to evaluate the proposed CS recovery algorithm: an IEC phantom study and five patient studies. In each case, 11% of the detectors of a GE PET/CT system were removed and the acquired sinogram data were recovered using the proposed DL algorithm. The recovered images (DL) as well as the partially sampled images (with detector gaps) for both experiments were then compared to the baseline. Comparisons were done by calculating RMSE, contrast recovery and SNR in ROIs drawn in the background, and spheres of the phantom as well as patient lesions.For the phantom experiment, the RMSE for the DL recovered images were 5.8% when compared with the baseline images while it was 17.5% for the partially sampled images. In the patients' studies, RMSE for the DL recovered images were 3.8%, while it was 11.3% for the partially sampled images. Our proposed CS with DL is a good approach to recover partially sampled PET data. This approach has implications toward reducing scanner cost while maintaining accurate PET image quantification.


Gene transfer into the airway epithelium of animals by targeting the polymeric immunoglobulin receptor.
Genes of interest can be targeted specifically to respiratory epithelial cells in intact animals with high efficiency by exploiting the receptor-mediated endocytosis of the polymeric immunoglobulin receptor. A DNA carrier, consisting of the Fab portion of polyclonal antibodies raised against rat secretory component covalently linked to poly-L-lysine, was used to introduce plasmids containing different reporter genes into airway epithelial cells in vivo. We observed significant levels of luciferase enzyme activity in protein extracts from the liver and lung, achieving maximum values of 13,795 +/- 4,431 and 346,954 +/- 199,120 integrated light units (ILU) per milligram of protein extract, respectively. No luciferase activity was detected in spleen or heart, which do not express the receptor. Transfections using complexes consisting of an irrelevant plasmid (pCMV lacZ) bound to the bona fide carrier or the expression plasmid (pGEMluc) bound to a carrier based on an irrelevant Fab fragment resulted in background levels of luciferase activity in all tissues examined. Thus, only tissues that contain cells bearing the polymeric immunoglobulin receptor are transfected, and transfection cannot be attributed to the nonspecific uptake of an irrelevant carrier-DNA complex. Specific mRNA from the luciferase gene was also detected in the lungs of transfected animals. To determine which cells in the lungs are transfected by this method, DNA complexes were prepared containing expression plasmids with genes encoding the bacterial beta-galactosidase or the human interleukin 2 receptor. Expression of these genes was localized to the surface epithelium of the airways and the submucosal glands, and not the bronchioles and alveoli. Receptor-mediated endocytosis can be used to introduce functional genes into the respiratory epithelium of rats, and may be a useful technique for gene therapy targeting the lung.


Structure of ubiquitin-conjugating enzyme 9 displays significant differences with other ubiquitin-conjugating enzymes which may reflect its specificity for sumo rather than ubiquitin.
The three-dimensional structure of ubiquitin-conjugating enzyme 9 (Ubc9) has been obtained to a resolution of 2.8 A by molecular replacement followed by a combination of automated refinement and graphical intervention. Diffraction data were recorded on a single crystal in space group P43 with cell dimensions a = b = 73.9, c = 42. 9 A. The final model has an R factor of 21.3% for all data to 2.8 A. Only the N-terminal methionine, a two-residue N-terminal extension and a four-residue loop are not located by the final electron-density map. Ubc9 is now known to be the first sumo, a new ubiquitin-like protein, conjugating enzyme and does not conjugate ubiquitin. The structure of Ubc9 shows important differences compared with the structures of known ubiquitin-conjugating enzymes. At the N-terminal helix, the structural and sequence alignments are out of register by one amino acid giving Ubc9 a different recognition surface compared to ubiquitin-conjugating enzymes. This is coupled to a profound change in the electrostatic surface of the molecular face remote from the catalytic site. These differences may be important in recognition of other proteins in the Sumo conjugation pathway. The catalytic cysteine in Ubc9 has a positively charged lip and a negatively charged ridge nearby. Both these features seem confined to sumo-conjugating enzymes, and a sequence alignment of sumo and ubiquitin suggests how these might play a role in sumo/ubiquitin discrimination.


Physical Activity, Sedentary Time, and Bone Strength From Childhood to Early Adulthood: A Mixed Longitudinal HR-pQCT study.
Bone strength is influenced by bone geometry, density, and bone microarchitecture, which adapt to increased mechanical loads during growth. Physical activity (PA) is essential for optimal bone strength accrual; however, less is known about how sedentary time influences bone strength and its determinants. Thus, our aim was to investigate the prospective associations between PA, sedentary time, and bone strength and its determinants during adolescence. We used HR-pQCT at distal tibia (8% site) and radius (7% site) in 173 girls and 136 boys (aged 9 to 20 years at baseline). We conducted a maximum of four annual measurements at the tibia (n = 785 observations) and radius (n = 582 observations). We assessed moderate-to-vigorous PA (MVPA) and sedentary time with accelerometers (ActiGraph GT1M). We aligned participants on maturity (years from age at peak height velocity) and fit a mixed-effects model adjusting for maturity, sex, ethnicity, leg muscle power, lean mass, limb length, dietary calcium, and MVPA in sedentary time models. MVPA was a positive independent predictor of bone strength (failure load [F.Load]) and bone volume fraction (BV/TV) at the tibia and radius, total area (Tt.Ar) and cortical porosity (Ct.Po) at the tibia, and negative predictor of load-to-strength ratio at the radius. Sedentary time was a negative independent predictor of Tt.Ar at both sites and Ct.Po at the tibia and a positive predictor of cortical thickness (Ct.Th), trabecular thickness (Tb.Th), and cortical bone mineral density (Ct.BMD) at the tibia. Bone parameters demonstrated maturity-specific associations with MVPA and sedentary time, whereby associations were strongest during early and mid-puberty. Our findings support the importance of PA for bone strength accrual and its determinants across adolescent growth and provide new evidence of a detrimental association of sedentary time with bone geometry but positive associations with microarchitecture. This study highlights maturity-specific relationships of bone strength and its determinants with loading and unloading. Future studies should evaluate the dose-response relationship and whether associations persist into adulthood. © 2017 American Society for Bone and Mineral Research.


Experience with cerebral perfusion in total aortic arch replacement.
The interruption of cerebral circulation is a major problem in the surgical repair of the aortic arch. This study was undertaken to identify the perioperative risk factors for mortality and neurological morbidity, and the outcome after total aortic arch replacement. Between June 1995 and March 2002, 23 patients (13 males) underwent total aortic arch replacement. The mean age was 61.7I9.4 years (range 35-77). All patients underwent total arch replacement with a period of hypothermic circulatory arrest (HCA). Selective cerebral perfusion was utilized as an adjunct to HCA (retrograde in 19 patients and antegrade in 4 patients). The elephant trunk technique was used in 18 patients, while proximal and middle portion of the descending aorta was also replaced in 5 patients. The patient information in our database was retrospectively reviewed. The risk factors affecting mortality and morbidity were analyzed by univariate analysis. The in-hospital mortality rate was 17.4%. None of the survivors developed major stroke. Temporary neurological dysfunction (TND) was seen in 5 patients. Univariate analysis revealed that excessive blood transfusion was the only factor correlated with hospital death among 18 perioperative variables (p<0.006). HCA lasting > 55 minutes and a history of hypertension were associated with the development of TND (p<0.032 and p<0.02, respectively). Total arch replacement can be performed with acceptable mortality and neurological morbidity. Midterm survival is excellent in hospital survivors. The duration of HCA is not associated with in-hospital mortality when selective cerebral perfusion (either antegrade or retrograde) is used as an adjunct.


Immune responses of locusts to challenge with the pathogenic fungus Metarhizium or high doses of laminarin.
Two isolates of Metarhizium anisopliae var acridum were tested for their effects on the locust immune system and for comparison with the effects of challenge by injection with laminarin. Isolate IMI 330189 (referred to hereafter as Met 189) is highly pathogenic whether applied topically as conidia or injected as blastospores. However, isolate ARSEF 728 (referred to hereafter as Met 728) is pathogenic only when injected as blastospores, suggesting that the lack of pathogenicity of topically applied conidia from this isolate is due to a failure to penetrate the insect cuticle and gain access to the haemocoel. After topical application of conidia from Met 189, no activation of prophenoloxidase is detected, but injection of blastospores from Met 189 brings about a transient increase in phenoloxidase activity in the haemolymph in both adult locusts and 5th instar nymphs, although this does not prevent fungal-induced mortality. Co-injection of adipokinetic hormone-I (AKH-I) with blastospores prolongs the activation of prophenoloxidase in the haemolymph of adult locusts, and enhances it in nymphs. It is argued that the lack of activation of prophenoloxidase in nymphs shown previously (Mullen, L., Goldsworthy, G., 2003. Changes in lipophorins are related to the activation of phenoloxidase in the haemolymph of Locusta migratoria in response to injection of immunogens. Insect Biochemistry and Molecular Biology 33, 661-670), reflects differences in the sensitivity of the immune system between adults and nymphs rather than distinct qualitative differences, and this is confirmed in this study by the demonstration that doses of laminarin higher than those used previously (>or=100 microg) do activate the prophenoloxidase cascade in 5th instar nymphs. Nodules are formed in locusts of all ages in response to fungal infection or injection of laminarin, although there is wide variation in the number, size and distribution of nodules formed. During the examination of 5th instar nymphs for nodule formation, a previously unknown phenomenon was observed in which the salivary glands melanise in response to injections of blastospores or high doses of laminarin. In c. 85% of such nymphs, this reaction is so strong that the whole salivary gland is intensely black. Such a response is not observed in the salivary glands of mature adult locusts.


Endemic nephropathy: the case for chronic poisoning by aristolochia.
To explore the hypothesis that chronic dietary poisoning by aristolochic acid could account for the unique geographical distribution, specific pattern of tubulointerstitial fibrosis, occurrence of chronic renal insufficiency, and an increased risk of developing upper urothelial cancer, all of which are associated with endemic nephropathy. This case-controlled epidemiologic study consisted of three groups of subjects residing in an endemic region of Croatia: (a) patients meeting WHO criteria for endemic nephropathy (n=28), (b) individuals who have been treated for renal insufficiency secondary to other forms of renal disease (n=30), and (c) apparently healthy residents of the endemic village (n= 30). A detailed questionnaire, designed to collect information on demographics, exposure to potentially toxic substances, diet, agricultural practices, and other factors potentially impacting endemic nephropathy was administered to the three study groups. The seeds of Aristolochia clematitis, obtained from plants growing in the endemic region, were extracted with ethanol and analyzed by high-performance liquid chromatography for their aristolochic acid content. The majority of subjects, including 90% of endemic nephropathy patients, recall that the plant Aristolochia clematitis (birthwort, vucja stopa in Croatian) was frequently found in local meadows and wheat fields between 20 and 30 years ago. At that time, endemic nephropathy patients encountered Aristolochia clematitis significantly more frequently than controls (P=0.035). Since then, all three study groups reported a significant increase in the use of herbicides (P<0.001) and reduction in the prevalence of Aristolochia clematitis (P<0.001). Chemical analysis established that the seeds of A. clematitis contain 0.65% aristolochic acid. It is likely that the harvesting process used by local farmers permitted the seeds of A. clematitis to mingle with the wheat grain. Flour used to bake bread, a dietary staple in the endemic region of Croatia, is derived from wheat grain which, in the past, is likely to have been contaminated with seeds of A. clematitis during harvesting. This observation supports the hypothesis that aristolochic acid, a major constituent of the seeds, plays a central role in the development of endemic nephropathy.


Latest advances in the discovery of fatty acid amide hydrolase inhibitors.
Fatty acid amide hydrolase (FAAH) is the major catabolic enzyme of the endocannabinoid N-arachidonoylethanolamine (anandamide) that, with different degrees of efficiency, also hydrolyzes other endogenous fatty acid ethanolamides. FAAH is increasingly being considered a relevant therapeutic target, especially in models of inflammatory pain. The opportunity to selectively increase the endocannabinoid tone only in those tissues where such an enhancement can be beneficial might result in a therapeutic benefit with more limited side effects, compared to the use of direct agonists of anandamide-binding receptors. Thus the research for selective FAAH inhibitors has become a hot topic in current drug discovery. This review highlights the advances in the development of different compounds belonging to different chemical families that have been proposed as FAAH inhibitors. Several classes of inhibitors have been reported so far, and they may be classified into two major classes: reversible and irreversible compounds. These inhibitors are reviewed herein with an emphasis on their potency and selectivity. In recent years, tremendous efforts have been made to develop the FAAH inhibitors, and consequently many novel chemical templates have been discovered. It is still a major challenge to identify the first inhibitor of FAAH suitable for clinical exploitation that satisfies the requirements of potency, selectivity versus proteins related to anandamide activity as well as other potential off-targets, reversibility versus irreversibility, and efficacy toward rat versus human FAAH.