The Schistosomiasis Clinical Trials Landscape: A Systematic Review of Antischistosomal Treatment Efficacy Studies and a Case for Sharing Individual Participant-Level Data (IPD).
Schistosomiasis control mainly relies on preventive chemotherapy with praziquantel (PZQ) distributed through mass drug administration. With a target of 260 million treatments yearly, reliably assessing and monitoring efficacy is all-important. Recommendations for treatment and control of schistosomiasis are supported by systematic reviews and meta-analyses of aggregated data, which however also point to limitations due to heterogeneity in trial design, analyses and reporting. Some such limitations could be corrected through access to individual participant-level data (IPD), which facilitates standardised analyses. A systematic literature review was conducted to identify antischistosomal drug efficacy studies performed since 2000; including electronic searches of the Cochrane Infectious Diseases Group specialised register and the Cochrane Library, PubMed, CENTRAL and Embase; complemented with a manual search for articles listed in past reviews. Antischistosomal treatment studies with assessment of outcome within 60 days post-treatment were eligible. Meta-data, i.e. study-level characteristics (Schistosoma species, number of patients, drug administered, country, etc.) and efficacy parameters were extracted from published documents to evaluate the scope of an individual-level data sharing platform. Out of 914 documents screened, 90 studies from 26 countries were included, enrolling 20,517 participants infected with Schistosoma spp. and treated with different PZQ regimens or other drugs. Methodologies varied in terms of diagnostic approaches (number of samples and test repeats), time of outcome assessment, and outcome measure (cure rate or egg reduction rate, as an arithmetic or geometric mean), making direct comparison of published data difficult. This review describes the landscape of schistosomiasis clinical research. The volume of data and the methodological and reporting heterogeneity identified all indicate that there is scope for an individual participant-level database, to allow for standardised analyses.


New insights into the genetics of 5-oxoprolinase deficiency and further evidence that it is a benign biochemical condition.
Inherited 5-oxoprolinase (OPLAH) deficiency is a rare inborn condition characterised by 5-oxoprolinuria. To date, three OPLAH mutations have been described: p.H870Pfs in a homozygous state, which results in a truncated protein, was reported in two siblings, and two heterozygous missense changes, p.S323R and p.V1089I, were independently identified in two unrelated patients. We describe the clinical context of a young girl who manifested 5-oxoprolinuria together with dusky episodes and who is compound heterozygote for two novel OPLAH variations: p.G860R and p.D1241V. To gain insight into the aetiology of the 5-oxoprolinase deficiency, we investigated the pathogenicity of all the reported missense mutations in the OPLAH gene. A yeast in vivo growth assay revealed that only p.S323R, p.G860R and p.D1241V affected the activity of the enzyme. Taken together, this report further suggests that hereditary 5-oxoprolinase deficiency is a benign biochemical condition caused by mutations in the OPLAH gene, which are transmitted in an autosomal recessive manner, but 5-oxoprolinuria may be a chance association in other disorders.


High precision and high yield fabrication of dense nanoparticle arrays onto DNA origami at statistically independent binding sites.
High precision, high yield, and high density self-assembly of nanoparticles into arrays is essential for nanophotonics. Spatial deviations as small as a few nanometers can alter the properties of near-field coupled optical nanostructures. Several studies have reported assemblies of few nanoparticle structures with controlled spacing using DNA nanostructures with variable yield. Here, we report multi-tether design strategies and attachment yields for homo- and hetero-nanoparticle arrays templated by DNA origami nanotubes. Nanoparticle attachment yield via DNA hybridization is comparable with streptavidin-biotin binding. Independent of the number of binding sites, >97% site-occupation was achieved with four tethers and 99.2% site-occupation is theoretically possible with five tethers. The interparticle distance was within 2 nm of all design specifications and the nanoparticle spatial deviations decreased with interparticle spacing. Modified geometric, binomial, and trinomial distributions indicate that site-bridging, steric hindrance, and electrostatic repulsion were not dominant barriers to self-assembly and both tethers and binding sites were statistically independent at high particle densities.


RACIAL DISPARITIES IN HEALTH: How Much Does Stress Really Matter?
Despite the widespread assumption that racial differences in stress exist and that stress is a key mediator linking racial status to poor health, relatively few studies have explicitly examined this premise. We examine the distribution of stress across racial groups and the role of stress vulnerability and exposure in explaining racial differences in health in a community sample of Black, Hispanic, and White adults, employing a modeling strategy that accounts for the correlation between types of stressors and the accumulation of stressors in the prediction of health outcomes. We find significant racial differences in overall and cumulative exposure to eight stress domains. Blacks exhibit a higher prevalence and greater clustering of high stress scores than Whites. American-born Hispanics show prevalence rates and patterns of accumulation of stressors comparable to Blacks, while foreign-born Hispanics have stress profiles similar to Whites. Multiple stressors correlate with poor physical and mental health, with financial and relationship stressors exhibiting the largest and most consistent effects. Though we find no support for the stress-vulnerability hypothesis, the stress-exposure hypothesis does account for some racial health disparities. We discuss implications for future research and policy.


French women's knowledge of and attitudes towards cervical cancer prevention and the acceptability of HPV vaccination among those with 14 - 18 year old daughters: a quantitative-qualitative study.
In France, it is recommended that girls and women aged 14-23 are vaccinated against the human papillomavirus (HPV). However, French women's knowledge of and attitude towards the vaccine has been little studied. Thirty-nine general practitioners, representative of those working in the large Rhône-Alpes region, offered a self-administered questionnaire on cervical cancer (CC) prevention to all 18-65 year-old women who came for consultation during June and July 2008. In addition, semi-structured interviews were undertaken with a sample of those who had daughters aged 14-18. Of the 1,478 women who completed the questionnaire, only 16.9% mentioned HPV as the cause of CC, even though 76.2% knew of the vaccine. 210 women had daughters aged 14-18, and 32 were interviewed. Compared with the wider group, more of these women were aware of the HPV vaccine (91.4%). 44.8% knew the target population and 17.1% the recommended ages for vaccination. 54.3% favoured HPV vaccination; 37.2% were undecided and only 0.9% were opposed. The main barrier to acceptance was the recency of the vaccine's introduction and concern about possible side effects (54.9%); 14.1% preferred to rely on their GP's decision. Factors associated with acceptance of the HPV vaccine were having previously vaccinated a child against pneumococcus (OR=3.28 [1.32-8.11]) and knowing the target population for HPV vaccination (OR=2.12 [1.15-3.90]). Knowing the recommended frequency of Papanicolaou smear testing (Pap test) screening was associated with lower acceptance (OR=0.32 [0.13-0.82]). Few mothers are opposed to HPV vaccination. Factors associated with acceptability were knowledge about the vaccine, acceptance of other vaccines and, unexpectedly, lack of knowledge about the recommended frequency of Pap testing. On multivariate analysis, compliance with recommendations for Pap test screening and socioeconomic factors had no effect on views about HPV vaccination. Given that concern about possible side effects is the major barrier to wider acceptance of the HPV vaccine in France, GPs have a key role in providing information.


PTH1R Mutants Found in Patients with Primary Failure of Tooth Eruption Disrupt G-Protein Signaling.
Primary failure of tooth eruption (PFE) is causally linked to heterozygous mutations of the parathyroid hormone receptor (PTH1R) gene. The mutants described so far lead to exchange of amino acids or truncation of the protein that may result in structural changes of the expressed PTH1R. However, functional effects of these mutations have not been investigated yet. In HEK293 cells, PTH1R wild type was co-transfected with selected PTH1R mutants identified in patients with PFE. The effects on activation of PTH-regulated intracellular signaling pathways were analyzed by ELISA and Western immunoblotting. Differential effects of wild type and mutated PTH1R on TRESK ion channel regulation were analyzed by electrophysiological recordings in Xenopus laevis oocytes. In HEK293 cells, activation of PTH1R wild type increases cAMP and in response activates cAMP-stimulated protein kinase as detected by phosphorylation of the vasodilator stimulated phosphoprotein (VASP). In contrast, the PTH1R mutants are functionally inactive and mutant PTH1R/Gly452Glu has a dominant negative effect on the signaling of PTH1R wild type. Confocal imaging revealed that wild type PTH1R is expressed on the cell surface, whereas PTH1R/Gly452Glu mutant is mostly retained inside the cell. Furthermore, in contrast to wild type PTH1R which substantially augmented K+ currents of TRESK channels, coupling of mutated PTH1R to TRESK channels was completely abolished. PTH1R mutations affect intracellular PTH-regulated signaling in vitro. In patients with primary failure of tooth eruption defective signaling of PTH1R mutations is suggested to occur in dento-alveolar cells and thus may lead to impaired tooth movement.


A cell culture system for study of the development of Toxoplasma gondii bradyzoites.
Toxoplasma gondii is a ubiquitous apicomplexan parasite and a major opportunistic pathogen under AIDS-induced conditions, where it causes encephalitis when the bradyzoite (cyst) stage is reactivated. A bradyzoite-specific Mab, 74.1.8, reacting with a 28 kDa antigen, was used to study bradyzoite development in vitro by immuno-electron microscopy and immunofluorescence in human fibroblasts infected with ME49 strain T. gondii. Bradyzoites were detected in tissue culture within 3 days of infection. Free floating cyst-like structures were also identified. Western blotting demonstrated the expression of bradyzoite antigens in these free-floating cysts as well as in the monolayer. Bradyzoite development was increased by using media adjusted to pH 6.8 or 8.2. The addition of gamma-interferon at day 3 of culture while decreasing the total number of cysts formed prevented tachyzoite overgrowth and enabled study of in vitro bradyzoites for up to 25 days. The addition of IL-6 increased the number of cysts released into the medium and increased the number of cysts formed at pH 7.2. Confirmation of bradyzoite development in vitro was provided by electron microscopy. It is possible that the induction of an acute phase response in the host cell may be important for bradyzoite differentiation. This system should allow further studies on the effect of various agents on the development of bradyzoites.


Chile's National Center for Health Information Systems: A Public-Private Partnership to Foster Health Care Information Interoperability.
Despite the continuous technical advancements around health information standards, a critical component to their widespread adoption involves political agreement between a diverse set of stakeholders. Countries that have addressed this issue have used diverse strategies. In this vision paper we present the path that Chile is taking to establish a national program to implement health information standards and achieve interoperability. The Chilean government established an inter-agency program to define the current interoperability situation, existing gaps, barriers, and facilitators for interoperable health information systems. As an answer to the identified issues, the government decided to fund a consortium of Chilean universities to create the National Center for Health Information Systems. This consortium should encourage the interaction between all health care stakeholders, both public and private, to advance the selection of national standards and define certification procedures for software and human resources in health information technologies.


Role of PXR in Hepatic Cancer: Its Influences on Liver Detoxification Capacity and Cancer Progression.
The role of nuclear receptor PXR in detoxification and clearance of xenobiotics and endobiotics is well-established. However, its projected role in hepatic cancer is rather illusive where its expression is reported altered in different cancers depending on the tissue-type and microenvironment. The expression of PXR, its target genes and their biological or clinical significance have not been examined in hepatic cancer. In the present study, by generating DEN-induced hepatic cancer in mice, we report that the expression of PXR and its target genes CYP3A11 and GSTa2 are down-regulated implying impairment of hepatic detoxification capacity. A higher state of inflammation was observed in liver cancer tissues as evident from upregulation of inflammatory cytokines IL-6 and TNF-α along with NF-κB and STAT3. Our data in mouse model suggested a negative correlation between down-regulation of PXR and its target genes with that of higher expression of inflammatory proteins (like IL-6, TNF-α, NF-κB). In conjunction, our findings with relevant cell culture based assays showed that higher expression of PXR is involved in reduction of tumorigenic potential in hepatic cancer. Overall, the findings suggest that inflammation influences the expression of hepatic proteins important in drug metabolism while higher PXR level reduces tumorigenic potential in hepatic cancer.


Mortality in Transition: Study Protocol of the PrivMort Project, a multilevel convenience cohort study.
Previous research using routine data identified rapid mass privatisation as an important driver of mortality crisis following the collapse of Communism in Central and Eastern Europe. However, existing studies on the mortality crisis relying on individual level or routine data cannot assess both distal (societal) and proximal (individual) causes of mortality simultaneously. The aim of the PrivMort Project is to overcome these limitations and to investigate the role of societal factors (particularly rapid mass privatisation) and individual-level factors (e.g. alcohol consumption) in the mortality changes in post-communist countries. The PrivMort conducts large-sample surveys in Russia, Belarus and Hungary. The approach is unique in comparing towns that have undergone rapid privatisation of their key industrial enterprises with those that experienced more gradual forms of privatisation, employing a multi-level retrospective cohort design that combines data on the industrial characteristics of the towns, socio-economic descriptions of the communities, settlement-level data, individual socio-economic characteristics, and individuals' health behaviour. It then incorporates data on mortality of different types of relatives of survey respondents, employing a retrospective demographic approach, which enables linkage of historical patterns of mortality to exposures, based on experiences of family members. By May 2016, 63,073 respondents provided information on themselves and 205,607 relatives, of whom 102,971 had died. The settlement-level dataset contains information on 539 settlements and 12,082 enterprises in these settlements in Russia, 96 settlements and 271 enterprises in Belarus, and 52 settlement and 148 enterprises in Hungary. In addition to reinforcing existing evidence linking smoking, hazardous drinking and unemployment to mortality, the PrivMort dataset will investigate the variation in transition experiences for individual respondents and their families across settlements characterized by differing contextual factors, including industrial characteristics, simultaneously providing information about how excess mortality is distributed across settlements with various privatization strategies.


The contribution of biotechnology toward progress in diagnosis, management, and treatment of allergic diseases.
'Biotechnology' has been intuitively used by humans since thousands of years for the production of foods, beverages, and drugs based on the experience without any scientific background. However, the golden era of this discipline emerged only during the second half of the last century. Incredible progresses have been achieved on all fields starting from the industrialization of the production of foods to the discovery of antibiotics, the decipherment of the genetic code, and rational approaches to understand and define the status we now call 'healthy'. The extremely complex interactions between genetic background, life style, and environmental factors influencing our continuously increasing life span have become more and more evident and steadily generate new questions which are only partly answered. Here, we try to summarize the contribution of biotechnology to our understanding, control, and cure of IgE-mediated allergic diseases. We are aware that a review of such a vast topic can never cover all aspects of the progress achieved in the different fields.


CGRP induction in cystic fibrosis airways alters the submucosal gland progenitor cell niche in mice.
In cystic fibrosis (CF), a lack of functional CF transmembrane conductance regulator (CFTR) chloride channels causes defective secretion by submucosal glands (SMGs), leading to persistent bacterial infection that damages airways and necessitates tissue repair. SMGs are also important niches for slow-cycling progenitor cells (SCPCs) in the proximal airways, which may be involved in disease-related airway repair. Here, we report that calcitonin gene-related peptide (CGRP) activates CFTR-dependent SMG secretions and that this signaling pathway is hyperactivated in CF human, pig, ferret, and mouse SMGs. Since CGRP-expressing neuroendocrine cells reside in bronchiolar SCPC niches, we hypothesized that the glandular SCPC niche may be dysfunctional in CF. Consistent with this hypothesis, CFTR-deficient mice failed to maintain glandular SCPCs following airway injury. In wild-type mice, CGRP levels increased following airway injury and functioned as an injury-induced mitogen that stimulated SMG progenitor cell proliferation in vivo and altered the proliferative potential of airway progenitors in vitro. Components of the receptor for CGRP (RAMP1 and CLR) were expressed in a very small subset of SCPCs, suggesting that CGRP indirectly stimulates SCPC proliferation in a non-cell-autonomous manner. These findings demonstrate that CGRP-dependent pathways for CFTR activation are abnormally upregulated in CF SMGs and that this sustained mitogenic signal alters properties of the SMG progenitor cell niche in CF airways. This discovery may have important implications for injury/repair mechanisms in the CF airway.


Development of a fully human assay combining NGN2-inducible neurons co-cultured with iPSC-derived astrocytes amenable for electrophysiological studies.
Neurogenin 2 encodes a neural-specific transcription factor (NGN2) able to drive neuronal fate on somatic and stem cells. NGN2 is expressed in neural progenitors within the developing central and peripheral nervous systems. Overexpression of NGN2 in human induced pluripotent stem cells (hiPSCs) or human embryonic stem cells has been shown to efficiently trigger conversion to neurons. Here we describe two gene-edited hiPSC lines harbouring a doxycycline (DOX)-inducible cassette in the AAVS1 locus driving expression of NGN2 (BIONi010-C-13) or NGN2-T2A-GFP (BIONi010-C-15). By introducing NGN2-expressing cassette, we reduce variability associated with conventional over-expression methods such as viral transduction, making these lines amenable for scale-up production and screening processes. DOX-treated hiPSCs convert to neural phenotype within one week and display the expression of structural neuronal markers such as Beta-III tubulin and tau. We performed functional characterization of NGN2-neurons co-cultured with hiPSC-derived astrocytes in a "fully-humanized" set up. Passive properties of NGN2-neurons were indistinguishable from mouse primary cells while displaying variable activity in extracellular recordings performed in multi-electrode arrays (MEAs). We demonstrate that hiPSC-derived astrocytes and neurons can be co-cultured and display functional properties comparable to the gold standard used in electrophysiology. Both lines are globally available via EBiSC repository at https://cells.ebisc.org/.


Design and implementation of a microelectrode assembly for use on noncontact in situ electroporation of adherent cells.
In situ electroporation of adherent cells provides significant advantages with respect to electroporation systems for suspension cells, such as causing minimal stress to cultured cells and simplifying and saving several steps within the process. In this study, a new electrode assembly design is shown and applied to in situ electroporate adherent cell lines growing in standard multiwell plates. We designed an interdigitated array of electrodes patterned on copper with printed circuit board technology and covered with nickel/gold. Small interelectrode distances were used to achieve effective electroporation with low voltages. Epoxy-based microseparators were constructed to avoid direct contact with the cells and to create more uniform electric fields. The device was successful in the electropermeabilization of two different adherent cell lines, C2C12 and HEK 293, as assessed by the intracellular delivery of the fluorescent dextran FD20S. Additionally, as a collateral effect, we observed cell electrofusion in HEK 293 cells, thus making this device also useful for performing cell fusion. In summary, we show the effectiveness of this minimally invasive device for electroporation of adherent cells cultured in standard multiwell plates. The cheap technologies used in the fabrication process of the electrode assembly indicate potential use as a low-cost, disposable device.


Empirical model of mesothelioma potency factors for different mineral fibers based on their chemical composition and dimensionality.
Context: The potency of various mineral fiber types to produce mesothelioma was previously evaluated for numerous cohorts, but the differences in potencies for distinct fiber types have yet to be explained. Objective: To develop an empirical model that would reconstruct mesothelioma potency factors for various types of fiber based on their chemical composition and dimensionality. Methods: Typical chemical composition and dimensionality metrics (aspect ratios) were obtained and combined with mesothelioma potency factors estimated by Hodgson and Darnton method for Quebec chrysotile, South Africa amosite, South Africa and Australian crocidolite, Russian anthophyllite, Libby amphiboles, and Turkey erionite. The forward stepwise log-log regression method was utilized to determine the best combination of input parameters. Results: Mesothelioma potency factors (RM) for selected cohorts were effectively reconstructed utilizing the median aspect ratio of fibers and equivalent fractions of SiO2, total Fe oxides or total equivalent Fe3+ as Fe2O3, and MgO. Modeled potency factors increase as the aspect ratio, SiO2, and total Fe oxide (or Fe2O3) content grow, and as the MgO content diminishes. Correlation coefficients up to 0.999, p < 0.01, were achieved. The models also yield reasonable estimates of mesothelioma potencies for other fiber types, including Bolivian crocidolite, Russian chrysotile, fluoro-edenite, and others. Conclusion: In spite of the empirical approach, the proposed models provide a starting point for targeted studies of mesothelioma mechanisms by elucidating significant contributing physicochemical factors. The models have an exploratory and preliminary character but can potentially be useful to introduce quantitative structure-activity relationship approaches for the toxicology of fibrous minerals.


The influence of malformation of Galen vein on the cardiovascular system in a newborn.
Asphyxia of the newborn has a varied etiology. Clinical consequences have a broad spectrum of presentations. Arteriovenous malformation associated with an aneurysm of the Galen vein can be the cause of focal ischemic changes in the nervous parenchyma. The authors report a case of a term newborn (birth weight 4, 000 grams, Apgar score 7/9). Physical investigation confirmed the presence of a continuous murmur in the area of the anterior fontanelle. Ultrasonic investigation of the brain detected a huge arteriovenous malformation of the Galen vein. Ultrasonic investigation of the heart excluded structural anomaly, but confirmed a huge retrograde flow in the aorta descendens, opened ductus arterious with suspected formation of coarctation of the aorta and dilatation of the vena cava superior. Congenital anomaly of the Galen vein has a negative influence on prenatal and postnatal development of the brain of a newborn. In the case of our patient, it led to rapid severe asphyxiated changes of the brain parenchyma. Diagnosis and management were established, yet endovascular therapy was not indicated in the early neonatal period.


Nutrition, sirtuins and aging.
Beyond our inherited genetic make-up environmental factors are central for health and disease and finally determine our life span. Amongst the environmental factors nutrition plays a prominent role in affecting a variety of degenerative processes that are linked to aging. The exponential increase of non-insulin-dependent diabetes mellitus in industrialized nations as a consequence of a long-lasting caloric supernutrition is an expression of this environmental challenge that also affects aging processes. The most consistent effects along the environmental factors that slow down aging - from simple organisms to rodents and primates - have been observed for caloric restriction. In the yeast Saccharomyces cerevisiae, the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, sirtuins (silencing information regulators) have been identified to mediate as "molecular sensors" the effects of caloric restriction on aging processes. Sirtuins are NAD(+)-dependent deacetylases that are activated when e.g. cell energy status is low and the NAD(+) over NADH ratio is high. As a consequence transcription rates of a variety of genes including that of the apoptosis inducing p(53) gene are reduced. Moreover, in C. elegans, sirtuins were shown to interact with proteins of the insulin/IGF-1 signaling cascade of which several members are known to extend life span of the nematodes when mutated. Downstream targets of this pathway include genes that encode antioxidative enzymes such as Superoxide dismutase (SOD) whose transcription is activated when receptor activation by insulin/IGF is low or when sirtuins are active and the ability of cells to resist oxidative damage appears to determine their life span. Amongst dietary factors that activate sirtuins are certain polyphenols such as quercetin and resveratrol. Whereas their ability to affect life span has been demonstrated in simple organisms, their efficacy in mammals awaits proof of principle.


Seasonal forecasting of green water components and crop yield of summer crops in Serbia and Austria.
A probabilistic crop forecast based on ensembles of crop model output estimates, presented here, offers an ensemble of possible realizations and probabilistic forecasts of green water components, crop yield and green water footprints (WFs) on seasonal scales for selected summer crops. The present paper presents results of an ongoing study related to the application of ensemble forecasting concepts in crop production. Seasonal forecasting of crop water use indicators (evapotranspiration (ET), water productivity, green WF) and yield of rainfed summer crops (maize, spring barley and sunflower), was performed using the AquaCrop model and ensemble weather forecast, provided by The European Centre for Medium-range Weather Forecast. The ensemble of estimates obtained was tested with observation-based simulations to assess the ability of seasonal weather forecasts to ensure that accuracy of the simulation results was the same as for those obtained using observed weather data. Best results are obtained for ensemble forecast for yield, ET, water productivity and green WF for sunflower in Novi Sad (Serbia) and maize in Groß-Enzersdorf (Austria) - average root mean square error (2006-2014) was <10% of observation-based values of selected variables. For variables yielding a probability distribution, capacity to reflect the distribution from which their outcomes will be drawn was tested using an Ignorance score. Average Ignorance score, for all locations, crops and variables varied from 1.49 (spring barley ET in Groß-Enzersdorf) to 3.35 (sunflower water productivity in Groß-Enzersdorf).


The yapA Encodes bZIP Transcription Factor Involved in Stress Tolerance in Pathogenic Fungus Talaromyces marneffei.
Talaromyces marneffei, formerly Penicillium marneffei, is a thermally dimorphic fungus. It causes a fatal disseminated disease in patients infected with the human immunodeficiency virus (HIV). Studies on the stress defense mechanism of T. marneffei can lead to a better understanding of the pathogenicity and the progression of the disease due to this fungus. The basic leucine-zipper (bZip) transcription factor gene in Saccharomyces cerevisiae, named yap1 (yeast activating protein-1), is known as a crucial central regulator of stress responses including those caused by oxidative agents, cadmium, and drugs. An ortholog of yap1, designated yapA, was identified in T. marneffei. We found that the yapA gene was involved in growth and fungal cell development. The yapA deletion mutant exhibited delays in the rate of growth, germination, and conidiation. Surprisingly, the yapA gene was also involved in the pigmentation of T. marneffei. Moreover, the mutant was sensitive to oxidative stressors such as H2O2 and menadione, similar to S. cerevisiae yap1 mutant, as well as the nitrosative stressor NaNO2. In addition, the yapA mutant demonstrated significantly decreased survival in human macrophage THP-1 compared to wild-type and complemented strains. This study reveals the role of yapA in fungal growth, cell development, stress response, and potential virulence in T. marneffei.


An elastic second skin.
We report the synthesis and application of an elastic, wearable crosslinked polymer layer (XPL) that mimics the properties of normal, youthful skin. XPL is made of a tunable polysiloxane-based material that can be engineered with specific elasticity, contractility, adhesion, tensile strength and occlusivity. XPL can be topically applied, rapidly curing at the skin interface without the need for heat- or light-mediated activation. In a pilot human study, we examined the performance of a prototype XPL that has a tensile modulus matching normal skin responses at low strain (<40%), and that withstands elongations exceeding 250%, elastically recoiling with minimal strain-energy loss on repeated deformation. The application of XPL to the herniated lower eyelid fat pads of 12 subjects resulted in an average 2-grade decrease in herniation appearance in a 5-point severity scale. The XPL platform may offer advanced solutions to compromised skin barrier function, pharmaceutical delivery and wound dressings.


Pupillary Responses to Words That Convey a Sense of Brightness or Darkness.
Theories about embodiment of language hold that when you process a word's meaning, you automatically simulate associated sensory input (e.g., perception of brightness when you process lamp) and prepare associated actions (e.g., finger movements when you process typing). To test this latter prediction, we measured pupillary responses to single words that conveyed a sense of brightness (e.g., day) or darkness (e.g., night) or were neutral (e.g., house). We found that pupils were largest for words conveying darkness, of intermediate size for neutral words, and smallest for words conveying brightness. This pattern was found for both visually presented and spoken words, which suggests that it was due to the words' meanings, rather than to visual or auditory properties of the stimuli. Our findings suggest that word meaning is sufficient to trigger a pupillary response, even when this response is not imposed by the experimental task, and even when this response is beyond voluntary control.


Hepatic insulin resistance and defects in substrate utilization in cystic fibrosis.
Patients with cystic fibrosis (CF)-related diabetes (CFRD) have clinical features of both type 1 and type 2 diabetes. Past studies have documented peripheral insulin resistance in CF, and some studies have noted high hepatic glucose production (HGP) in CF patients. We hypothesized that patients with CF, similar to patients with type 2 diabetes, have hepatic insulin resistance. Cystic fibrosis is a catabolic condition, yet the etiology of catabolism is poorly understood. De novo lipogenesis is energy wasteful and precludes ketogenesis. Patients with CFRD rarely develop ketogenesis, despite insulin deficiency. We speculated that CF patients have de novo lipogenesis, and therefore evaluated substrate utilization in CF. Using [6,6-2H2]glucose and a three-step hyperinsulinemic-euglycemic clamp, we measured HGP in 29 adult CF subjects and 18 control volunteers. Using indirect calorimetry, we measured lipid oxidation, oxidative glucose metabolism, and resting energy expenditure at baseline and at high levels of insulin. All subjects were characterized by oral glucose tolerance testing (OGTT) and National Diabetes Data Group criteria. The CF subjects had increased HGP when compared with control subjects (CF, 3.5+/-0.6; control, 2.5+/-0.5 mg x kg(-1) x h(-1); P = 0.002). Baseline HGP correlated with glucose levels obtained 2 h after a glucose load given for OGTT (r = 0.69, P = 0.001). Suppression of HGP by insulin was significantly less in all CF subgroups than in control subjects at peripheral insulin levels of 16 and 29 microU/ml. At peripheral insulin levels of 100 microU/ml and 198 microU/ml, there was no difference in insulin suppression of HGP between CF and control subjects. At baseline, there was no significant difference between control and CF subjects for glucose or lipid oxidation. During maximum insulin stimulation, there was a greater tendency for nonoxidative glucose metabolism in all CF subjects. The CF subjects with abnormal glucose tolerance also had de novo lipogenesis. Our results indicate that CF patients have several defects in substrate utilization, including de novo lipogenesis. Furthermore, these results suggest that high hepatic glucose production and hepatic insulin resistance contribute to the high incidence of abnormal glucose tolerance in CF.


Changes in ultrasound findings in posterior uveal melanoma after Ruthenium 106 brachytherapy.
To analyze the postbrachytherapy ultrasonographic dynamics of uveal melanoma tumor height and internal reflectivity. Prospective, comparative, observational case series. One hundred forty-seven patients (147 eyes) with posterior uveal melanoma having a mean age of 61 years (range, 29-97 years) who were treated with Ruthenium 106 brachytherapy. Patients were followed-up with ultrasonography using both A and B modes of standardized echography every 6.7 +/- 0.3 months (mean +/- standard error of the mean) for a total of 1001 ultrasound examinations. On average, each patient was examined 5.8 times (range, 3-17 times). The echographic parameters included tumor base size, height, internal reflectivity, regularity, vascularity, and extra-scleral extension. To compare the response of tumors of different sizes, each tumor was standardized to its initial size at brachytherapy. The dynamics of the tumor height and internal reflectivity. At the time of brachytherapy, the mean height of the tumors was 5.2 mm (range, 2.2-11.8 mm). After brachytherapy, 142 tumors (96.6%) responded by a decrease in height. The decrease in height was at an initial rate of approximately 3% per month. Most of the tumors did not regress entirely; rather, their height stabilized on a constant value (on average 61% of the initial height) after approximately 18 to 24 months. The decrease in height after brachytherapy was best fitted by the sum of a first order exponential decay and a constant (h = 61 + 35*e(-0.12t), in which t = time in months). The half-life of the decay was 5.8 months. Large tumors (>8 mm) had a faster initial decrease in height, and stabilized on a lower percentage of their initial height (50%) compared with small tumors (70%). Thus, the half-life of the height exponential decay was 5.3 months for small tumors (2-4 mm) and 3.3 months for the large tumors (>8 mm). Internal reflectivity increased from a mean of 40% before therapy to 70% after 2 years. The dynamics of the reflectivity were best fitted with the function: f = 45 + 24(1-e(-0.09t)). Larger tumors, which initially had lower internal reflectivity, presented with a slower increase in internal reflectivity (t() = 8.7 months) compared with smaller tumors (t(1/2) = 5 months). The postbrachytherapy ultrasonographic dynamics of uveal melanomas resemble a function composed of the sum of a constant and a first order exponent, suggesting the possible existence of two components (cell populations), one unaffected by brachytherapy and the other a radiosensitive population that reacts to brachytherapy in an exponential decay. An exponential decay can imply that the postbrachytherapy death of each tumor cell is a stochastic Markovian process that is independent of the death of other tumor cells.


Asbestos pleural effusion: a clinical entity.
In a case-control study asbestos exposure in 64 consecutive men with idiopathic pleural effusion and 129 randomly sampled age matched male controls was compared. Furthermore, seven women and 64 men with idiopathic pleural effusion were studied, including a three year re-examination, in an attempt to identify characteristics that might distinguish asbestos exposed from non-exposed patients. Asbestos exposure was significantly (p less than 0.01) more frequent in men with idiopathic effusions than in controls. The idiopathic effusions seen in asbestos exposed patients were compatible with the diagnosis "asbestos pleural effusion." Two features were characteristic of patients with asbestos pleural effusion: a chest radiograph at the initial examination showing converging pleural linear structures or rounded atelectasis or a history of recurrent pleural effusion, or both.


Determination of chlorpyrifos and its metabolites in rat brain tissue using coupled-column liquid chromatography/electrospray ionization tandem mass spectrometry.
A method has been developed to quantify chlorpyrifos (O,O-diethyl-O-[3,5,6,-trichloro-2-pyridyl] phosphorothionate) and its metabolites chlorpyrifos-oxon (O,O-diethyl-O-[3,5,6,trichloro-2-pyridinyl] phosphate) and TCP (3,5,6,-trichloro-2-pyridinol) in rat brain tissue by coupled-column liquid chromatography/electrospray ionization tandem mass spectrometry (LC/LC/ESI-MS/MS). Rat brains were homogenized and treated by protein precipitation using ice-cold acetonitrile. The supernatant was directly injected onto the coupled-column system. Sample clean-up was achieved on a Zorbax Extend-C(18) column (2.1 x 50 mm, 5 microm) using a mobile phase of acetonitrile/water with 0.0025% formic acid (40:60, v/v). The compounds were separated isocratically on a Zorbax Eclipse XDB C(8) column (2.0 x 150 mm, 5 microm) using a mobile phase of acetonitrile/water with 0.0025% formic acid (75:25, v/v). Chlorpyrifos and chlorpyrifos-oxon were detected in positive ion mode using multiple reaction monitoring (MRM). TCP was detected in negative ion mode using precursor-to-precursor transition monitoring. The method was validated and the specificity, linearity, limit of quantitation (LOQ), precision, accuracy, stability, and recoveries were determined. Calibration curves for all three analytes yielded correlation coefficients of 0.993 or greater. The LOQs were 25.3 ng/g for chlorpyrifos and 6.3 ng/g for chlorpyrifos-oxon and TCP. All precision relative standard deviations (RSDs) were less than 16% for the LOQ and less than 11% for the other QC samples. This method was successfully applied to six rats that were injected subcutaneously with chlorpyrifos.


Genomoviridae: a new family of widespread single-stranded DNA viruses.
Here, we introduce a new family of eukaryote-infecting single-stranded (ss) DNA viruses that was created recently by the International Committee on Taxonomy of Viruses (ICTV). The family, named Genomoviridae, contains a single genus, Gemycircularvirus, which currently has one recognized virus species, Sclerotinia gemycircularvirus 1. Sclerotinia sclerotiorum hypovirulence-associated DNA virus 1 (SsHADV-1) is currently the sole representative isolate of the family; however, a great number of SsHADV-1-like ssDNA virus genomes has been sequenced from various environmental, plant- and animal-associated samples, indicating that members of family Genomoviridae are widespread and abundant in the environment.


Pre-hospital trauma care resources for road traffic injuries in a middle-income country--a province based study on need and access in Iran.
Access to pre-hospital trauma care can help minimize many of traffic related mortality and morbidity in low- and middle-income countries with high rate of traffic deaths such as Iran. The aim of this study was to assess if the distribution of pre-hospital trauma care facilities reflect the burden of road traffic injury and mortality in different provinces in Iran. This national cross-sectional study is based on ecological data on road traffic mortality (RTM), road traffic injuries (RTIs) and pre-hospital trauma facilities for all 30 provinces in Iran in 2006. Lorenz curves and Gini coefficients were used to describe the distributions of RTM/RTIs and pre-hospital trauma care facilities across provinces. Spearman rank-order correlation was performed to assess the relationship between RTM/RTI and pre-hospital trauma care facilities. RTM and RTIs as well as pre-hospital trauma care facilities were distributed unequally between different provinces. There was no significant association between the rate of RTM and RTIs and the number of pre-hospital trauma care facilities across the country. The distribution of pre-hospital trauma care facilities does not reflect the needs in terms of RTM and RTIs for different provinces. These results suggest that traffic related mortality and morbidity could be reduced if the needs in terms of RTM and RTIs were taken into consideration when distributing pre-hospital trauma care facilities between the provinces.


The impact of unstructured games of fantasy and role playing on an inpatient unit for adolescents.
Games of fantasy and role playing such as Dungeons and Dragons (1983) have become increasingly popular among adolescents and young adults. This article reviews the negative impact of such games on an adolescent inpatient treatment setting. The unrestricted play of such games contributed to the disruption of a treatment setting, resistances to treatment, reinforcement of character pathology, disruption of individual treatments, and to the normalization of violence. When such games begin to be played on a psychiatric inpatient unit or are prominent in discussions of individual patients, treaters should examine them in the context of their potential to reinforce and foster resistance and maladaptive patterns of relating to the environment. Treaters are also encouraged to attempt to understand the meaning and risks of such games in the context of an individual patient's psychiatric difficulties and of group dynamics, both within the patient group and between patients and treaters.


Effects of Long-Term Sclerostin Deficiency on Trabecular Bone Mass and Adaption to Limb Loading Differ in Male and Female Mice.
A new therapeutic option to treat osteoporosis is focused on Wnt signaling and its inhibitor sclerostin, a product of the Sost gene. In this work, we study the effect of sclerostin deficiency on trabecular bone formation and resorption in male and female mice and whether it affects mechano-responsiveness. Male and female 10- and 26-week-old Sost knockout (KO) and littermate controls (LCs) were subjected to in vivo mechanical loading of the left tibia for 2 weeks. The right tibia served as internal control. The mice were imaged using in vivo micro-computed tomography at days 0, 5, 10, and 15 and tibiae were collected for histomorphometric analyses after euthanasia. Histomorphometry and micro-CT-based 3D time-lapse morphometry revealed an anabolic and anti-catabolic effect of Sost deficiency although increased trabecular bone resorption accompanied by diminished trabecular bone formation occurred with age. Loading led to diminished resorption in adult female but not in male mice. A net gain in bone volume could be achieved with mechanical loading in Sost KO adult female mice, which occurred through a further reduction in resorbed bone volume. Our data show that sclerostin deficiency has a particularly positive effect in adult female mice. Sclerostin antibodies are approved to treat postmenopausal women with high risk of osteoporotic fractures. Further studies are required to clarify whether both sexes benefit equally from sclerostin inhibition.


The condensin complex is a mechanochemical motor that translocates along DNA.
Condensin plays crucial roles in chromosome organization and compaction, but the mechanistic basis for its functions remains obscure. We used single-molecule imaging to demonstrate that Saccharomyces cerevisiae condensin is a molecular motor capable of adenosine triphosphate hydrolysis-dependent translocation along double-stranded DNA. Condensin's translocation activity is rapid and highly processive, with individual complexes traveling an average distance of ≥10 kilobases at a velocity of ~60 base pairs per second. Our results suggest that condensin may take steps comparable in length to its ~50-nanometer coiled-coil subunits, indicative of a translocation mechanism that is distinct from any reported for a DNA motor protein. The finding that condensin is a mechanochemical motor has important implications for understanding the mechanisms of chromosome organization and condensation.


Speciation along environmental gradients.
Traditional discussions of speciation are based on geographical patterns of species ranges. In allopatric speciation, long-term geographical isolation generates reproductively isolated and spatially segregated descendant species. In the absence of geographical barriers, diversification is hindered by gene flow. Yet a growing body of phylogenetic and experimental data suggests that closely related species often occur in sympatry or have adjacent ranges in regions over which environmental changes are gradual and do not prevent gene flow. Theory has identified a variety of evolutionary processes that can result in speciation under sympatric conditions, with some recent advances concentrating on the phenomenon of evolutionary branching. Here we establish a link between geographical patterns and ecological processes of speciation by studying evolutionary branching in spatially structured populations. We show that along an environmental gradient, evolutionary branching can occur much more easily than in non-spatial models. This facilitation is most pronounced for gradients of intermediate slope. Moreover, spatial evolutionary branching readily generates patterns of spatial segregation and abutment between the emerging species. Our results highlight the importance of local processes of adaptive divergence for geographical patterns of speciation, and caution against pitfalls of inferring past speciation processes from present biogeographical patterns.


Electronically tunable single-mode external-cavity diode laser.
A six-stage birefringent filter placed in an external cavity of an AlGaAs diode laser is used to scan the laser electronically over 10.3 nm, hopping single modes of the external cavity. Continuous electronic tuning of the single mode over the free spectral range of the external cavity, 182 MHz, is also demonstrated by using a variable-phase plate. All tuning mechanisms use nematic liquid-crystal electro-optic effects operating at <2 V.


Chelation-assisted, copper(II)-acetate-accelerated azide-alkyne cycloaddition.
We described in a previous communication a variant of the popular Cu(I)-catalyzed azide-alkyne cycloaddition (AAC) process where 5 mol % of Cu(OAc)(2) in the absence of any added reducing agent is sufficient to enable the reaction. 2-Picolylazide (1) and 2-azidomethylquinoline (2) were found to be by far the most reactive carbon azide substrates that convert to 1,2,3-triazoles in as short as a few minutes under the discovered conditions. We hypothesized that the abilities of 1 and 2 to chelate Cu(II) contribute significantly to the observed high reaction rates. The current work examines the effect of auxiliary ligands near the azido group other than pyridyl for Cu(II) on the efficiency of the Cu(OAc)(2)-accelerated AAC reaction. The carbon azides capable of binding to the catalytic copper center at the alkylated azido nitrogen in a chelatable fashion were indeed shown to be superior substrates under the reported conditions. The chelation between carbon azide 11 and Cu(II) was demonstrated in an X-ray single-crystal structure. In a limited set of examples, the ligand tris(benzyltriazolylmethyl)amine (TBTA), developed by Fokin et al. for assisting the original Cu(I)-catalyzed AAC reactions, also dramatically enhances the Cu(OAc)(2)-accelerated AAC reactions involving nonchelating azides. This observation leads to the hypothesis of an additional effect of chelating azides on the efficiencies of Cu(OAc)(2)-accelerated AAC reactions, which is to facilitate the rapid reduction of Cu(II) to highly catalytic Cu(I) species. Mechanistic studies on the AAC reactions with particular emphasis on the role of carbon azide/copper interactions will be conducted based on the observations reported in this work. Finally, the immediate utility of the product 1,2,3-triazole molecules derived from chelating azides as multidentate metal coordination ligands is demonstrated. The resulting triazolyl-containing ligands are expected to bind with transition metal ions via the N(2) nitrogen of the 1,2,3-triazolyl group to form nonplanar coordination rings. The Cu(II) complexes of bidentate T1 and tetradentate T6 and the Zn(II) complex of T6 were characterized by X-ray crystallography. The structure of [Cu(T1)(2)(H(2)O)(2)](ClO(4))(2) reveals the interesting synergistic effect of hydrogen bonding, π-π stacking interactions, and metal coordination in forming a one-dimensional supramolecular construct in the solid state. The tetradentate coordination mode of T6 may be incorporated into designs of new molecule sensors and organometallic catalysts.


Epithelial-mesenchymal transition and its implications for fibrosis.
Epithelial to mesenchymal transition (EMT) is a central mechanism for diversifying the cells found in complex tissues. This dynamic process helps organize the formation of the body plan, and while EMT is well studied in the context of embryonic development, it also plays a role in the genesis of fibroblasts during organ fibrosis in adult tissues. Emerging evidence from studies of renal fibrosis suggests that more than a third of all disease-related fibroblasts originate from tubular epithelia at the site of injury. This review highlights recent advances in the process of EMT signaling in health and disease and how it may be attenuated or reversed by selective cytokines and growth factors.


18F-FDG PET and PET/CT in the Localization and Characterization of Lesions in Patients with Ovarian Cancer.
The aim was to compare the imaging findings of (18)F-fluorodeoxyglucose ((18)F-FDG) PET and integrated PET/CT in patients with primary, recurrent or metastatic ovarian cancer. 21 women with ovarian cancer were evaluated. All patients had a integrated PET/CT scan. Localization, infiltration and uptake intensity of [(18)F]FDG were evaluated on PET and PET/CT. The certainty of localisation and characterisation was scored on a 3 point scale (L1 definite localisation; L2 probable localisation; L3 uncertain localisation; C1 benign; C2 equivocal; C3 malignant). PET scored as L1 54 lesions (44%), as L2 51 (42%), and as L3 17 (14%). On the other hand, PET/CT scored as L1 120 lesions (98%), as L2 2 (2%), and none as L3. Thus PET/CT allowed a better localization in 54% of lesions. Moreover, PET scored as C1 25 lesions (20%), as C2 62 (51%), and as C3 35 (29%). On the other hand, PET/CT scored as C1 57 lesions (47%), as C2 13 (11%), and as C3 52 (42%). Thus PET/CT allowed a sensible reduction in the number of equivocal lesions (40%). Even when patients were subgrouped on the basis of clinical stage of the disease, PET/CT was capable of better definition of the lesions either for localization and for characterization. In patients with ovarian cancer, PET/CT allows better anatomical localisation of pathologic uptake providing high accuracy for staging and restaging of ovarian cancer when compared with PET alone.


The relationship of swimming exercise to bone mass in men and women.
Exercise appears to be capable of exerting a positive effect on bone mass, but how exercise can be used to best advantage in the prevention and therapy of osteopenia is unclear. Weight-bearing activity has been commonly considered to be essential for the beneficial effects of exercise on the skeleton, and, therefore, swimming has been considered valueless in the maintenance of bone mass. To examine this issue we measured radial and vertebral bone mineral density in a group of subjects aged 40 to 85 years who had been swimming regularly for at least 3 years as well as in a similar group of nonexercising control subjects. The swimmers engaged in no other forms of regular exercise, and no subject had other conditions known to affect bone or mineral metabolism. Dietary calcium and protein intakes were similar in the two groups. At both radial (0.84 +/- 0.08 vs 0.81 +/- 0.09 g/cm2) and vertebral (123 +/- 27 vs 108 +/- 31 mg/cm3) sites the male swimmers had significantly greater bone mineral density than did the nonexercisers. In women, however, no relationship of swimming to bone mineral density could be identified. These results suggest that swimming exercise may be beneficial in the prevention or therapy of osteopenia and that its usefulness in this regard should be further investigated.


Intranodal palisaded myofibroblastoma.
Intranodal palisaded myofibroblastoma (IPM) usually presents as a painless, slow-growing inguinal mass. Our review of 42 cases from 13 publications indicates that two thirds of IPMs occur between the ages of 45 and 55 years, the male-female ratio is 2:1, and there is a lack of ethnic predilection. Grossly, the IPM cut surface shows areas of hemorrhage. Five microscopic features are seen: (a) compressed remnants of lymphoid tissue at the periphery; (b) spindle cells with nuclear palisading; (c) intraparenchymal hemorrhage and erythrocyte extravasation; (d) so-called amianthoid fibers; and (e) intracellular and extracellular fuchsinophilic bodies that stain positive for smooth muscle actin. Immunohistochemically, IPM is positive for smooth muscle actin and cyclin D1 and negative for S100, glial fibrillary acidic protein, CD34, and desmin, and it shows a low proliferative index of Ki-67. Electron microscopy demonstrates features of myofibroblasts and smooth muscle cells. Excellent prognosis is seen after surgical treatment, with an approximately 6% recurrence rate and no malignant transformation.


Geometry of the DNA strands within the RecA nucleofilament: role in homologous recombination.
Homologous recombination consists of exchanging DNA strands of identical or almost identical sequence. This process is important for both DNA repair and DNA segregation. In prokaryotes, it involves the formation of long helical filaments of the RecA protein on DNA. These filaments incorporate double-stranded DNA from the cell's genetic material, recognize sequence homology and promote strand exchange between the two DNA segments. DNA processing by these nucleofilaments is characterized by large amplitude deformations of the double helix, which is stretched by 50% and unwound by 40% with respect to B-DNA. In this article, information concerning the structure and interactions of the RecA, DNA and ATP molecules involved in DNA strand exchange is gathered and analyzed to present a view of their possible arrangement within the filament, their behavior during strand exchange and during ATP hydrolysis, the mechanism of RecA-promoted DNA deformation and the role of DNA deformation in the process of homologous recombination. In particular, the unusual characteristics of DNA within the RecA filament are compared to the DNA deformations locally induced by architectural proteins which bind in the DNA minor groove. The possible role and location of two flexible loops of RecA are discussed.


Chromatin signatures at transcriptional start sites separate two equally populated yet distinct classes of intergenic long noncoding RNAs.
Mammalian transcriptomes contain thousands of long noncoding RNAs (lncRNAs). Some lncRNAs originate from intragenic enhancers which, when active, behave as alternative promoters producing transcripts that are processed using the canonical signals of their host gene. We have followed up this observation by analyzing intergenic lncRNAs to determine the extent to which they might also originate from intergenic enhancers. We integrated high-resolution maps of transcriptional initiation and transcription to annotate a conservative set of intergenic lncRNAs expressed in mouse erythroblasts. We subclassified intergenic lncRNAs according to chromatin status at transcriptional initiation regions, defined by relative levels of histone H3K4 mono- and trimethylation. These transcripts are almost evenly divided between those arising from enhancer-associated (elncRNA) or promoter-associated (plncRNA) elements. These two classes of 5' capped and polyadenylated RNA transcripts are indistinguishable with regard to their length, number of exons or transcriptional orientation relative to their closest neighboring gene. Nevertheless, elncRNAs are more tissue-restricted, less highly expressed and less well conserved during evolution. Of considerable interest, we found that expression of elncRNAs, but not plncRNAs, is associated with enhanced expression of neighboring protein-coding genes during erythropoiesis. We have determined globally the sites of initiation of intergenic lncRNAs in erythroid cells, allowing us to distinguish two similarly abundant classes of transcripts. Different correlations between the levels of elncRNAs, plncRNAs and expression of neighboring genes suggest that functional lncRNAs from the two classes may play contrasting roles in regulating the transcript abundance of local or distal loci.


The congenital myasthenic syndromes.
The congenital myasthenic syndromes (CMS) are rare inherited disorders of neuromuscular transmission characterised by fatigable muscle weakness. Thus far, genetic analysis has identified mutations in eleven different genes but it is clear that additional phenotypic subgroups exist where the underlying genetics has not yet been defined. Although each syndrome results from defective synaptic transmission at the neuromuscular junction, the patients show a variable set of phenotypes. Here, we provide a brief clinical review.


Quantitative detection of promoter hypermethylation as a biomarker of acute kidney injury during transplantation.
Aberrant promoter hypermethylation, also known as epigenetics, is thought to be a promising biomarker approach to diagnose malignancies. Kidney repair after injury is a recapitulation of normal morphogenesis, with similarities to malignant transformation. We hypothesized that changes in urine epigenetics could be a biomarker approach during early kidney transplant injury and repair. We examined urine DNA for aberrant methylation of two gene promoters (DAPK and CALCA) by quantitative methylation-specific polymerase chain reaction from 13 deceased and 10 living donor kidney transplant recipients on postoperative day 2 and 65 healthy controls. Results were compared with clinical outcomes and to results of the kidney biopsy. Transplant recipients were significantly more likely to have aberrant hypermethylation of the CALCA gene promoter in urine than healthy controls (100% vs 31%; P < .0001). There was increased CALCA hypermethylation in the urine of deceased versus living donor transplants (21.60 +/- 12.5 vs 12.19 +/- 4.7; P = .04). Furthermore, there was a trend toward increased aberrant hypermethylation of urine CALCA in patients with biopsy-proven acute tubular necrosis versus acute rejection and slow or prompt graft function (mean: 20.40 +/- 6.9, 13.87 +/- 6.49, 17.17 +/- 13.4; P = .67). However, there was no difference of CALCA hypermethylation in urine of patients with delayed graft function versus those with slow or prompt graft function (16.9 +/- 6.2 vs 18.5 +/- 13.7, respectively; P = .5). There was no aberrant hypermethylation of DAPK in the urine of transplant patients. Urine epigenetics is a promising biomarker approach for acute ischemic injury in transplantation that merits future study.


Regional economic conditions and crash fatality rates--a cross-county analysis.
Most studies that evaluate the relationship between economic conditions and traffic fatalities focus on the time-series relationship between the two factors. This analysis considers the cross-sectional perspective by estimating the cross-county correlation between per capita income and fatalities per vehicle mile traveled (VMT) in Ohio. The empirical model employed in this analysis allows for interaction effects between per capita income and highway usage, in the determination of fatality rates. The resultant least squares estimates indicate that a significant interaction effect exists between per capita income and the percentage of highway VMT, indicating a nonlinear correlation between per capita income and fatality rates. This correlation rises as the proportion of VMT on highways rises, such that there is an inverse relationship with fatality rates when the highway share of county VMT is low and a direct relationship with fatality rates when the highway share of county VMT is high. Additionally, population density, the presence of interstate highways in rural counties, the prior prevalence of severe alcohol abuse, and the proportion of teen drivers all proved to be significant correlates with county fatality rates. These observations suggest factors that state and federal policy makers should consider when allocating resources that impact (whether directly or indirectly) traffic fatalities.


Every dog has its prey: Range-wide assessment of links between diet patterns, livestock depredation and human interactions for an endangered carnivore.
Livestock depredation is the most ubiquitous type of negative interaction between humans and carnivores. We conducted a range-wide assessment linking diet patterns of the endangered dhole Cuon alpinus, with livestock consumption and human-dhole interactions. We first performed a reanalysis of dhole diet data from all published studies (1973-2013) incorporating a recently-developed non-linear correction factor for quantifying prey biomass consumed. We then determined the relative livestock numbers consumed by dholes over time across its range, compared these with earlier estimates, and investigated the relative importance of wild vs. non-wild prey in dhole diet. Using information from >70 studies, we explored links between livestock consumption by dholes, availability of wild versus non-wild prey, sympatric depredation-prone carnivores, and people's perception of dholes as livestock predators. We found that (a) dhole diet profiles varied regionally, (b) dholes consumed fewer livestock compared to estimates generated using other, widely used methods, (c) livestock consumption by dholes was associated with wild and non-wild prey densities, and number of co-predator species, and (d) people's negative perception of dholes was associated with pack sizes, levels of livestock depredation and number of sympatric carnivore species. Global efforts for dhole conservation should involve different strategies based on region-specific realities that account for ecological context as well as human perceptions, which would require well-designed studies of dhole social and population dynamics, and human-dhole interactions. We also call for more such range-wide assessments of livestock depredation by wild canids, complemented with direct investigations of human-canid interactions.


Leishmania amazonensis: xylitol as inhibitor of macrophage infection and stimulator of macrophage nitric oxide production.
Xylitol is a sugar alcohol being explored for clinical uses. The aim was to evaluate the effects of xylitol on Leishmania amazonensis-infected J774A.1 macrophages. Macrophages were infected with L. amazonensis for 3h, washed and incubated with 2.5 or 5.0% xylitol for 24, 48, and 72 h at 37 degrees C. Infection indexes for macrophages incubated only in medium were compared to those treated with xylitol. Cell viability and nitric oxide production were determined each time. Xylitol did not affect L. amazonensis or J774A.1 cell viabilities. Xylitol at 5.0% stimulated nitric oxide production by macrophages at 72 h (p<0.01). At 2.5 and 5.0%, xylitol inhibited nitric oxide production by L. amazonensis at 48 h (p<0.05) when compared to control. Infection indexes were significantly lower at 72 h (p<0.05), (16.9% and 9.6%) in cells cultivated with 2.5 and 5.0% xylitol, respectively, compared to control (38.4%). Results suggest a potential leishmanicidal action of the xylitol on infected macrophages.


Influence of acute and chronic streptozotocin-induced diabetes on the rat tendon extracellular matrix and mechanical properties.
Diabetes is a major risk factor for tendinopathy, and tendon abnormalities are common in diabetic patients. The purpose of the present study was to evaluate the effect of streptozotocin (60 mg/kg)-induced diabetes and insulin therapy on tendon mechanical and cellular properties. Sprague-Dawley rats (n = 40) were divided into the following four groups: nondiabetic (control), 1 wk of diabetes (acute), 10 wk of diabetes (chronic), and 10 wk of diabetes with insulin treatment (insulin). After 10 wk, Achilles tendon and tail fascicle mechanical properties were similar between groups (P > 0.05). Cell density in the Achilles tendon was greater in the chronic group compared with the control and acute groups (control group: 7.8 ± 0.5 cells/100 μm(2), acute group: 8.3 ± 0.4 cells/100 μm(2), chronic group: 10.9 ± 0.9 cells/100 μm(2), and insulin group: 9.2 ± 0.8 cells/100 μm(2), P < 0.05). The density of proliferating cells in the Achilles tendon was greater in the chronic group compared with all other groups (control group: 0.025 ± 0.009 cells/100 μm(2), acute group: 0.019 ± 0.005 cells/100 μm(2), chronic group: 0.067 ± 0.015, and insulin group: 0.004 ± 0.004 cells/100 μm(2), P < 0.05). Patellar tendon collagen content was ∼32% greater in the chronic and acute groups compared with the control or insulin groups (control group: 681 ± 63 μg collagen/mg dry wt, acute group: 938 ± 21 μg collagen/mg dry wt, chronic: 951 ± 52 μg collagen/mg dry wt, and insulin group: 596 ± 84 μg collagen/mg dry wt, P < 0.05). In contrast, patellar tendon hydroxylysyl pyridinoline cross linking and collagen fibril organization were unchanged by diabetes or insulin (P > 0.05). Our findings suggest that 10 wk of streptozotocin-induced diabetes does not alter rat tendon mechanical properties even with an increase in collagen content. Future studies could attempt to further address the mechanisms contributing to the increase in tendon problems noted in diabetic patients, especially since our data suggest that hyperglycemia per se does not alter tendon mechanical properties.


Sequential immunizations with rgp120s from independent isolates of human immunodeficiency virus type 1 induce the preferential expansion of broadly crossreactive B cells.
The gp120 envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) is a dominant target against which the host's humoral immune response is directed. Unfortunately, gp120 proteins from different isolates of HIV are antigenically distinct, complicating the use of the envelope glycoprotein in vaccines designed to prevent acquired immunodeficiency syndrome. Using an enzyme-linked immunosorbent spot assay (ELISA), BALB/c mice immunized and boosted with recombinant purified gp120 were studied at the single cell level for their humoral immune response to HIV-1 envelope proteins. Approximately 90% of responding B cells produced antibodies reactive with the immunizing form of gp120 but not with gp120s from other strains of HIV. A novel sandwich ELISA was then used to analyze the frequency with which individual in vivo activated B cells produced antibodies that crossreacted with heterologous gp120s. Repeated immunizations with a single gp120 or with a mixture of different gp120s resulted in the activation of primarily mono-specific (noncrossreactive) B cells. In contrast, the sequential immunization of mice with recombinant purified envelope proteins from different strains of HIV (IIIB, SF2, and Zr6) induced the selective expansion of B cells producing highly crossreactive antibodies.


Anthropogenic 236U and 129I in the Mediterranean Sea: First comprehensive distribution and constrain of their sources.
The first basin-wide distribution of 236U/238U atom ratios and 129I concentrations is presented for the Mediterranean Sea. During the GEOTRACES GA04S-MedSeA expedition in 2013 seawater was collected from 10 vertical profiles covering the principal sub-basins of the Mediterranean Sea. The main objective was to understand the distributions of 236U and 129I in relation to the water masses, and to constrain their sources in this region. The 236U/238U atom ratios and the 129I concentrations ranged from (710±40)×10-12 to (2220±60)×10-12 and from (4.0±0.1)×107 to (13.8±0.3)×107at·kg-1, respectively. The results show that radionuclide-poor Atlantic Water is entering at the surface through the Strait of Gibraltar whereas comparably radionuclide-enriched Levantine Intermediate Water is sinking in the Eastern Basin and flowing westward at intermediate depths. Low radionuclide levels were found in the oldest water masses at about 1000-2000m depth in the Eastern Basin. At greater depths, waters were relatively enriched in 236U and 129I due to dense water formation occurring in both, the Eastern and Western Basins. The inventories of 236U and 129I cannot be explained only by global fallout from atmospheric nuclear bomb testings carried out in the 1950s and 1960s. We estimate that the liquid input of 236U from the nuclear reprocessing facility of Marcoule (France), via the Rhône river, was of the same order of magnitude than the contribution from global fallout, whereas liquid and gaseous releases of 129I from Marcoule were up to two orders of magnitude higher than global fallout. For both radionuclides, the contribution from the Chernobyl accident is found to be minor.


Safety of a conservative strategy of permanent pacemaker implantation after transcatheter aortic CoreValve implantation.
Conduction abnormalities are frequent after transcatheter aortic valve implantation with the CoreValve (Medtronic, Minneapolis, MN) and are often treated with liberal permanent pacemaker (PPM) implantation. Our aim was to assess the 1-year outcome of a conservative approach to pacing and to identify its predictors. We analyzed 275 consecutive patients without a PPM before transcatheter aortic valve implantation who underwent successful CoreValve implantation at our 3 centers, sharing a conservative approach to pacing. Of the 47 patients (17.1%) who developed postprocedural complete atrioventricular block, 14 recovered spontaneous atrioventricular conduction <72 hours and did not receive a PPM. Sixty-six patients (24.0%) received a PPM before discharge, and 74 more patients (26.9%) developed a new left bundle-branch block (LBBB). Independent predictors of PPM implantation were as follows: lower CoreValve implantation below the aortic annulus (odds ratio [OR] 1.16/mm, 95% CI 1.03-1.30, P = .01), right bundle-branch block (OR 3.72, 95% CI 1.5-9.2, P = .004), left anterior hemiblock (OR 2.34, 95% CI 1.1-5.1, P = .03), and longer PR interval (OR 1.02/ms, 95% CI 1.00-1.04, P = .03). One-year survival was similar between patients who received a PPM and patients who did not receive a PPM (P = .90), with no case of sudden death in the latter group, and between patients with a new LBBB not receiving a PPM and patients without postprocedural LBBB (P = .37). A high CoreValve implantation level and avoidance of prophylactic pacing in patients with new LBBB without persistent bradyarrhythmias allowed for a relatively low rate of PPM implantation. This conservative approach spared unwarranted pacing and did not affect 1-year survival.


Stop and Smell the Pollen: The Role of Olfaction and Vision of the Oriental Honey Buzzard in Identifying Food.
The importance of olfaction for various avian behaviors has become increasingly evident. So far, the use of olfaction for food detection among raptors has only been demonstrated for Cathartes vultures. The Oriental honey buzzard (Pernis orientalis) is a resident and migrant in Taiwan and regularly forages in apiaries. One of its foods in apiaries is yellow pollen dough, a softball-sized mixture of pollen, soybeans, and sugar that beekeepers provide as a supplementary food for bees. Given that pollen dough is not similar to any naturally occurring food, we hypothesized that buzzards identify the dough's nutritious contents using olfaction, perhaps in combination with vision. Using a series of choice experiments in which individuals could choose between two doughs, we showed that (1) buzzards almost unerringly chose pollen-containing over pollen lacking doughs when otherwise the doughs were identical in size, shape, and yellow color; (2) buzzards always preferred yellow over black or green doughs if both doughs contained pollen; (3) buzzards still preferred pollen-containing over pollen-lacking doughs when both doughs were black, but at a lower rate than in (1). We statistically excluded the possible influences of the doughs' relative brightness or of repeat visits by the same individuals. Our experiments thus suggest the use of a 'multi-modal foraging strategy' among buzzards whereby olfaction and vision are likely to be both used in identifying food at close distances. We also estimated the olfactory receptor gene repertoire size in the buzzard's genome which is almost five times as large as that of three other raptor species. Therefore, olfaction is likely of far greater ecological importance to this species than to other raptor species. We suggest that olfaction should be considered in the design of behavioral and genetic studies to better understand the use of multiple senses in avian behaviors.


A framework for the correction of slow physiological drifts during MR-guided HIFU therapies: Proof of concept.
While respiratory motion compensation for magnetic resonance (MR)-guided high intensity focused ultrasound (HIFU) interventions has been extensively studied, the influence of slow physiological motion due to, for example, peristaltic activity, has so far been largely neglected. During lengthy interventions, the magnitude of the latter can exceed acceptable therapeutic margins. The goal of the present study is to exploit the episodic workflow of these therapies to implement a motion correction strategy for slow varying drifts of the target area and organs at risk over the entire duration of the intervention. The therapeutic workflow of a MR-guided HIFU intervention is in practice often episodic: Bursts of energy delivery are interleaved with periods of inactivity, allowing the effects of the beam on healthy tissues to recede and/or during which the plan of the intervention is reoptimized. These periods usually last for at least several minutes. It is at this time scale that organ drifts due to slow physiological motion become significant. In order to capture these drifts, the authors propose the integration of 3D MR scans in the therapy workflow during the inactivity intervals. Displacements were estimated using an optical flow algorithm applied on the 3D acquired images. A preliminary study was conducted on ten healthy volunteers. For each volunteer, 3D MR images of the abdomen were acquired at regular intervals of 10 min over a total duration of 80 min. Motion analysis was restricted to the liver and kidneys. For validating the compatibility of the proposed motion correction strategy with the workflow of a MR-guided HIFU therapy, an in vivo experiment on a porcine liver was conducted. A volumetric HIFU ablation was completed over a time span of 2 h. A 3D image was acquired before the first sonication, as well as after each sonication. Following the volunteer study, drifts larger than 8 mm for the liver and 5 mm for the kidneys prove that slow physiological motion can exceed acceptable therapeutic margins. In the animal experiment, motion tracking revealed an initial shift of up to 4 mm during the first 10 min and a subsequent continuous shift of ∼2 mm/h until the end of the intervention. This leads to a continuously increasing mismatch of the initial shot planning, the thermal dose measurements, and the true underlying anatomy. The estimated displacements allowed correcting the planned sonication cell cluster positions to the true target position, as well as the thermal dose estimates during the entire intervention and to correct the nonperfused volume measurement. A spatial coherence of all three is particularly important to assure a confluent ablation volume and to prevent remaining islets of viable malignant tissue. This study proposes a motion correction strategy for displacements resulting from slowly varying physiological motion that might occur during a MR-guided HIFU intervention. The authors have shown that such drifts can lead to a misalignment between interventional planning, energy delivery, and therapeutic validation. The presented volunteer study and in vivo experiment demonstrate both the relevance of the problem for HIFU therapies and the compatibility of the proposed motion compensation framework with the workflow of a HIFU intervention under clinical conditions.


Resilience among women and men aged 60 years and over in Sweden and in Thailand.
The purpose of this study was to compare the level of resilience of people aged > or = 60 years in Sweden and Thailand. In a randomized sample of 422 people in Sweden and a convenience sample of 200 people in Thailand, the level of resilience was measured by using the Resilience Scale. A chi(2)-analysis was used for the differences between proportions. The relationships between the background variables and the resilience scores were analyzed by using stepwise multiple linear regression. The mean scores of resilience were 144 for the Swedish participants and 146 for the Thai participants. The two samples differed in their background characteristics. The Thai participants were more likely to be women, to be widowed, and to have more children, while among the Swedish participants, more women were married and more participants were aged > or = 80 years. Despite different background characteristics, the Swedish and the Thai participants' scores were almost the same on the Resilience Scale. More studies are necessary to address aspects of gender and ethnicity in relation to resilience.


[Structuralization of a human teeth bank].
A Human Teeth Bank (HTB) is a nonprofit institution, associated to a college, to a university or to some other institution. Its purpose is to fulfill academic needs, by supplying human teeth for research or for preclinical laboratory training of students, thus eliminating the illegal commerce of teeth that still takes place in dental schools. It is also up to an HTB to work for the elimination of cross-infection caused by indiscriminate handling of extracted teeth. In order to work properly, an HTB should have a strict control of its internal procedures, which include separation and stocking of teeth, as well as an appropriate maintaining of donors' and beneficiaries' records. In this article, we discuss the functions that an HTB can perform, and how the Human Teeth Bank, School of Dentistry, University of S o Paulo, works and organizes itself today.


Current insights into fungal species diversity and perspective on naming the environmental DNA sequences of fungi.
The global bio-diversity of fungi has been extensively investigated and their species number has been estimated. Notably, the development of molecular phylogeny has revealed an unexpected fungal diversity and utilisation of culture-independent approaches including high-throughput amplicon sequencing has dramatically increased number of fungal operational taxonomic units. A number of novel taxa including new divisions, classes, orders and new families have been established in last decade. Many cryptic species were identified by molecular phylogeny. Based on recently generated data from culture-dependent and -independent survey on same samples, the fungal species on the earth were estimated to be 12 (11.7-13.2) million compared to 2.2-3.8 million species recently estimated by a variety of the estimation techniques. Moreover, it has been speculated that the current use of high-throughput sequencing techniques would reveal an even higher diversity than our current estimation. Recently, the formal classification of environmental sequences and permission of DNA sequence data as fungal names' type were proposed but strongly objected by the mycologist community. Surveys on fungi in unusual niches have indicated that many previously regarded "unculturable fungi" could be cultured on certain substrates under specific conditions. Moreover, the high-throughput amplicon sequencing, shotgun metagenomics and a single-cell genomics could be a powerful means to detect novel taxa. Here, we propose to separate the fungal types into physical type based on specimen, genome DNA (gDNA) type based on complete genome sequence of culturable and uncluturable fungal specimen and digital type based on environmental DNA sequence data. The physical and gDNA type should have priority, while the digital type can be temporal supplementary before the physical type and gDNA type being available. The fungal name based on the "digital type" could be assigned as the "clade" name + species name. The "clade" name could be the name of genus, family or order, etc. which the sequence of digital type affiliates to. Facilitating future cultivation efforts should be encouraged. Also, with the advancement in knowledge of fungi inhabiting various environments mostly because of rapid development of new detection technologies, more information should be expected for fungal diversity on our planet.


Complex molecular relationship between vegetative compatibility groups (VCGs) in Verticillium dahliae: VCGs do not always align with clonal lineages.
Verticillium wilts caused by the soilborne fungus Verticillium dahliae are among the most challenging diseases to control. Populations of this pathogen have been traditionally studied by means of vegetative compatibility groups (VCGs) under the assumption that VCGs comprise genetically related isolates that correlate with clonal lineages. We aimed to resolve the phylogenetic relationships among VCGs and their subgroups based on sequences of the intergenic spacer region (IGS) of the ribosomal DNA and six anonymous polymorphic sequences containing single-nucleotide polymorphisms (VdSNPs). A collection of 68 V. dahliae isolates representing the main VCGs and subgroups (VCGs 1A, 1B, 2A, 2B, 3, 4A, 4B, and 6) from different geographic origins and hosts was analyzed using the seven DNA regions. Maximum parsimony (MP) phylogenies inferred from IGS and VdSNP sequences showed five and six distinct clades, respectively. Phylogenetic analyses of individual and combined data sets indicated that certain VCG subgroups (e.g., VCGs 1A and 1B) are closely related and share a common ancestor; however, other subgroups (e.g., VCG 4B) are more closely related to members of a different VCG (e.g., VCG 2A) than to subgroups of the same VCG (VCG 4B). Furthermore, MP analyses indicated that VCG 2B is polyphyletic, with isolates placed in at least three distinct phylogenetic lineages based on IGS sequences and two lineages based on VdSNP sequences. Results from our study suggest the existence of main VCG lineages that contain VCGs 1A and 1B; VCGs 2A and 4B; and VCG 4A, for which both phylogenies agree; and the existence of other VCGs or VCG subgroups that seem to be genetically heterogeneous or show discrepancies in their phylogenetic placement: VCG 2B, VCG 3, and VCG 6. These results raise important caveats regarding the interpretation of VCG analyses: genetic homogeneity and close evolutionary relationship between members of a VCG should not be assumed.


Polyethylene wear in a non-congruous unicompartmental knee replacement: a retrieval analysis.
Polyethylene wear is considered a threat to the long-term survival of unicompartmental knee replacement (UKR). This study aims to determine the linear penetration and volumetric wear associated with a non-congruent commonly used UKR, the St Georg Sled. This prosthesis has a biconvex femoral component which articulates with a flat polyethylene tibial component resulting in point contact. Components were retrieved from the knees of 19 patients undergoing revision for a failed UKR after primary replacement. Linear penetration and volumetric wear was measured using a coordinate measuring machine. Using an un-used implant, a three-dimensional computer model of the surface was generated and compared to the explanted specimen. Most patients had revisions because of disease progression to other compartments rather than specific wear related pathology. The mean linear wear for the sample was 0.89 mm (S.D. 0.59 mm) over an average period of 5.6 years giving the mean linear penetration rate of 0.15 mm/year. The mean volumetric wear was 99.7 mm3 (S.D. 79.3 mm3) over the same period giving a mean annual volumetric wear rate of 17.3 mm3/year. The results in this study indicate that clinically significant wear is not necessarily a feature of this fixed bearing unicompartmental knee replacement. The pattern of wear is consistent with clinical findings and indicates excavation of the polyethylene after implantation but at a slower rate than would be anticipated.


A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response.
Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.


Fluorescent zinc(ii) complexes for gene delivery and simultaneous monitoring of protein expression.
Two new zinc(ii) complexes, [Zn(l-His)(NIP)]+(1) and [Zn(acac)2(NIP)](2) (where NIP is 2-(naphthalen-1-yl)-1H-imidazo[4,5-f][1,10]phenanthroline, acac = acetyl acetone), have been synthesized and characterized by elemental analysis, UV-vis, fluorescence, IR, 1H NMR and electron spray ionization mass spectroscopies. Gel retardation assay, atomic force microscopy and dynamic light scattering studies show that 1 and 2 can induce the condensation of circular plasmid pBR322 DNA into nanometer size particles under ambient conditions. Treatment of 2 with 5 mM EDTA restored 30% of the supercoiled form of DNA, revealing partial reversibility of DNA condensation. The in vitro transfection experiment demonstrates that the complexes can be used to deliver pCMV-tdTomato-N1 plasmid which expresses red fluorescent protein. The confocal studies show that the fluorescent nature of complexes is advantageous for visualizing the intracellular delivery of metal complexes as well as transfection efficiency using two distinct emission windows.


Pediatric neurosurgery during Operation Enduring Freedom.
Operation Enduring Freedom (OEF) is the current US military conflict against terrorist elements in Afghanistan. Deepening US involvement in this conflict and increasing coalition casualties prompted the establishment of continuous neurosurgical assets at Craig Joint Theater Hospital (CJTH) at Bagram Airfield, Afghanistan, in September 2007. As part of the military's medical mission, children with battlefield-related injuries and, on a selective case-by-case basis, non-war-related pathological conditions are treated at CJTH. A prospectively maintained record was created in which all rotating neurosurgeons at CJTH recorded their personal procedures. From this record, the authors were able to extract all cases involving patients 18 years of age or younger. Variables recorded included: age, sex, and category of patient (for example, local national, enemy combatant), date, indication and description of the neurosurgical procedure, mechanism of injury, and in-hospital morbidity and mortality data. From September 2007 to October 2009, 296 neurosurgical procedures were performed at CJTH. Fifty-seven (19%) were performed in 43 pediatric patients (16 girls and 27 boys) with an average age of 7.5 years (range 11 days-18 years). Thirty-one of the 57 procedures (54%) were for battlefield-related trauma and 26 for humanitarian reasons (46%). The vast majority of cases were cranial (49/57, 86%) compared with spinal (7/54, 13%), with one peripheral nerve case. Craniotomies or craniectomies for penetrating brain injuries were the most common procedures. There were 5 complications (11.6%) and 4 in-hospital deaths (9.3%). As in previous military conflicts, children are the unfortunate victims of the current Afghanistan campaign. Extremely limited pediatric neurosurgical service and care is rendered under challenging conditions and Air Force neurosurgeons provide valuable, life-saving pediatric treatment for both war-related injuries and humanitarian needs. As the conflict in Afghanistan continues, military neurosurgeons will continue to care for injured children to the best of their abilities.


Is population bone mineral density variation linked to the marker D11S987 on chromosome 11q12-13?
Our purpose is to test linkage of human chromosome 11q12-13 to BMD variation. Chromosome 11q12-13 has been linked to three BMD-related phenotypes that are inherited as Mendelian traits in human pedigrees: an autosomal dominant high bone mass trait, autosomal recessive osteoporosis pseudoglioma, and autosomal recessive osteopetrosis. A sibling pair study with 374 sibships showed significant linkage of D11S987 to normal BMD variation, with a maximum logarithm of odds score of 3.5. However, a subsequent linkage study with a total of 595 sibling pairs demonstrated reduced significance for linkage of D11S987 to bone mineral density variation, with a logarithm of odds score less than 2.2. We genotyped five markers in a genomic region of approximately 27 cM centering on D11S987 and measured bone mineral density and other traits (weight, etc.) for 635 individuals from 53 human pedigrees. Each of these pedigrees was ascertained through a proband with bone mineral density Z-scores less than -1.28 at the hip or spine. Adjusting for age, sex, and weight as covariates, we performed two-point and multipoint linkage analyses using the variance component linkage analysis method implemented in Sequential Oligogenic Linkage Analysis Routines. We found little evidence of linkage of these five markers to bone mineral density at the spine, hip, wrist and total body bone mineral content. The maximum logarithm of odds score at these five markers was 0.25, and the maximum logarithm of odds score at D11S987 was 0.15. Therefore, although we cannot exclude the linkage of D11S987 region to bone mineral density variation, there is no evidence for linkage of the marker D11S987 on human chromosome 11q12-13 to bone mineral density variation in our study population.


July 2012 Greenland melt extent enhanced by low-level liquid clouds.
Melting of the world's major ice sheets can affect human and environmental conditions by contributing to sea-level rise. In July 2012, an historically rare period of extended surface melting was observed across almost the entire Greenland ice sheet, raising questions about the frequency and spatial extent of such events. Here we show that low-level clouds consisting of liquid water droplets ('liquid clouds'), via their radiative effects, played a key part in this melt event by increasing near-surface temperatures. We used a suite of surface-based observations, remote sensing data, and a surface energy-balance model. At the critical surface melt time, the clouds were optically thick enough and low enough to enhance the downwelling infrared flux at the surface. At the same time they were optically thin enough to allow sufficient solar radiation to penetrate through them and raise surface temperatures above the melting point. Outside this narrow range in cloud optical thickness, the radiative contribution to the surface energy budget would have been diminished, and the spatial extent of this melting event would have been smaller. We further show that these thin, low-level liquid clouds occur frequently, both over Greenland and across the Arctic, being present around 30-50 per cent of the time. Our results may help to explain the difficulties that global climate models have in simulating the Arctic surface energy budget, particularly as models tend to under-predict the formation of optically thin liquid clouds at supercooled temperatures--a process potentially necessary to account fully for temperature feedbacks in a warming Arctic climate.


Trees grow on money: urban tree canopy cover and environmental justice.
This study examines the distributional equity of urban tree canopy (UTC) cover for Baltimore, MD, Los Angeles, CA, New York, NY, Philadelphia, PA, Raleigh, NC, Sacramento, CA, and Washington, D.C. using high spatial resolution land cover data and census data. Data are analyzed at the Census Block Group levels using Spearman's correlation, ordinary least squares regression (OLS), and a spatial autoregressive model (SAR). Across all cities there is a strong positive correlation between UTC cover and median household income. Negative correlations between race and UTC cover exist in bivariate models for some cities, but they are generally not observed using multivariate regressions that include additional variables on income, education, and housing age. SAR models result in higher r-square values compared to the OLS models across all cities, suggesting that spatial autocorrelation is an important feature of our data. Similarities among cities can be found based on shared characteristics of climate, race/ethnicity, and size. Our findings suggest that a suite of variables, including income, contribute to the distribution of UTC cover. These findings can help target simultaneous strategies for UTC goals and environmental justice concerns.