Single-, Double-, and Triple-Network Macroporous Rubbers as a Passive Sampler.
Over the past decades, large quantities of organic compounds including polycyclic aromatic hydrocarbons (PAHs) entering aquatic systems create acutely toxic effects and chronic abnormalities in aquatic organisms. Passive sampling is an effective technique to detect organic compounds at very low concentrations in water by accumulating them in their structure to a measurable concentration level. Polymeric passive samplers reported so far have a nonporous structure, and hence, the absorption of organic compounds into the passive sampler is governed by their slow diffusion process. We present here novel macroporous rubber sorbents as monophasic passive samplers with tunable pore morphologies, extraordinary mechanical properties, and high sorption rates and capacities for PAHs. Sorbent materials based on single-network (SN), double-network (DN), and triple-network (TN) butyl rubber were prepared via the cryogelation technique from butyl rubber solutions in benzene as the solvent at -18 °C using a sulfur monochloride cross-linker. To obtain macroporous rubbers with DN and TN structures, the reactions were conducted in the macropores of SN and DN rubber networks, respectively. The porous morphology and the mechanical behavior of the rubbers can be tuned by adjusting the weight ratio wR of the network components. The rubbers exhibit two generations of pores, namely, large and small pores with diameters 40-240 and 14-54 μm, respectively. The sizes of both large and small pores decrease and approach each other as wR is increased. Four PAH compounds, namely, naphthalene, phenanthrene, fluoranthene, and pyrene with two to four aromatic rings, dissolved in filtered seawater with a salinity of 22 ppt were used to highlight the correlations between the properties of macroporous rubbers and their absorption rates and capacities. Nonporous silicone rubber reported before as a passive sampler has the lowest absorption rate and capacity as compared to the macroporous rubbers. The SN rubber absorbs most rapidly PAHs because of its largest porosity, whereas the TN rubber with the smallest pores exhibits the highest sorption capacity.


Pyruvate: metabolic protector of cardiac performance.
Pyruvate, a metabolic product of glycolysis and an oxidizable fuel in myocardium, increases cardiac mechanical performance and energy reserves, especially when supplied at supraphysiological concentrations. The inotropic effects of pyruvate are most impressive in hearts that have been reversibly injured (stunned) by ischemia/reperfusion stress. Glucose appears to be an essential co-substrate for pyruvate's salutary effects in stunned hearts, but other fuels including lactate, acetate, fatty acids, and ketone bodies produce little or no improvement in postischemic function over glucose alone. In contrast to pharmacological inotropism by catecholamines, metabolic inotropism by pyruvate increases cardiac energy reserves and bolsters the endogenous glutathione antioxidant system. Pyruvate enhancement of cardiac function may result from one or more of the following mechanisms: increased cytosolic ATP phosphorylation potential and Gibbs free energy of ATP hydrolysis, enhanced sarcoplasmic reticular calcium ion uptake and release, decreased cytosolic inorganic phosphate concentration, oxyradical scavenging via direct neutralization of peroxides and/or enhancement of the intracellular glutathione/NADPH antioxidant system, and/or closure of mitochondrial permeability transition pores. This review aims to summarize evidence for each of these mechanisms and to consider the potential utility of pyruvate as a therapeutic intervention for clinical management of cardiac insufficiency.


Statistical methods for the time-to-event analysis of individual participant data from multiple epidemiological studies.
Meta-analysis of individual participant time-to-event data from multiple prospective epidemiological studies enables detailed investigation of exposure-risk relationships, but involves a number of analytical challenges. This article describes statistical approaches adopted in the Emerging Risk Factors Collaboration, in which primary data from more than 1 million participants in more than 100 prospective studies have been collated to enable detailed analyses of various risk markers in relation to incident cardiovascular disease outcomes. Analyses have been principally based on Cox proportional hazards regression models stratified by sex, undertaken in each study separately. Estimates of exposure-risk relationships, initially unadjusted and then adjusted for several confounders, have been combined over studies using meta-analysis. Methods for assessing the shape of exposure-risk associations and the proportional hazards assumption have been developed. Estimates of interactions have also been combined using meta-analysis, keeping separate within- and between-study information. Regression dilution bias caused by measurement error and within-person variation in exposures and confounders has been addressed through the analysis of repeat measurements to estimate corrected regression coefficients. These methods are exemplified by analysis of plasma fibrinogen and risk of coronary heart disease, and Stata code is made available. Increasing numbers of meta-analyses of individual participant data from observational data are being conducted to enhance the statistical power and detail of epidemiological studies. The statistical methods developed here can be used to address the needs of such analyses.


Aspergillus flavus malignant external otitis in a diabetic patient: case report and literature review.
Malignant external otitis is an aggressive and potentially life-threatening infection. This rare disorder is typically caused by Pseudomonas aeruginosa and affects almost exclusively elderly diabetic patients. However, fungal malignant external otitis have been identified, especially in immunocompromised hosts. We report a rare case of invasive malignant external otitis caused by Aspergillus flavus in a diabetic patient without other underlying immunosuppression. A review of Aspergillus spp. malignant external otitis since voriconazole became the first line for invasive aspergillosis was performed. A 72-year-old man with diabetes mellitus developed invasive malignant external otitis with a vascular involvement. The patient was treated with empiric courses of antibiotics until a fungal infection was diagnosed. Proven Apsergillus infection was based on histopathological examination and isolation of A. flavus from culture of osteo-meningeal biopsies. Despite optimal antimicrobial therapy with voriconazole, the patient presented with cerebral infarction in the setting of an angioinvasive fungal infection leading to a fatal outcome. From a review of the literature, we found 39 previously published cases of proven Aspergillus spp. malignant external otitis treated with new triazoles. Given our experience and the literature review, a fungal etiology should be considered early in the course of malignant external otitis unresponsive to a conventional broad spectrum antibiotic therapy, with the need for a tissue biopsy to confirm the diagnosis.


Predicting Soybean Rust Incursions into the North American Continental Interior Using Crop Monitoring, Spore Trapping, and Aerobiological Modeling.
Between 2005 and 2009, millions of U.S. and Canadian soybean acres that would have received fungicide application remained untreated for soybean rust due to information disseminated through the Integrated Pest Management Pest Information Platform for Extension and Education (ipmPIPE), increasing North American producers' profits by hundreds of millions of dollars each year. The results of our analysis of Phakopsora pachyrhizi urediniospores in rain collections, aerobiology model output, and observations of soybean rust spread in 2007 and 2008 show a strong correspondence between spore collections and model predictions for the continental interior of North America, where soybean is an important crop. The analysis suggests that control practices based on up-to-date maps of soybean rust observations and associated commentary from Extension Specialists delivered by the ipmPIPE may have suppressed the number and strength of inoculum source areas in the southern states and retarded the northward progress of seasonal soybean rust incursions into continental North America. The analysis further indicates that spore trapping and aerobiological modeling can reduce our reliance on the costly Sentinel Plot Network while maintaining the effectiveness of the ipmPIPE system for soybean rust management.


Microscopic Diffusion of Atomic Hydrogen and Water in HER Catalyst MoS2 Revealed by Neutron Scattering.
The design of novel and abundant catalytic materials for electrolysis is crucial for reaching carbon neutrality of the global energy system. A deliberate approach to catalyst design requires both theoretical and experimental knowledge not only of the target reactions but also of the supplementary mechanisms affecting the catalytic activity. In this study, we focus on the interplay of hydrogen mobility and reactivity in the hydrogen evolution reaction catalyst MoS2. We have studied the diffusion of atomic hydrogen and water by means of neutron and X-ray photoelectron spectroscopies combined with classical molecular dynamics simulations. The observed interaction of water with single-crystal MoS2 shows the possibility of intercalation within volume defects, where it can access edge sites of the material. Our surface studies also demonstrate that atomic hydrogen can be inserted into MoS2, where it then occupies various adsorption sites, possibly favoring defect vicinities. The motion of H atoms parallel to the layers of MoS2 is fast with D ≈ 1 × 10-9 m2/s at room temperature and exhibits Brownian diffusion behavior with little dependence on temperature, i.e., with a very low diffusion activation barrier.


Different recommendations for empiric first-choice antibiotic treatment of uncomplicated urinary tract infections in Europe.
Uncomplicated urinary tract infection (uUTI) is a common reason for antibiotic treatment in primary health care. Due to the increasing prevalence of antibiotic-resistant uropathogens it is crucial to use the most appropriate antibiotics for first-choice empiric treatment of uUTI. Particularly, it is important to avoid antibiotics associated with a high rate of antimicrobial resistance. This study compares national recommendations from six European countries, investigating recommendations for first-choice antibiotic therapy of uUTI. General practice in six European countries. Searches were undertaken on PubMed, the Cochrane Library databases, Google, and Google Scholar. Recommendations from different geographical regions in Europe were investigated: Northern Europe (Denmark, Sweden), Western Europe (Scotland), Central Europe (Germany), Southern Europe (Spain), and Eastern Europe (Croatia). The six countries recommended seven different antibiotics. Five countries recommended more than one antibiotic as first-choice treatment. Half of the countries recommended antibiotics associated with a high rate (> 10-20%) of resistant E. coli. All countries recommended at least one antibiotic associated with a low (< 5%) resistance rate. The differences in first-choice treatment of uUTI could not be explained by differences in local bacterial aetiology or by different patterns of antimicrobial resistance. Despite resistance rates exceeding 10-20%, sulphamethizole, trimethoprim. or fluoroquinolones were recommended in half of the countries. Within the European countries there are considerable differences in recommendations for empiric first-choice antibiotic treatment of uUTI. In order to reduce the increasing antimicrobial resistance in Europe, it is important to agree on the most appropriate antibiotics for empiric treatment of uUTI.


Anterior inferior petrosectomy: defining the role of endonasal endoscopic techniques for petrous apex approaches.
Historically, surgery to the petrous apex has been addressed via craniotomy and open microscopic anterior petrosectomy (OAP). However, with the popularization of endoscopic approaches, the petrous apex can further be approached endonasally by way of an endoscopic endonasal anterior petrosectomy (EAP). Endonasal anterior petrosectomy is a relatively new procedure and has not been compared anatomically with OAP. The authors hypothesized that the EAP and OAP techniques approach different portions of the petrous apex and therefore may have different applications. Four cadaveric heads were used. An OAP was performed on one side and an EAP was performed on the contralateral side; the limits of bony resection were defined. The extent of bony resection was then evaluated using predissection and postdissection thin-slice CT scans. The comparative resection was then reconstructed using 3D modeling on Brainlab workstations. The average resection volumes for EAP and OAP were 0.297 cm(3) and 0.649 cm(3), respectively, representing a comparative percentage of 46% (EAP/OAP). An EAP and OAP achieved resection of 29% and 64% of the total petrous apex volume, respectively. Indeed, EAP addressed the inferior portion of the petrous apex located adjacent to the petroclival suture more completely than OAP, where 45% of the bone overlying the petroclival suture (petroclival angle to the jugular foramen) was resected with the EAP, while 0% was resected with the OAP. In anatomically normal cadavers, OAP achieved nearly a 50% larger volumetric resection than EAP. Furthermore, while OAP appears to completely address the superior portion of the petrous apex, EAP appears to have a niche in approaches to lesions in the inferior petrous apex. Given these results, the authors propose that OAP be redefined as the "superior anterior petrosectomy," while EAP be referred to as the "inferior anterior petrosectomy," which more clearly defines the role of each approach in anterior petrosectomy.


Centripetal versus centrifugal bias in visual line bisection: focusing attention on two hypotheses.
A variety of stimulus factors have been shown to influence the degree of leftward displacement of perceived line midpoint (i.e., pseudoneglect), which typifies the performance of normal subjects in line bisection tasks [M.E. McCourt & G. Jewell: Neuropsychologia 37, 843-855 (1999); G. Jewell & M.E. McCourt: Neuropsychologia 38, 93-110 (2000)]. One such factor is the position of lines within the visual field, where two conflicting patterns of bisection error have been reported. Some authors report a centrifugal pattern of error, where perceived line midpoint shifts away from the vertical midline, regardless of line position, i.e., relatively leftward for leftward displaced lines and vice versa. Others have reported a centripetal pattern of bisection error, where perceived line midpoint is always displaced centrally, toward the vertical midline, regardless of line position. There is no satisfactory explanation for these discrepant findings. An experiment using a tachistoscopic forced-choice line bisection protocol is described which discloses that neurologically normal right-handed subjects (N=82) typically display a centrifugal pattern of bisection error when lines are azimuthally displaced over a relatively small range, whereas a centripetal pattern is observed when lines are displaced over a wider range. Results from ancillary control experiments, in which eye position was measured during testing, confirm that systematic differences in gaze direction do not occur as a function of line position, and thus cannot account for the different patterns of bisection error. We conclude that stimulus context significantly modulates the strategy with which observers deploy spatial attention. When line position is constant, or varies over a narrow range, observers hold attention steady and widen its aperture to accommodate the relevant range of spatial location. Centrifugal bisection error is thus produced by the asymmetric cueing effect of laterally displaced lines, according to the activation-orientation theory [M. Kinsbourne: Acta Psychologica 33, 193-201 (1970)]. When the range of line position exceeds the aperture of focal attention, we hypothesize that observers adopt a strategy in which attention is dynamically scanned in the direction of azimuthally displaced lines. The effects of attentional scanning on line bisection performance are quite robust. The centripetal scanning proposed to occur for widely displaced lines is consistent with the centripetal pattern of bisection error in this condition.


New Strategies in Breast Cancer: Immunotherapy.
More than 70% of breast cancers contain lymphocytic infiltration in the stroma, and preclinical studies suggest that immunoediting and partial control of cancer progression by the local immune microenvironment operate in most breast cancers. Consistent with this hypothesis, a large number of studies demonstrated a favorable prognostic and chemotherapy response predictive role for immune infiltration in breast cancer. The evidence is particularly strong for triple-negative and HER2-positive cancers. The development of clinically effective immune checkpoint inhibitors now provides an opportunity to test the therapeutic potential of augmenting the local antitumor immune response. Several phase I clinical trials using single-agent anti-PD-1 and anti-PD-L1 antibodies demonstrated objective tumor response rates, with remarkably durable responses, in heavily pretreated, metastatic, triple-negative cancers and somewhat lower responses in estrogen receptor-positive cancers. Currently, close to 50 ongoing, or soon to open, clinical trials evaluate the role of this new treatment modality in breast cancer. Clin Cancer Res; 22(9); 2105-10. ©2016 AACR.


Uncontrolled sepsis: a systematic review of translational immunology studies in intensive care medicine.
The design of clinical immunology studies in sepsis presents several fundamental challenges to improving the translational understanding of pathologic mechanisms. We undertook a systematic review of bed-to-benchside studies to test the hypothesis that variable clinical design methodologies used to investigate immunologic function in sepsis contribute to apparently conflicting laboratory data, and identify potential alternatives that overcome various obstacles to improve experimental design. We performed a systematic review of the design methodology employed to study neutrophil function (respiratory burst), monocyte endotoxin tolerance and lymphocyte apoptosis in the intensive care setting, over the past 15 years. We specifically focussed on how control samples were defined, taking into account age, gender, ethnicity, concomitant therapies, timing of sample collection and the criteria used to diagnose sepsis. We identified 57 eligible studies, the majority of which (74%) used case-control methodology. Healthy volunteers represented the control population selected in 83% of studies. Comprehensive demographic data on age, gender and ethnicity were provided in ≤48% of case control studies. Documentation of diseases associated with immunosuppression, malignancy and immunomodulatory therapies was rare. Less than half (44%) of studies undertook independent adjudication for the diagnosis of sepsis while 68% provided microbiological data. The timing of sample collection was defined by highly variable clinical criteria. By contrast, surgical studies avoided many such confounders, although only one study in surgical patients monitored the study group for development of sepsis. We found several important and common limitations in the clinical design of translational immunologic studies in human sepsis. Major elective surgery overcame many of these methodological limitations. The failure of adequate clinical design in mechanistic studies may contribute to the lack of translational therapeutic progress in intensive care medicine.


Modelling of long-term simultaneous nitrification and denitrification (SNDN) performance of a pilot scale membrane bioreactor.
Nutrient removal capability of the MBR process has attracted more attention than organics removal in the past few years. Apart from the conventional schemes for nitrogen removal in MBR process, simultaneous nitrification-denitrification (SNDN) requires the most attention for further research. In order to fully understand the fundemantals and mechanism of SNDN in MBRs, a pilot plant was set up. A mathematical model was adopted for investigation and calibration against the observed values. This paper reports a study focusing on evaluating major mechanisms that govern nitrogen removal from domestic wastewater in membrane bioreactors. Two items need to be emphasized in this evaluation: (i) an MBR is basically regarded as an activated sludge process-a suspended growth bioreactor with total biomass recycle and substantially higher biomass concentration; (ii) in this context an AS model, namely ASM1R modified for endogenous respiration, is used for dynamic modelling and calibration of experimental results. The impact of diffusion through biomass which obviously exerts a significant effect on system performance and denitrification is evaluated with success using the adopted model by means of switch functions that regulate nitrification-denitrification with respect to dissolved oxygen concentration in the bulk liquid.


Synchrony of Eukaryotic and Prokaryotic Planktonic Communities in Three Seasonally Sampled Austrian Lakes.
Freshwater systems are characterized by an enormous diversity of eukaryotic protists and prokaryotic taxa. The community structures in different lakes are thereby influenced by factors such as habitat size, lake chemistry, biotic interactions, and seasonality. In our study, we used high throughput 454 sequencing to study the diversity and temporal changes of prokaryotic and eukaryotic planktonic communities in three Austrian lakes during the ice-free season. In the following year, one lake was sampled again with a reduced set of sampling dates to observe reoccurring patterns. Cluster analyses (based on SSU V9 (eukaryotic) and V4 (prokaryotic) OTU composition) grouped samples according to their origin followed by separation into seasonal clusters, indicating that each lake has a unique signature based on OTU composition. These results suggest a strong habitat-specificity of microbial communities and in particular of community patterns at the OTU level. A comparison of the prokaryotic and eukaryotic datasets via co-inertia analysis (CIA) showed a consistent clustering of prokaryotic and eukaryotic samples, probably reacting to the same environmental forces (e.g., pH, conductivity). In addition, the shifts in eukaryotic and bacterioplanktonic communities generally occurred at the same time and on the same scale. Regression analyses revealed a linear relationship between an increase in Bray-Curtis dissimilarities and elapsed time. Our study shows a pronounced coupling between bacteria and eukaryotes in seasonal samplings of the three analyzed lakes. However, our temporal resolution (biweekly sampling) and data on abiotic factors were insufficient to determine if this was caused by direct biotic interactions or by reacting to the same seasonally changing environmental forces.


On the Source of Human Irrationality.
Reasoning and decision making are error prone. This is often attributed to a fast, phylogenetically old System 1. It is striking, however, that perceptuo-motor decision making in humans and animals is rational. These results are consistent with perceptuo-motor strategies emerging in Bayesian brain theory that also appear in human data selection. People seem to have access, although limited, to unconscious generative models that can generalise to explain other verbal reasoning results. Error does not emerge predominantly from System 1, but rather seems to emerge from the later evolved System 2 that involves working memory and language. However language also sows the seeds of error correction by moving reasoning into the social domain. This reversal of roles suggests key areas of theoretical integration and new empirical directions.


Copy number variant hotspots in Han Taiwanese population induced pluripotent stem cell lines - lessons from establishing the Taiwan human disease iPSC Consortium Bank.
The Taiwan Human Disease iPSC Service Consortium was established to accelerate Taiwan's growing stem cell research initiatives and provide a platform for researchers interested in utilizing induced pluripotent stem cell (iPSC) technology. The consortium has generated and characterized 83 iPSC lines: 11 normal and 72 disease iPSC lines covering 21 different diseases, several of which are of high incidence in Taiwan. Whether there are any reprogramming-induced recurrent copy number variant (CNV) hotspots in iPSCs is still largely unknown. We performed genome-wide copy number variant screening of 83 Han Taiwanese iPSC lines and compared them with 1093 control subjects using an Affymetrix genome-wide human SNP array. In the iPSCs, we identified ten specific CNV loci and seven "polymorphic" CNV regions that are associated with the reprogramming process. Additionally, we established several differentiation protocols for our iPSC lines. We demonstrated that our iPSC-derived cardiomyocytes respond to pharmacological agents and were successfully engrafted into the mouse myocardium demonstrating their potential application in cell therapy. The CNV hotspots induced by cell reprogramming have successfully been identified in the current study. This finding may be used as a reference index for evaluating iPSC quality for future clinical applications. Our aim was to establish a national iPSC resource center generating iPSCs, made available to researchers, to benefit the stem cell community in Taiwan and throughout the world.


Monocyte recruitment to the dermis and differentiation to dendritic cells increases the targets for dengue virus replication.
Dengue virus (DENV) causes the most prevalent arthropod-borne viral disease in humans. Although Aedes mosquitoes transmit DENV when probing for blood in the skin, no information exists on DENV infection and immune response in the dermis, where the blood vessels are found. DENV suppresses the interferon response, replicates, and causes disease in humans but not wild-type mice. Here, we used mice lacking the interferon-α/β receptor (Ifnar(-/-)), which had normal cell populations in the skin and were susceptible to intradermal DENV infection, to investigate the dynamics of early DENV infection of immune cells in the skin. CD103(+) classical dendritic cells (cDCs), Ly6C(-) CD11b(+) cDCs, and macrophages in the steady-state dermis were initial targets of DENV infection 12-24 hours post-inoculation but then decreased in frequency. We demonstrated recruitment of adoptively-transferred Ly6C(high) monocytes from wild-type and Ifnar(-/-) origin to the DENV-infected dermis and differentiation to Ly6C(+) CD11b(+) monocyte-derived DCs (moDCs), which became DENV-infected after 48 hours, and were then the major targets for virus replication. Ly6C(high) monocytes that entered the DENV-infected dermis expressed chemokine receptor CCR2, likely mediating recruitment. Further, we show that ∼ 100-fold more hematopoietic cells in the dermis were DENV-infected compared to Langerhans cells in the epidermis. Overall, these results identify the dermis as the main site of early DENV replication and show that DENV infection in the skin occurs in two waves: initial infection of resident cDCs and macrophages, followed by infection of monocytes and moDCs that are recruited to the dermis. Our study reveals a novel viral strategy of exploiting monocyte recruitment to increase the number of targets for infection at the site of invasion in the skin and highlights the skin as a potential site for therapeutic action or intradermal vaccination.


Microinjection of activated phosphatidylinositol-3 kinase induces process outgrowth in rat PC12 cells through the Rac-JNK signal transduction pathway.
We have previously shown that sustained phosphatidylinositol (PI)-3 kinase activity is necessary for neurite outgrowth of PC12 cells induced by nerve growth factor (NGF). Microinjection of a constitutively active mutant of PI-3 kinase induced process formation suggesting that PI-3 kinase is indeed involved in the neurite outgrowth. However, the processes appeared to be incomplete neurites as they had very poor organization of F-actin and GAP43 antigen. The microtubule network was enhanced in the process-bearing cells and process formation was inhibited by colchicine suggesting that microtubules play an important role in process formation downstream of PI-3 kinase. These cell responses were inhibited by dominant-negative mutants of Rac and Sek1/SAPK but not by a dominant-negative mutant Ras and PD98059, a MAP kinase kinase (MEK) inhibitor, suggesting that not the Ras-MAP kinase pathway but the Rac-Jun N-terminal kinase (JNK) pathway is involved in process formation.


CBD Reverts the Mesenchymal Invasive Phenotype of Breast Cancer Cells Induced by the Inflammatory Cytokine IL-1β.
Cannabidiol (CBD) has been used to treat a variety of cancers and inflammatory conditions with controversial results. In previous work, we have shown that breast cancer MCF-7 cells, selected by their response to inflammatory IL-1β cytokine, acquire a malignant phenotype (6D cells) through an epithelial-mesenchymal transition (EMT). We evaluated CBD as a potential inhibitor of this transition and inducer of reversion to a non-invasive phenotype. It decreased 6D cell viability, downregulating expression of receptor CB1. The CBD blocked migration and progression of the IL-1β-induced signaling pathway IL-1β/IL-1RI/β-catenin, the driver of EMT. Cannabidiol reestablished the epithelial organization lost by dispersion of the cells and re-localized E-cadherin and β-catenin at the adherens junctions. It also prevented β-catenin nuclear translocation and decreased over-expression of genes for ∆Np63α, BIRC3, and ID1 proteins, induced by IL-1β for acquisition of malignant features. Cannabidiol inhibited the protein kinase B (AKT) activation, a crucial effector in the IL-1β/IL-1RI/β-catenin pathway, indicating that at this point there is crosstalk between IL-1β and CBD signaling which results in phenotype reversion. Our 6D cell system allowed step-by-step analysis of the phenotype transition and better understanding of mechanisms by which CBD blocks and reverts the effects of inflammatory IL-1β in the EMT.


Care of patients with acute pulmonary emboli: a clinical review with cardiovascular focus.
Acute pulmonary embolism (PE) is a common, multidisciplinary disease with substantial associated morbidity, mortality and healthcare expense. In this article we present a succinct review of diagnostic tools, risk stratification and medical therapies for cardiovascular care of patients with acute PE. While pulmonary angiography remains the 'gold standard' for diagnosis, a host of diagnostic modalities, interpreted in the setting of clinical probability, are available for patient assessment, including ECG, chest radiography, D-dimer, lower-extremity venous ultrasound, ventilation-perfusion scans, computed tomography and magnetic resonance angiography, and echocardiography, each with associated value. Diagnostic algorithms incorporate multiple tools in order to obtain a more comprehensive evaluation. Therapeutic anticoagulation remains the mainstay of therapy in PE. In massive PE, utilization of thrombolysis is reasonable in the absence of contraindications. Submassive PE, characterized by right ventricular dysfunction as assessed by echocardiography and ECG, is associated with higher mortality. Use of thrombolysis in submassive PE remains controversial. Catheter-directed therapies are emerging as an added approach to acute PE and have the potential to improve outcomes in PE. Use of inferior vena cava filters should be pursued in a select patient population as they serve to reduce recurrent acute PE; however, they are associated with more frequent deep venous thrombosis and provide no mortality benefit. In risk-stratified hemodynamically stable patients, an outpatient management strategy inclusive of therapeutic anticoagulation and careful clinical follow-up may be appropriate.


Enhanced effect of local fields in subwavelength metallic series nanocavities from surface plasmon polaritons.
The enhancement and confinement characteristics of the local field in the two-dimensional (2D) subwavelength-size series cavities structure are investigated numerically by using the boundary integral method. The series cavities are built of two pieces of finite silver thin slabs with subwavelength corrugations on their inner boundaries, set in a face-to-face arrangement with a separating space, and the central part is a narrow channel (NC). We calculate the average amplitude of the local field in the NC as a function of the wavelength for exploring the influence of the structural parameters and demonstrate the amplitude distribution of the magnetic field in the structure and the cross-section distributions of the local field in the NC region along both the longitudinal axis direction and the transverse directions. The simulations show that the local field in the NC has significant enhancement, up to 2 orders of magnitude, of the incident light field, and the local light field is confined to a small region less than one fifth of the resonant wavelength in the longitudinal direction and one twentieth of the resonant wavelength in the lateral direction. Replacing the metallic material of the cavity walls with the semiconductor germanium leads to the complete disappearance of the enhancement of the local field. It is clearly shown that surface plasmon polaritons on the metal play a critical role for this enhancement phenomenon. The influences of various geometric parameters on the resonant wavelength and the peak value of the average amplitude of the local field are extensively investigated.


Cadherin expression delineates the divisions of the postnatal and adult mouse amygdala.
The amygdaloid complex represents a group of telencephalic nuclei and cortical areas that control emotional and social behavior. Amygdalar development is poorly understood. It is generally accepted that the structures of the amygdala originate from the neuroepithelium at both sides of the pallial-subpallial boundary. In the present study, we mapped the expression of 13 members of the cadherin superfamily of cell adhesion molecules, which provide an adhesive code for the development and maintenance of functional structures in the central nervous system (CNS). Five classic cadherins (Cdh4, Cdh6, Cdh7, Cdh8, Cdh11) and eight delta-protocadherins (Pcdh1, Pcdh7, Pcdh8, Pcdh9, Pcdh10, Pcdh11, PCdh17, PCdh19) were studied by in situ hybridization in the postnatal (P5) and adult mouse amygdala. In the different parts of the amygdala, each of these (proto-) cadherins shows a distinct and spatially restricted expression pattern that is highly similar at postnatal and adult stages. The combinatorial expression of (proto-) cadherins allows the distinction of multiple molecular subdivisions within the amygdala that partially coincide with previously described morphological divisions. Beyond these expected results, a number of novel molecular subdivisions and subpopulations of cells were identified; for example, additional molecular subdomains, patches, or cell aggregates with distinct (proto-) cadherin expression in several nuclei/areas of the amygdala. We also show that several cadherins are molecular markers for particular functional subsystems within the amygdala, such as in the olfactory projections. In summary, (proto-) cadherins provide a code of potentially adhesive cues that can aid the understanding of functional organization in the amygdala.


The recent understanding of the neurotrophin's role in skeletal muscle adaptation.
This paper summarizes the various effects of neurotrophins in skeletal muscle and how these proteins act as potential regulators of the maintenance, function, and regeneration of skeletal muscle fibers. Increasing evidence suggests that this family of neurotrophic factors influence not only the survival and function of innervating motoneurons but also the development and differentiation of myoblasts and muscle fibers. Muscle contractions (e.g., exercise) produce BDNF mRNA and protein in skeletal muscle, and the BDNF seems to play a role in enhancing glucose metabolism and may act for myokine to improve various brain disorders (e.g., Alzheimer's disease and major depression). In adults with neuromuscular disorders, variations in neurotrophin expression are found, and the role of neurotrophins under such conditions is beginning to be elucidated. This paper provides a basis for a better understanding of the role of these factors under such pathological conditions and for treatment of human neuromuscular disease.


Safer care at home: use of simulation training to improve standards.
One of the fundamental problems facing providers and commissioners of health services is how to maintain the skills and knowledge of the workforce during the initial development and implementation of home care services. This small-scale project sought to ascertain if it was possible to use human patient simulation scenarios to educate community nurses about how to recognize when care at home is appropriate and when it is not. A series of scenarios were developed and delivered to small groups of community nursing staff. A total of 18 qualified nurses took part in the project. Participants were asked to report their level of confidence in the diagnosis, management and recognition of patient deterioration for each of the scenarios prior to and after the session. The results show increased confidence across all participants in each of the scenarios.


Yersinia enterocolitica: the charisma continues.
Yersinia enterocolitica, a gram-negative coccobacillus, comprises a heterogeneous group of bacterial strains recovered from animal and environmental reservoirs. The majority of human pathogenic strains are found among distinct serogroups (e.g. O:3, O:5,27, O:8, O:9) and contain both chromosome- and plasmid (60 to 75 kb)-mediated virulence factors that are absent in "avirulent" strains. While Y. enterocolitica is primarily a gastrointestinal tract pathogen, it may produce extraintestinal infections in hosts with underlying predisposing factors. Postinfection sequelae include arthritis and erythema nodosum, which are seen mainly in Europe among patients with serogroups O:3 and O:9 infection and HLA-B27 antigen. Y. enterocolitica is acquired through the oral route and is epidemiologically linked to porcine sources. Bacteremia is prominent in the setting of immunosuppression or in patients with iron overload or those being treated with desferrioxamine. metastatic foci following bacteremia are common and often involve the liver and spleen. Of particular concern is blood transfusion-related bacteremia. Evidence has accumulated substantiating the role of Y. enterocolitica as a food-borne pathogen that has caused six major outbreaks in the United States. The diagnosis of Y. enterocolitica gastroenteritis is best achieved through isolation of the bacterium on routine or selective bacteriologic media. When necessary, serogrouping, biogrouping, and assessment for plasmid-encoded virulence traits may aid in distinguishing virulent from "avirulent" strains. Epidemiologically, outside of identified food-borne outbreaks, the source (reservoir) of Y. enterocolitica in sporadic cases is speculative. Therefore, prevention and control measures are difficult to institute.


Progesterone increases rat neural progenitor cell cycle gene expression and proliferation via extracellularly regulated kinase and progesterone receptor membrane components 1 and 2.
Progesterone receptor (PR) expression and regulation of neural progenitor cell (NPC) proliferation was investigated using NPC derived from adult rat brain. RT-PCR revealed that PRA mRNA was not detected in rat NPCs, whereas membrane-associated PRs, PR membrane components (PGRMCs) 1 and 2, mRNA were expressed. Progesterone-induced increase in 5-bromo-2-deoxyuridine incorporation was confirmed by fluorescent-activated cell sorting analysis, which indicated that progesterone promoted rat NPC exit of G(0)/G(1) phase at 5 h, followed by an increase in S-phase at 6 h and M-phase at 8 h, respectively. Microarray analysis of cell-cycle genes, real-time PCR, and Western blot validation revealed that progesterone increased expression of genes that promote mitosis and decreased expression of genes that repress cell proliferation. Progesterone-induced proliferation was not dependent on conversion to metabolites and was antagonized by the ERK(1/2) inhibitor UO126. Progesterone-induced proliferation was isomer and steroid specific. PGRMC1 small interfering RNA treatment, together with computational structural analysis of progesterone and its isomers, indicated that the proliferative effect of progesterone is mediated by PGRMC1/2. Progesterone mediated NPC proliferation and concomitant regulation of mitotic cell cycle genes via a PGRMC/ERK pathway mechanism is a potential novel therapeutic target for promoting neurogenesis in the mammalian brain.


Safety and immunogenicity of a recombinant nonglycosylated erythrocyte binding antigen 175 Region II malaria vaccine in healthy adults living in an area where malaria is not endemic.
Erythrocyte binding antigen region II (EBA-175) is a conserved antigen of Plasmodium falciparum that is involved in binding of the parasite to the host's erythrocytes. We evaluated the safety and immunogenicity of a recombinant EBA-175 vaccine with aluminum phosphate adjuvant in healthy young adults living in the United States. Eighteen subjects/group received ascending doses (5, 20, 80, or 160 μg) of the vaccine at 0, 1, and 6 months; 8 subjects received placebo. Most of the injection site and systemic reactions were mild to moderate in intensity. After 2 or 3 doses of the vaccine at any concentration, antibody levels measured by enzyme-linked immunosorbent assay were significantly higher than those for the placebo group. Sera from subjects who received 3 doses of the vaccine at any concentration inhibited the growth of erythrocyte-stage P. falciparum at low levels compared to sera from placebo recipients or preimmune sera. In conclusion, the EBA-175 vaccine with adjuvant was safe and immunogenic in malaria-naïve subjects.


The global flood protection savings provided by coral reefs.
Coral reefs can provide significant coastal protection benefits to people and property. Here we show that the annual expected damages from flooding would double, and costs from frequent storms would triple without reefs. For 100-year storm events, flood damages would increase by 91% to $US 272 billion without reefs. The countries with the most to gain from reef management are Indonesia, Philippines, Malaysia, Mexico, and Cuba; annual expected flood savings exceed $400 M for each of these nations. Sea-level rise will increase flood risk, but substantial impacts could happen from reef loss alone without better near-term management. We provide a global, process-based valuation of an ecosystem service across an entire marine biome at (sub)national levels. These spatially explicit benefits inform critical risk and environmental management decisions, and the expected benefits can be directly considered by governments (e.g., national accounts, recovery plans) and businesses (e.g., insurance).


Prognostic impact of anemia on the mortality of United Arab Emirates nationals with cardiovascular disease.
Cardiovascular disease is the leading cause of death worldwide. Multiple risk factors, including low hemoglobin levels, have been associated with poor outcomes in patients with cardiovascular disease. However, the long-term impact of anemia on death has not been investigated in high-risk patients in the United Arab Emirates. Therefore, this study evaluated whether anemia is a significant predictor of mortality in United Arab Emirates nationals with cardiovascular disease over 10 years. A retrospective cohort study was conducted in an adult population of United Arab Emirates nationals with a history of cardiovascular disease, recruited from a tertiary healthcare facility. Electronic medical records between April 2008 and December 2008 were reviewed, and follow-up was conducted until December 2019. The survival functions for all-cause mortality in the presence and absence of anemia were compared using univariate Kaplan-Meier analysis with a log-rank test. The association between anemia and all-cause mortality was evaluated using a multivariable Cox regression model. A total of 224 patients were included in the follow-up for 10.5 years. At baseline, 46% of the patients had anemia, with a mean Hgb level of 105.5 ± 28.0 g/L. Patients with anemia were older (68 vs. 63 years, p = 0.001) and had a higher rate of chronic kidney disease (37.5% vs. 17.5%, p = 0.001) than those without anemia. A total of 77 (34.4%) deaths were recorded by the end of the follow-up period. Risk of all-cause mortality was significantly higher in patients with anemia than in those without (hazard ratio = 2.03, 95% confidence interval = 1.22-3.40, p = 0.006). Age and chronic kidney disease were also statistically significant predictors of death (p < 0.001 and p = 0.001, respectively). Anemia is an independent predictor of all-cause mortality in United Arab Emirates nationals with underlying cardiovascular disease. Early intervention and treatment for anemia may improve clinical outcomes in this population.


Independent-elementary-field model for three-dimensional spatially partially coherent sources.
The independent-elementary-source model recently developed for planar sources [Opt. Express 14, 1376 (2006)] is extended to volume source distributions. It is shown that the far-field radiation pattern is independent of the three-dimensional (3D) distribution of the coherent elementary sources, but the absolute value of the complex degree of spectral coherence is determined by the 3D Fourier transform of the weight function of the elementary fields. Some methods to determine an 'effective' three-dimensional source distribution with partial transverse and longitudinal spatial coherence properties are outlined. Especially in its longitudinal extension, this effective source volume can be very different from the primary emitting volume of the source. The application of the model to efficient numerical propagation of partially coherent fields is discussed.


Delayed induction, not impaired recruitment, of specific CD8⁺ T cells causes the late onset of acute hepatitis C.
Hepatitis C virus (HCV) infection is characterized by lack of immune-mediated liver injury despite a high level of HCV replication during the incubation phase, which lasts about 8 weeks. We investigated whether this results from delayed recruitment of HCV-specific T cells and whether it facilitates HCV persistence. Six chimpanzees were infected with HCV; blood and liver samples were collected for 28 weeks and analyzed for immune cells and chemokines. Two chimpanzees developed self-limited infections, whereas the remaining 4 developed chronic infections. Levels of the chemokines CXCL10, CXCL11, CCL4, and CCL5 increased in blood and liver samples from all chimpanzees within 1 month of HCV infection. Chemokine induction correlated with intrahepatic type I interferon (IFN) responses in vivo and was blocked by neutralizing antibodies against IFN-β in vitro. Despite the early-stage induction of chemokines, the intrahepatic lymphocytic infiltrate started to increase no earlier than 8 weeks after HCV infection, when HCV-specific, tetramer-positive CD8(+) T cells appeared in the circulation. The HCV-specific CD8(+) T cells expressed chemokine receptors when they were initially detected in blood samples, so they could be recruited to the liver as soon as they entered the circulation. Chemokines are induced during early stages of HCV infection, which requires a type I IFN-mediated response. The delayed onset of acute hepatitis does not result from delayed recruitment of HCV-specific T cells, but could instead be related to a primary delay in the induction of HCV-specific T cells. Divergent outcomes occur without evident differences in chemokine induction and T-cell recruitment.


Genetic deletion of the bacterial sensor NOD2 improves murine Crohn's disease-like ileitis independent of functional dysbiosis.
Although genetic polymorphisms in NOD2 (nucleotide-binding oligomerization domain-containing 2) have been associated with the pathogenesis of Crohn's disease (CD), little is known regarding the role of wild-type (WT) NOD2 in the gut. To date, most murine studies addressing the role of WT Nod2 have been conducted using healthy (ileitis/colitis-free) mouse strains. Here, we evaluated the effects of Nod2 deletion in a murine model of spontaneous ileitis, i.e., the SAMP1Yit/Fc (SAMP) strain, which closely resembles CD. Remarkably, Nod2 deletion improved both chronic cobblestone ileitis (by 50% assessed, as the % of abnormal mucosa at 24 wks of age), as well as acute dextran sodium sulfate (DSS) colitis. Mechanistically, Th2 cytokine production and Th2-transcription factor activation (i.e., STAT6 phosphorylation) were reduced. Microbiologically, the effects of Nod2 deletion appeared independent of fecal microbiota composition and function, assessed by 16S rRNA and metatranscriptomics. Our findings indicate that pharmacological blockade of NOD2 signaling in humans could improve health in Th2-driven chronic intestinal inflammation.


Is there a role for child psychiatry in Vietnam?
(i) To describe the need for child psychiatric services in Vietnam; (ii) to review child psychiatry's present role within the Vietnamese health care system; (iii) to identify cultural, economic and manpower obstacles to the development of child mental health services; and (iv) to recommend a course for the future development of child psychiatry in Vietnam. The existing literature relevant to the Vietnamese health and mental health care systems, traditional practices and beliefs regarding health and mental health, and the current status of psychiatry and child psychiatry in Vietnam was reviewed. In addition, discussions regarding these topics, and the future of child psychiatry in Vietnam, were held with leading Vietnamese health and mental health professionals. The current role of child psychiatry in Vietnam is limited by the health care system's focus on infectious diseases and malnutrition, and by cultural, economic and manpower factors. Treatment is reserved for the most severely afflicted, especially patients with epilepsy and mental retardation. Specialised care is available in only a few urban centres. In rural areas treatment is provided by allied health personnel, paraprofessionals and community organisations. While the present role of child psychiatry in Vietnam is limited, it can still make important contributions. These include: research defining the need for child and adolescent mental health services, identifying priority child psychiatric disorders and assessing the effectiveness of priority disease treatment; and training to enhance the skills of primary health care providers in the treatment of priority disorders.


Imaging Vascular Disease and Amyloid in the Aging Brain: Implications for Treatment.
Vascular risk factors (e.g. hypertension, dyslipidemia and diabetes) are well known risk factors for Alzheimer' disease. These vascular risk factors lead to vascular brain injuries, which also increase the likelihood of dementia. The advent of amyloid PET imaging has helped establish that vascular risk factors also lead to Alzheimer's disease via pathways that are independent from vascular brain injuries, at least, when vascular brain injuries are measured as white matter lesions and infarcts. While vascular brain injuries (white matter lesions and infarcts) do not seem to influence amyloid pathology, some evidence from amyloid imaging suggests that increased vascular risk is related to increased amyloid burden. Furthermore, while vascular brain injuries and amyloid have an additive and independent impact on brain integrity, vascular risk factors might potentiate the impact of amyloid on cortical thickness on brain regions vulnerable to Alzheimer's disease. New research should further explore and confirm, or refute, possible interactions between amyloid and vascular risk factors on brain integrity and cognition. Neuroimaging tools used to assess vascular brain integrity should also be expanded. Measuring cortical blood flow or damage to the capillary system might, for instance, give insight about how vascular risk factors can be associated to amyloid burden and impact. These findings also stress the need for monitoring vascular risk factors in midlife as a strategy for Alzheimer's disease prevention.


Cytotoxicity and Antiproliferative Activity Assay of Clove Mistletoe (Dendrophthoe pentandra (L.) Miq.) Leaves Extracts.
Clove mistletoe (Dendrophthoe pentandra (L.) Miq.) is a semiparasitic plant that belongs to Loranthaceae family. Clove mistletoe was traditionally used for cancer treatment in Indonesia. In the present study, we examined cytotoxicity of clove mistletoe leaves extracts against brine shrimps and conducted their antiproliferative activity on K562 (human chronic myelogenous leukemia) and MCM-B2 (canine benign mixed mammary) cancer cell lines in vitro. The tested samples were water extract, ethanol extract, ethanol fraction, ethyl acetate fraction, and n-hexane fraction. Cytotoxicity was screened using Brine Shrimp Lethality Test (BSLT). Antiproliferative activity was conducted using Trypan Blue Dye Method and cells were counted using haemocytometer. The results showed that n-hexane fraction exhibited significant cytotoxicity with LC50 value of 55.31 μg/mL. The n-hexane fraction was then considered for further examination. The n-hexane fraction of clove mistletoe could inhibit growth of K562 and MCM-B2 cancer cell lines in vitro. The inhibition activity of clove mistletoe n-hexane fraction at concentration of 125 μg/mL on K562 cancer cell lines was 38.69%, while on MCM-B2 it was 41.5%. Therefore, it was suggested that clove mistletoe had potential natural anticancer activity.


Hydroxychloroquine or Chloroquine for Treatment or Prophylaxis of COVID-19: A Living Systematic Review.
Hydroxychloroquine and chloroquine have antiviral effects in vitro against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To summarize evidence about the benefits and harms of hydroxychloroquine or chloroquine for the treatment or prophylaxis of coronavirus disease 2019 (COVID-19). PubMed (via MEDLINE), EMBASE (via Ovid), Scopus, Web of Science, Cochrane Library, bioRxiv, Preprints, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and the Chinese Clinical Trials Registry from 1 December 2019 until 8 May 2020. Studies in any language reporting efficacy or safety outcomes from hydroxychloroquine or chloroquine use in any setting in adults or children with suspected COVID-19 or at risk for SARS-CoV-2 infection. Independent, dually performed data extraction and quality assessments. Four randomized controlled trials, 10 cohort studies, and 9 case series assessed treatment effects of the medications, but no studies evaluated prophylaxis. Evidence was conflicting and insufficient regarding the effect of hydroxychloroquine on such outcomes as all-cause mortality, progression to severe disease, clinical symptoms, and upper respiratory virologic clearance with antigen testing. Several studies found that patients receiving hydroxychloroquine developed a QTc interval of 500 ms or greater, but the proportion of patients with this finding varied among the studies. Two studies assessed the efficacy of chloroquine; 1 trial, which compared higher-dose (600 mg twice daily for 10 days) with lower-dose (450 mg twice daily on day 1 and once daily for 4 days) therapy, was stopped owing to concern that the higher dose therapy increased lethality and QTc interval prolongation. An observational study that compared adults with COVID-19 receiving chloroquine phosphate, 500 mg once or twice daily, with patients not receiving chloroquine found minor fever resolution and virologic clearance benefits with chloroquine. There were few controlled studies, and control for confounding was inadequate in observational studies. Evidence on the benefits and harms of using hydroxychloroquine or chloroquine to treat COVID-19 is very weak and conflicting. Agency for Healthcare Research and Quality.


Antimicrobial use in aquaculture re-examined: its relevance to antimicrobial resistance and to animal and human health.
The worldwide growth of aquaculture has been accompanied by a rapid increase in therapeutic and prophylactic usage of antimicrobials including those important in human therapeutics. Approximately 80% of antimicrobials used in aquaculture enter the environment with their activity intact where they select for bacteria whose resistance arises from mutations or more importantly, from mobile genetic elements containing multiple resistance determinants transmissible to other bacteria. Such selection alters biodiversity in aquatic environments and the normal flora of fish and shellfish. The commonality of the mobilome (the total of all mobile genetic elements in a genome) between aquatic and terrestrial bacteria together with the presence of residual antimicrobials, biofilms, and high concentrations of bacteriophages where the aquatic environment may also be contaminated with pathogens of human and animal origin can stimulate exchange of genetic information between aquatic and terrestrial bacteria. Several recently found genetic elements and resistance determinants for quinolones, tetracyclines, and β-lactamases are shared between aquatic bacteria, fish pathogens, and human pathogens, and appear to have originated in aquatic bacteria. Excessive use of antimicrobials in aquaculture can thus potentially negatively impact animal and human health as well as the aquatic environment and should be better assessed and regulated.


Health-related quality-of-life measurement in patients with Parkinson's disease.
Outcome measures are increasingly used to assess the impact of diseases such as Parkinson's disease (PD) from the patient's perspective. These measures, in the form of questionnaires to assess health-related quality of life (HR-QOL), are of 2 main kinds: generic and disease-specific. The former is intended to be relevant to the widest range of health problems; the latter is developed specifically to assess HR-QOL for a specific condition. Possible consequences of PD have been assessed by generic instruments such as the Sickness Impact Profile (SIP), the Nottingham Health Profile (NHP), the Medical Outcomes Study 36-Item Short Form (SF-36) Health Survey and also by disease-specific instruments; in particular, the Parkinson's Disease Quality-of-Life Questionnaire (PDQL) and 39-Item Parkinson's Disease Questionnaire (PDQ-39). This article summarises the criteria whereby such instruments should be evaluated by potential users and describes in more detail the methods of developing and testing such disease-specific instruments for use in PD. There is a range of valid and feasible methods available for taking into account patients' views of PD outcomes. These will become important outcome measures in future clinical trials of treatment regimes.


Occupational Therapy Interventions to Improve Performance of Instrumental Activities of Daily Living for Community-Dwelling Older Adults: A Systematic Review.
We examined the effectiveness of interventions within the scope of occupational therapy to improve the performance of instrumental activities of daily living (IADLs) for community-dwelling older adults. We searched and examined the literature (2008 through 2016) using four electronic databases. Fourteen studies met the inclusion criteria and were critically appraised and synthesized. Analysis revealed four thematic areas: cognitive, self-management, prevention, and home-based multidisciplinary rehabilitation interventions. Strong evidence supports the use of tailored, multidisciplinary, home-based care programs to support older adults to maintain IADL improvements over time and the use of cognitive interventions to improve memory, executive function, functional status, and everyday problem solving. In addition, strong evidence indicates that tailored home-based preventive sessions were beneficial to mediate functional disability and satisfaction with performance. Evidence supports tailored interventions designed to enhance IADL performance. More studies are needed that focus on IADLs specifically and that use IADLs in their interventions.


Improving Mobile Phone Speech Recognition by Personalized Amplification: Application in People with Normal Hearing and Mild-to-Moderate Hearing Loss.
In this study, the authors evaluated the effect of personalized amplification on mobile phone speech recognition in people with and without hearing loss. This prospective study used double-blind, within-subjects, repeated measures, controlled trials to evaluate the effectiveness of applying personalized amplification based on the hearing level captured on the mobile device. The personalized amplification settings were created using modified one-third gain targets. The participants in this study included 100 adults of age between 20 and 78 years (60 with age-adjusted normal hearing and 40 with hearing loss). The performance of the participants with personalized amplification and standard settings was compared using both subjective and speech-perception measures. Speech recognition was measured in quiet and in noise using Cantonese disyllabic words. Subjective ratings on the quality, clarity, and comfortableness of the mobile signals were measured with an 11-point visual analog scale. Subjective preferences of the settings were also obtained by a paired-comparison procedure. The personalized amplification application provided better speech recognition via the mobile phone both in quiet and in noise for people with hearing impairment (improved 8 to 10%) and people with normal hearing (improved 1 to 4%). The improvement in speech recognition was significantly better for people with hearing impairment. When the average device output level was matched, more participants preferred to have the individualized gain than not to have it. The personalized amplification application has the potential to improve speech recognition for people with mild-to-moderate hearing loss, as well as people with normal hearing, in particular when listening in noisy environments.


Advance distribution of misoprostol for the prevention of postpartum hemorrhage in South Sudan.
To determine if high uterotonic coverage can be achieved in South Sudan through a facility- and community-focused postpartum hemorrhage (PPH) prevention program. The program was implemented from October 2012 to March 2013. At health facilities, active management of the third stage of labor (AMTSL) was emphasized. During prenatal care and home visits, misoprostol was distributed to pregnant women at approximately 32 weeks of pregnancy for the prevention of PPH at home births. Data on uterotonic coverage and other program outcomes were collected through facility registers, home visits, and postpartum interviews. In total, 533 home births and 394 facility-based births were reported. Misoprostol was distributed in advance to 787 (84.9%) pregnant women, of whom 652 (82.8%) received the drug during home visits. Among the women who delivered at home, 527 (98.9%) reported taking misoprostol. A uterotonic for PPH prevention was provided at 342 (86.8%) facility-based deliveries. Total uterotonic coverage was 93.7%. No adverse events were reported. It is feasible to achieve high coverage of uterotonic use in a low-resource and postconflict setting with few skilled birth attendants through a combination of advance misoprostol distribution and AMTSL at facilities. Advance distribution through home visits was key to achieving high coverage of misoprostol use.


ERP correlates of the bilateral redundancy gain for words.
Neurophysiological correlates of hemispheric asymmetry and interhemispheric interaction in lexical processing were investigated in a lexical decision task with tachistoscopic stimulus presentation either unilaterally, to the right or left visual field, or bilaterally, with identical stimulus copies to each visual hemi-field. Behavioral data confirmed both right visual field advantage and bilateral redundancy gain for words but not for pronounceable orthographically regular pseudowords. ERPs showed a significant amplitude increase 160-200 after stimulus presentation specifically for words after bilateral redundant stimulation, which was present in the recordings from both hemispheres. Localization of cortical sources using minimum norm estimation indicated stronger cortical activity for words in temporal regions of both hemispheres after bilateral presentation compared with each of the unilateral stimulation conditions individually. Pseudoword presentation did not lead to a general increase of cortical activation in the bilateral condition compared with unilateral presentation. The specific activation increase for words in the bilateral redundant condition relative to unilateral stimulation and the absence of this effect for pseudowords, which became manifest in a significant interaction of the factors lexicality and presentation mode, is best explained by summation of neuronal activation from both hemispheres within distributed lexical circuits. Source estimation indicates that temporal areas, particularly in the left hemisphere, are the primary cortical loci where such stimulus-specific activity increases occurred.


Vulnerability in research ethics: a way forward.
Several foundational documents of bioethics mention the special obligation researchers have to vulnerable research participants. However, the treatment of vulnerability offered by these documents often relies on enumeration of vulnerable groups rather than an analysis of the features that make such groups vulnerable. Recent attempts in the scholarly literature to lend philosophical weight to the concept of vulnerability are offered by Luna and Hurst. Luna suggests that vulnerability is irreducibly contextual and that Institutional Review Boards (Research Ethics Committees) can only identify vulnerable participants by carefully examining the details of the proposed research. Hurst, in contrast, defines the vulnerable as those especially at risk of incurring the wrongs to which all research ethics participants are exposed. We offer a more substantive conception of vulnerability than Luna but one that gives rise to a different rubric of responsibilities from Hurst's. While we understand vulnerability to be an ontological condition of human existence, in the context of research ethics, we take the vulnerable to be research subjects who are especially prone to harm or exploitation. Our analysis rests on developing a typology of sources of vulnerability and showing how distinct sources generate distinct obligations on the part of the researcher. Our account emphasizes that the researcher's first obligation is not to make the research participant even more vulnerable than they already are. To illustrate our framework, we consider two cases: that of a vulnerable population involved in international research and that of a domestic population of people with diminished capacity.


Increased DNA damage and repair deficiency in granulosa cells are associated with ovarian aging in rhesus monkey.
Ovarian aging is closely tied to the decline in ovarian follicular reserve and oocyte quality. During the prolonged reproductive lifespan of the female, granulosa cells connected with oocytes play critical roles in maintaining follicle reservoir, oocyte growth and follicular development. We tested whether double-strand breaks (DSBs) and repair in granulosa cells within the follicular reservoir are associated with ovarian aging. Ovaries were sectioned and processed for epi-fluorescence microscopy, confocal microscopy, and immunohistochemistry. DNA damage was revealed by immunstaining of γH2AX foci and telomere damage by γH2AX foci co-localized with telomere associated protein TRF2. DNA repair was indicated by BRCA1 immunofluorescence. DSBs in granulosa cells increase and DSB repair ability, characterized by BRCA1 foci, decreases with advancing age. γH2AX foci increase in primordial, primary and secondary follicles with advancing age. Likewise, telomere damage increases with advancing age. In contrast, BRCA1 foci in granulosa cells of primordial, primary and secondary follicles decrease with monkey age. BRCA1 positive foci in the oocyte nuclei also decline with maternal age. Increased DSBs and reduced DNA repair in granulosa cells may contribute to ovarian aging. Discovery of therapeutics that targets these pathways might help maintain follicle reserve and postpone ovarian dysfunction with age.


Geochemical and microbial characterizations of flowback and produced water in three shale oil and gas plays in the central and western United States.
Limited understanding of wastewater streams produced from shale oil and gas wells impedes best practices of wastewater treatment and reuse. This study provides a comprehensive and comparative analysis of flowback and produced water from three major and newly developed shale plays (the Bakken shale, North Dakota; the Barnett shale, Texas; and the Denver-Julesburg (DJ) basin, Colorado) in central and western United States. Geochemical features that included more than 10 water quality parameters, dissolved organic matter, as well as microbial community structures were characterized and compared. Results showed that wastewater from Bakken and Barnett shales has extremely high salinity (∼295 g/L total dissolved solids (TDS)) and low organic concentration (80-252 mg/L dissolved organic carbon (DOC)). In contrast, DJ basin showed an opposite trend with low TDS (∼30 g/L) and high organic content (644 mg/L DOC). Excitation-emission matrix (EEM) fluorescence spectra demonstrated that more humic acid and fluvic acid-like organics with higher aromaticity existed in Bakken wastewater than that in Barnett and DJ basin. Microbial communities of Bakken samples were dominated by Fe (III)-reducing bacteria Geobacter, lactic acid bacteria Lactococcus and Enterococcus, and Bradyrhizobium, while DJ basin water showed higher abundance of Rhodococcus, Thermovirga, and sulfate reducing bacteria Thermotoga and Petrotoga. All these bacteria are capable of hydrocarbon degradation. Hydrogenotrophic methanogens dominated the archaeal communities in all samples.


Inhibiting lung elastase activity enables lung growth in mechanically ventilated newborn mice.
Mechanical ventilation with O₂-rich gas (MV-O₂) offers life-saving treatment for respiratory failure, but also promotes lung injury. We previously reported that MV-O2 of newborn mice increased lung elastase activity, causing elastin degradation and redistribution of elastic fibers from septal tips to alveolar walls. These changes were associated with transforming growth factor (TGF)-β activation and increased apoptosis leading to defective alveolarization and lung growth arrest, as seen in neonatal chronic lung disease. To determine if intratracheal treatment of newborn mice with the serine elastase inhibitor elafin would prevent MV-O₂-induced lung elastin degradation and the ensuing cascade of events causing lung growth arrest. Five-day-old mice were treated via tracheotomy with recombinant human elafin or vehicle (lactated-Ringer solution), followed by MV with 40% O₂ for 8-24 hours; control animals breathed 40% O₂ without MV. At study's end, lungs were harvested to assess key variables noted below. MV-O₂ of vehicle-treated pups increased lung elastase and matrix metalloproteinase-9 activity when compared with unventilated control animals, causing elastin degradation (urine desmosine doubled), TGF-β activation (pSmad-2 tripled), and apoptosis (cleaved-caspase-3 increased 10-fold). Quantitative lung histology showed larger and fewer alveoli, greater inflammation, and scattered elastic fibers. Elafin blocked these MV-O₂-induced changes. Intratracheal elafin, by blocking lung protease activity, prevented MV-O₂-induced elastin degradation, TGF-β activation, apoptosis, and dispersion of matrix elastin, and attenuated lung structural abnormalities noted in vehicle-treated mice after 24 hours of MV-O₂. These findings suggest that elastin breakdown contributes to defective lung growth in response to MV-O₂ and might be targeted therapeutically to prevent MV-O₂-induced lung injury.


Liposome suppression of proliferative vitreoretinopathy. Rabbit model using antimetabolite encapsulated liposomes.
The effects of the antimetabolites, cytarabine (Ara-C) and 5-fluorouridine 5'-monophosphate (FUMP), encapsulated in multivesicular liposomes on formation of vitreous fibroproliferative membranes in New Zealand white (NZW) rabbits were studied. In pharmacokinetic studies, the drug half-life in the vitreous cavity was 124 hr after intravitreal administration of 1.0 mg of FUMP in liposomes. By contrast, the drug half-life after a single injection in nonliposome-treated controls was only 4.5 hr. In a heterologous dermal fibroblast model of proliferative vitreoretinopathy (PVR), there was a 92% decrease in frequency of tractional retinal detachments in rabbits receiving a single intravitreal injection of liposome-encapsulated 0.1 mg of FUMP compared with controls receiving liposomes without drug. A dose of 1 mg of Ara-C in liposome-treated rabbits was associated with only a 46% reduction in tractional detachment compared with controls. Multivesicular liposome-encapsulated FUMP may be useful for inhibiting formation of fibroproliferative membranes in the vitreous after vitreoretinal surgery.


Management of Coronary Disease in Patients with Advanced Kidney Disease.
Clinical trials that have assessed the effect of revascularization in patients with stable coronary disease have routinely excluded those with advanced chronic kidney disease. We randomly assigned 777 patients with advanced kidney disease and moderate or severe ischemia on stress testing to be treated with an initial invasive strategy consisting of coronary angiography and revascularization (if appropriate) added to medical therapy or an initial conservative strategy consisting of medical therapy alone and angiography reserved for those in whom medical therapy had failed. The primary outcome was a composite of death or nonfatal myocardial infarction. A key secondary outcome was a composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. At a median follow-up of 2.2 years, a primary outcome event had occurred in 123 patients in the invasive-strategy group and in 129 patients in the conservative-strategy group (estimated 3-year event rate, 36.4% vs. 36.7%; adjusted hazard ratio, 1.01; 95% confidence interval [CI], 0.79 to 1.29; P = 0.95). Results for the key secondary outcome were similar (38.5% vs. 39.7%; hazard ratio, 1.01; 95% CI, 0.79 to 1.29). The invasive strategy was associated with a higher incidence of stroke than the conservative strategy (hazard ratio, 3.76; 95% CI, 1.52 to 9.32; P = 0.004) and with a higher incidence of death or initiation of dialysis (hazard ratio, 1.48; 95% CI, 1.04 to 2.11; P = 0.03). Among patients with stable coronary disease, advanced chronic kidney disease, and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of death or nonfatal myocardial infarction. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).


Stable between-subject statistical inference from unstable within-subject functional connectivity estimates.
Spatial or temporal aspects of neural organization are known to be important indices of how cognition is organized. However, measurements and estimations are often noisy and many of the algorithms used are probabilistic, which in combination have been argued to limit studies exploring the neural basis of specific aspects of cognition. Focusing on static and dynamic functional connectivity estimations, we propose to leverage this variability to improve statistical efficiency in relating these estimations to behavior. To achieve this goal, we use a procedure based on permutation testing that provides a way of combining the results from many individual tests that refer to the same hypothesis. This is needed when testing a measure whose value is obtained from a noisy process, which can be repeated multiple times, referred to as replications. Focusing on functional connectivity, this noisy process can be: (a) computational, for example, when using an approximate inference algorithm for which different runs can produce different results or (b) observational, if we have the capacity to acquire data multiple times, and the different acquired data sets can be considered noisy examples of some underlying truth. In both cases, we are not interested in the individual replications but on the unobserved process generating each replication. In this note, we show how results can be combined instead of choosing just one of the estimated models. Using both simulations and real data, we show the benefits of this approach in practice.


Burden of disease attributed to ambient PM2.5 and PM10 exposure in 190 cities in China.
Particulate air pollution is becoming a serious public health concern in urban cities of China. Association of disability-adjusted life years (DALYs) and economic loss with air pollution-related health effects demand quantitative analysis for correctional measures in air quality. This study applies an epidemiology-based exposure-response function to obtain the quantitative estimate of health impact of particulate matter PM2.5 and PM10 across 190 cities of China during years 2014-2015. The annual average concentration of PM2.5 and PM10 is 57 ± 18 μg/m3 (ranging from 18 to 119 μg/m3) and 97.7 ± 34.2 μg/m3 (ranging from 33.5 to 252.8 μg/m3), respectively. Based on the present study, the total estimated annual premature mortality due to PM2.5 is 722,370 [95% confidence interval (CI) = 322,716-987,519], 79% of which accounts for adult cerebrovascular disease (stroke) and ischemic heart disease (IHD). The premature mortality in megacities is very high, such as Chongqing (25,162/year), Beijing (19,702/year), Shanghai (19,617/year), Tianjin (13,726/year), and Chengdu (12,356/year). PM10 pollution has caused 1,491,774 (95% CI = 972,770-1,960,303) premature deaths (age >30) in China. Further, 3,614,064 cases of chronic bronchitis (CB); 13,759,894 cases of asthma attack among all ages; 191,709 COPD-related hospital admission (HA) cases; 499,048 respiratory-related HA; 357,816 cerebrovascular HA; and 308,129 cardiovascular-related HA due to PM10 pollution have been estimated during 2014-2015. Chongqing, Beijing, Baoding, Tianjin, and Shijiazhuang are the top five contributors to pollution-related mortality, accounting for 3.10, 2.71, 2.49, 2.20, and 2.02%, respectively, of the total deaths caused by PM10 pollution. The total DALYs associated with PM2.5 and PM10 pollution in China is 7.2 and 20.66 million in 2014-2015, and mortality and chronic bronchitis shared about 93.3% of the total DALYs for PM10. During this period, the economic cost of health impact due to PM10 is approximately US$304,122 million, which accounts for about 2.94% of China's gross domestic product (GDP). Megacities are expected to contribute relatively more to the total costs. The present methodology could be used as a tool to help policy makers and pollution control board authorities, to further analyze costs and benefits of air pollution management programs in China.


HiQuant: Rapid Postquantification Analysis of Large-Scale MS-Generated Proteomics Data.
Recent advances in mass-spectrometry-based proteomics are now facilitating ambitious large-scale investigations of the spatial and temporal dynamics of the proteome; however, the increasing size and complexity of these data sets is overwhelming current downstream computational methods, specifically those that support the postquantification analysis pipeline. Here we present HiQuant, a novel application that enables the design and execution of a postquantification workflow, including common data-processing steps, such as assay normalization and grouping, and experimental replicate quality control and statistical analysis. HiQuant also enables the interpretation of results generated from large-scale data sets by supporting interactive heatmap analysis and also the direct export to Cytoscape and Gephi, two leading network analysis platforms. HiQuant may be run via a user-friendly graphical interface and also supports complete one-touch automation via a command-line mode. We evaluate HiQuant's performance by analyzing a large-scale, complex interactome mapping data set and demonstrate a 200-fold improvement in the execution time over current methods. We also demonstrate HiQuant's general utility by analyzing proteome-wide quantification data generated from both a large-scale public tyrosine kinase siRNA knock-down study and an in-house investigation into the temporal dynamics of the KSR1 and KSR2 interactomes. Download HiQuant, sample data sets, and supporting documentation at http://hiquant.primesdb.eu .


Progestins both stimulate and inhibit breast cancer cell cycle progression while increasing expression of transforming growth factor alpha, epidermal growth factor receptor, c-fos, and c-myc genes.
This study documents a biphasic change in the rate of cell cycle progression and proliferation of T-47D human breast cancer cells treated with synthetic progestins, consisting of an initial transient acceleration in transit through G1, followed by cell cycle arrest and growth inhibition. Both components of the response were mediated via the progesterone receptor. The data are consistent with a model in which the action of progestins is to accelerate cells already progressing through G1, which are then arrested early in G1 after completing a round of replication, as are cells initially in other phases of the cell cycle. Such acceleration implies that progestins act on genes or gene products which are rate limiting for cell cycle progression. Increased production of epidermal growth factor and transforming growth factor alpha, putative autocrine growth factors in breast cancer cells, does not appear to account for the initial response to progestins, since although the mRNA abundance for these growth factors is rapidly induced by progestins, cells treated with epidermal growth factor or transforming growth factor alpha did not enter S phase until 5 to 6 h later than those stimulated by progestin. The proto-oncogenes c-fos and c-myc were rapidly but transiently induced by progestin treatment, paralleling the well-known response of these genes to mitogenic signals in other cell types. The progestin antagonist RU 486 inhibited progestin regulation of both cell cycle progression and c-myc expression, suggesting that this proto-oncogene may participate in growth modulation by progestins.


Bioprospecting Trichoderma: A Systematic Roadmap to Screen Genomes and Natural Products for Biocontrol Applications.
Natural products derived from microbes are crucial innovations that would help in reaching sustainability development goals worldwide while achieving bioeconomic growth. Trichoderma species are well-studied model fungal organisms used for their biocontrol properties with great potential to alleviate the use of agrochemicals in agriculture. However, identifying and characterizing effective natural products in novel species or strains as biological control products remains a meticulous process with many known challenges to be navigated. Integration of recent advancements in various "omics" technologies, next generation biodesign, machine learning, and artificial intelligence approaches could greatly advance bioprospecting goals. Herein, we propose a roadmap for assessing the potential impact of already known or newly discovered Trichoderma species for biocontrol applications. By screening publicly available Trichoderma genome sequences, we first highlight the prevalence of putative biosynthetic gene clusters and antimicrobial peptides among genomes as an initial step toward predicting which organisms could increase the diversity of natural products. Next, we discuss high-throughput methods for screening organisms to discover and characterize natural products and how these findings impact both fundamental and applied research fields.


Historic Treponema pallidum genomes from Colonial Mexico retrieved from archaeological remains.
Treponema pallidum infections occur worldwide causing, among other diseases, syphilis and yaws. In particular sexually transmitted syphilis is regarded as a re-emerging infectious disease with millions of new infections annually. Here we present three historic T. pallidum genomes (two from T. pallidum ssp. pallidum and one from T. pallidum ssp. pertenue) that have been reconstructed from skeletons recovered from the Convent of Santa Isabel in Mexico City, operational between the 17th and 19th century. Our analyses indicate that different T. pallidum subspecies caused similar diagnostic presentations that are normally associated with syphilis in infants, and potential evidence of a congenital infection of T. pallidum ssp. pertenue, the causative agent of yaws. This first reconstruction of T. pallidum genomes from archaeological material opens the possibility of studying its evolutionary history at a resolution previously assumed to be out of reach.


An umbrella review of adverse effects associated with antipsychotic medications: the need for complementary study designs.
Antipsychotic medications are widely prescribed in psychotic illnesses and other mental disorders. Effectiveness is well-established, particularly for reducing symptoms such as delusions and hallucinations, but can be impacted by tolerability. Adverse effects are wide-ranging, and vary between antipsychotics, which is clinically important. This umbrella review aimed to comprehensively summarise the extent and quality of evidence for adverse effects associated with antipsychotic use in people with mental disorders. We included 32 meta-analyses of randomised trials and observational studies. The overall robustness of reported associations was considered in terms of review quality, heterogeneity, excess significance bias, and prediction intervals. Using this approach, endocrine and metabolic, movement-related, and sedation and sleep problems were the clinical domains with strongest evidence. The overall quality of included meta-analyses was low, and individual adverse effects were not typically examined in meta-analyses of both randomised trials and observational study designs. Future reviews should focus on adhering to methodological guidelines, consider the complementary strengths of different study designs, and integrate clinically relevant information on absolute rates and severity of adverse effects.


Career choices for obstetrics and gynaecology: national surveys of graduates of 1974-2002 from UK medical schools.
To report the trends in career choices for obstetrics and gynaecology among UK medical graduates. Postal questionnaire surveys of qualifiers from all UK medical schools in nine qualification years since 1974. United Kingdom. All graduates from UK medical schools in 1974, 1977, 1980, 1983, 1993, 1996, 1999, 2000 and 2002. Postal questionnaire surveys. Career choices for obstetrics and gynaecology and factors influencing career choices for obstetrics and gynaecology. Seventy-four percent (24,623/33,417) and 73% (20,709/28,468) of doctors responded at 1 and 3 years after qualification. Choices for obstetrics and gynaecology fell sharply during the 1990s from 4.2% of 1996 qualifiers to 2.2% of 1999 qualifiers, and rose slightly to 2.8% of 2002 qualifiers. Only 0.8% of male graduates of 2002 chose obstetrics and gynaecology compared with 4.1% of women. Forty-six percent of those who chose obstetrics and gynaecology 1 year after qualification were working in it 10 years after qualifying. Experience of the subject as a student, and the influence of a particular teacher or department, affected long-term career choices more for obstetrics and gynaecology than for other careers. The unwillingness of young doctors to enter obstetrics and gynaecology may be attributable to concerns about workforce planning and career progression problems, rather than any lack of enthusiasm for the specialty. The number of men choosing obstetrics and gynaecology is now very small; the reasons and the future role of men in the specialty need to be debated.


UGT2B17 Expedites Progression of Castration-Resistant Prostate Cancers by Promoting Ligand-Independent AR Signaling.
Castration-resistant prostate cancer (CRPC) is characterized by a shift in androgen receptor (AR) signaling from androgen-dependent to androgen (ligand)-independent. UDP-glucuronosyltransferase 2B17 (UGT2B17) is a key enzyme that maintains androgen homeostasis by catabolizing AR agonists into inactive forms. Although enhanced UGT2B17 expression by antiandrogens has been reported in androgen-dependent prostate cancer, its roles in regulating AR signaling transformation and CRPC progression remain unknown. In this study, we show that higher UGT2B17 protein expression in prostate tumors is associated with higher Gleason score, metastasis, and CRPC progression. UGT2B17 expression and activity were higher in androgen-independent compared to androgen-dependent cell lines. UGT2B17 stimulated cancer cell proliferation, invasion, and xenograft progression to CRPC after prolonged androgen deprivation. Gene microarray analysis indicated that UGT2B17 suppressed androgen-dependent AR transcriptional activity and enhanced of ligand-independent transcriptional activity at genes associated with cell mitosis. These UGT2B17 actions were mainly mediated by activation of the c-Src kinase. In CRPC tumors, UGT2B17 expression was associated positively with c-Src activation. These results indicate that UGT2B17 expedites CRPC progression by enhancing ligand-independent AR signaling to activate cell mitosis in cancer cells. Cancer Res; 76(22); 6701-11. ©2016 AACR.


Exercise-induced oxidative stress leads hemolysis in sedentary but not trained humans.
Intravascular hemolysis is one of the most emphasized mechanisms for destruction of erythrocytes during and after physical activity. Exercise-induced oxidative stress has been proposed among the different factors for explaining exercise-induced hemolysis. The validity of oxidative stress following exhaustive cycling exercise on erythrocyte damage was investigated in sedentary and trained subjects before and after antioxidant vitamin treatment (A, C, and E) for 2 mo. Exercise induced a significant increase in thiobarbituric acid-reactive substance and protein carbonyl content levels in sedentary subjects and resulted in an increase of osmotic fragility and decrease in deformability of erythrocytes, accompanied by signs for intravascular hemolysis (increase in plasma hemoglobin concentration and decrease in haptoglobulin levels). Administration of antioxidant vitamins for 2 mo prevented exercise-induced oxidative stress (thiobarbituric acid-reactive substance, protein carbonyl content) and deleterious effects of exhaustive exercise on erythrocytes in sedentary subjects. Trained subjects' erythrocyte responses to exercise were different from those of sedentary subjects before antioxidant vitamin treatment. Osmotic fragility and deformability of erythrocytes, plasma hemoglobin concentration, and haptoglobulin levels were not changed after exercise, although the increased oxidative stress was observed in trained subjects. After antioxidant vitamin treatment, functional and structural parameters of erythrocytes were not altered in the trained group, but exercise-induced oxidative stress was prevented. Increased percentage of young erythrocyte populations was determined in trained subjects by density separation of erythrocytes. These findings suggest that the exercise-induced oxidative stress may contribute to exercise-induced hemolysis in sedentary humans.


Degradation of ZnGa2O4:Cr3+ luminescent nanoparticles in lysosomal-like medium.
The ultimate goal of in vivo imaging is to provide safe tools to probe the inside of a body in order to obtain pathological information, monitor activities, and examine disease progression or regression. In this context zinc gallate doped with chromium III (ZGO) nanoparticles with persistent luminescence properties have been previously developed, and their biodistribution as well as in vitro toxicity were evaluated. However, to date, nothing is known about their potential transformations in biological media, which may hinder their biomedical applications. In order to know if these nanoparticles could degrade, the present work consists of studying their fate over time depending on both their coating and the aqueous media in which they are dispersed. ZGO nanoparticles have been dispersed in three different aqueous solutions for up to 90 days and characterized by numerous techniques. Among the evaluated dispersion media, Artificial Lysosomal Fluid (ALF) mimicking the intracellular lysosome environment elicited significant degradation of ZGO nanoparticles. The chelating agents present in ALF have proved to play a major role in the degradation of the ZGO, by stabilizing the nanoparticles and increasing the contact. An important time decrease of the luminescence properties has also been observed, which correlated with the release of ions from ZGO nanoparticles as well as their decreasing size. This information is valuable since it indicates, for the first time, the long-term degradation of persistent luminescent nanoprobes in an in vivo like model medium. Therefore, possible elimination of the imaging probes after in vivo preclinical applications could be foreseen.


The Triple Combination Phentermine Plus 5-HTP/Carbidopa Leads to Greater Weight Loss, With Fewer Psychomotor Side Effects Than Each Drug Alone.
Obesity has become a serious public health problem. Although diet, surgery, and exercise are the primary treatments for obesity, these activities are often supplemented using appetite suppressants. A previous study reported that obesity specialists frequently prescribed a new drug combination for its treatment that includes phentermine (Phen; dopaminergic appetite suppressant), a serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP; an appetite suppressant that increases the 5-HT concentration), and carbidopa (CB; peripheral blocker of conversion of 5-HTP to 5-HT). Despite its widespread use, there is neither a preclinical study confirming the drug efficacy nor studies of its effects on the brain. To fill this gap, in rats for seven consecutive days, we administered Phen intraperitoneally at different doses either alone or in combination with a fixed dose of 5-HTP/CB. In a different group, we infused drugs via an intraperitoneal catheter while extracellular-recordings were performed in the nucleus accumbens shell (NAcSh), a brain region with dopamine-releasing effects that is involved in the action of appetite suppressants. We found that the triple-drug combination leads to greater weight-loss than each drug alone. Moreover, and as the treatment progresses, the triple drug combination partially reversed psychomotor side-effects induced by Phen. Electrophysiological results revealed that Phen alone evoked a net inhibitory imbalance in NAcSh population activity that correlated with the onset of psychomotor effects. In addition, and unlike the greater weight loss, the addition of 5-HTP/CB did not alter the Phen-evoked inhibitory imbalance in NAcSh responses. Subsequent experiments shed light on the underlying mechanism. That is the majority of NAcSh neurons modulated by 5-HTP/CB were suppressed by Phen. Notably, and despite acting via a different mechanism of action (DA for Phen vs. 5-HT for 5-HTP/CB), both drugs recruited largely overlapping NAcSh neuronal ensembles. These data suggest that the neural correlates of the greater weight loss could be located outside the NAcSh, in other brain circuits. Furthermore, we conclude that Phen + 5-HTP/CB is a potential treatment for overweight and obesity.


Evaluation of passive samplers for the collection of dissolved organic matter in streams.
Traditional sampling methods for dissolved organic matter (DOM) in streams limit opportunities for long-term studies due to time and cost constraints. Passive DOM samplers were constructed following a design proposed previously which utilizes diethylaminoethyl (DEAE) cellulose as a sampling medium, and they were deployed throughout a temperate stream network in Indiana. Two deployments of the passive samplers were conducted, during which grab samples were frequently collected for comparison. Differences in DOM quality between sites and sampling methods were assessed using several common optical analyses. The analyses revealed significant differences in optical properties between sampling methods, with the passive samplers preferentially collecting terrestrial, humic-like DOM. We assert that the differences in DOM composition from each sampling method were caused by preferential binding of complex humic compounds to the DEAE cellulose in the passive samplers. Nonetheless, the passive samplers may provide a cost-effective, integrated sample of DOM in situations where the bulk DOM pool is composed mainly of terrestrial, humic-like compounds.