Prevalence of urinary incontinence, risk factors and its impact: multivariate analysis from Indonesian nationwide survey.
to describe the profile of urinary infection (UI) and to analyze its risk factors and impacts. subjects were enrolled consecutively from pediatric, urology, obstetrics and gynecology, and geriatric outpatient clinics at six teaching hospitals in various regions of Indonesia. Those with urinary tract infection and diabetes mellitus were excluded. The UI questionnaire was adapted from the 3 Incontinence Questions (3IQ). Written informed consent was obtained prior to the interview. about 2765 completed questionnaires were obtained. The overall UI prevalence was 13.0%, which consisted of prevalence of stress UI (4.0%), urgency UI/wet OAB (4.1%), dry OAB (1.6%), mixed UI (1.6%), overflow UI (0.4%), enuresis (0.4%), other UI (0.7%). The prevalence of UI was significantly higher (p<0.001) in geriatric population (22.2%) compared to the adult (12.0%), and pediatric population (6.8%). There was no prevalence difference (p>0.05) between male and female subjects. Enuresis and urgency UI/wet OAB were the most common UI in pediatric population. The prevalence was 2.3% and 2.1% respectively. Urgency UI and stress UI were the two most common type in adult and geriatric population. Both have an equal prevalence of 4.6%. The multivariate analysis showed that the prevalence of UI increased with LUTS (PR 4.22, 95%CI 2.98-5.97), chronic cough (PR 2.08, 95% CI 1.32-3.28), and fecal incontinence (PR 1.85, 95% CI 1.03-3.32). We found that UI impaired family life (25.3%), sexual relationship (13.6%), and job/school performance (23.7%). Frequent toilet use and reducing fluid intake were the two most common behavior changes. the prevalence of UI in Indonesia is nearly similar to other Asian countries. It increases with age and is not affected by gender. LUTS, chronic cough, and fecal incontinence may have significant effects on the prevalence. UI seems to impact daily life and behavior.


The impact of intervening in green space in Dutch deprived neighbourhoods on physical activity and general health: results from the quasi-experimental URBAN40 study.
Many problems concentrate in deprived neighbourhoods, among which is poor health. One possible way to address these health problems is to invest in the green space in deprived neighbourhoods. The number of evaluations of the public health impact of actual changes in neighbourhood green space is still limited. This study investigated the impact of real-life changes in the quality or quantity of green space in severely deprived neighbourhoods on physical activity and perceived general health. Repeated cross-sectional surveys from 2004 till 2011 yielded self-reported information on leisure time walking, cycling and sports, and perceived general health of 48,132 adult residents. We fitted generalised mixed models to assess the rate of change per half year, estimate the linear trend, and the change in trends before and after the start of the urban regeneration mid-2008. Using a quasi-experimental design, we compared the trends in the intervention neighbourhoods with different selections of control areas. The deprived neighbourhoods that intervened in green space did not show more favourable changes in the trend of physical activity and good general health compared to all the different groups of control areas. We did not observe short-term positive effects on physical activity and general health among adults from improvements in green space in deprived neighbourhoods. This suggests that greening interventions that have been carried out in the context of the Dutch District Approach did not achieve short-term health gains among adults.


Activation of G-protein-coupled receptors in cell-derived plasma membranes supported on porous beads.
G-protein-coupled receptors (GPCRs) are ubiquitous mediators of signal transduction across cell membranes and constitute a very important class of therapeutic targets. In order to study the complex biochemical signaling network coupling to the intracellular side of GPCRs, it is necessary to engineer and control the downstream signaling components, which is difficult to realize in living cells. We have developed a bioanalytical platform enabling the study of GPCRs in their native membrane transferred inside-out from live cells to lectin-coated beads, with both membrane sides of the receptor being accessible for molecular interactions. Using heterologously expressed adenosine A(2A) receptor carrying a yellow fluorescent protein, we showed that the tethered membranes comprised fully functional receptors in terms of ligand and G protein binding. The interactions between the different signaling partners during the formation and subsequent dissociation of the ternary signaling complex on single beads could be observed in real time using multicolor fluorescence microscopy. This approach of tethering inside-out native membranes accessible from both sides is straightforward and readily applied to other transmembrane proteins. It represents a generic platform suitable for ensemble as well as single-molecule measurements to investigate signaling processes at plasma membranes.


Universal lower bound on the free-energy cost of molecular measurements.
The living cell uses a variety of molecular receptors to read and process chemical signals that vary in space and time. We model the dynamics of such molecular level measurements as Markov processes in steady state, with a coupling between the receptor and the signal. We prove exactly that, when the signal dynamics is not perturbed by the receptors, the free energy consumed by the measurement process is lower bounded by a quantity proportional to the mutual information. Our result is completely independent of the receptor architecture and dependent on signal properties alone, and therefore holds as a general principle for molecular information processing.


GP4 of porcine reproductive and respiratory syndrome virus contains a neutralizing epitope that is susceptible to immunoselection in vitro.
Glycoprotein 4 (GP4) of porcine reproductive and respiratory syndrome virus (PRRSV) contains a highly variable neutralizing epitope. The present study aimed to investigate whether this epitope is susceptible to immunoselection by antibodies in vitro. Cultivation of PRRSV in vitro in the continuous presence of neutralizing monoclonal antibodies (mAbs) directed against this epitope resulted in the selection of mAb-resistant PRRSV strains within five passages. Comparison of the GP4 amino acid (aa) sequence of the original PRRSV strain with the GP4 aa sequences of the mAb-resistant PRRSV strains revealed aa substitutions within this epitope. In conclusion, this study shows that the neutralizing epitope on GP4 is susceptible to immunoselection by antibodies in vitro.


Cost-effectiveness analysis of prognostic gene expression signature-based stratification of early breast cancer patients.
The individual risk of recurrence in hormone receptor-positive primary breast cancer patients determines whether adjuvant endocrine therapy should be combined with chemotherapy. Clinicopathological parameters and molecular tests such as EndoPredict(®) (EPclin) can support decision making in patients with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative cancer. Using a life-long Markov state transition model, we determined the health economic impact and incremental cost effectiveness of EPclin-based risk stratification in combination with clinical guidelines [German-S3, National Comprehensive Cancer Center Network (NCCN), and St. Gallen] to decide on chemotherapy use. Information on overall and metastasis-free survival came from Austrian Breast & Colorectal Cancer Study Group clinical trials 6/8 (n = 1,619) and published literature. Effectiveness was assessed as quality-adjusted life-years (QALYs). Costs (2010) were assessed from a German third-party payer perspective. Lifetime costs per patient ranged from <euro>28,268 (St.Gallen and EPclin) to <euro>33,756 (NCCN). Due to an imperfect prognostic value and differences in chemotherapy use, strategies achieved between 13.165 QALYs (NCCN) and 13.173 QALYs (EPclin alone) per patient. Using German-S3 as reference, three strategies showed dominant results (St. Gallen and EPclin, German-S3 and EPclin, EPclin alone). Compared to German-S3, the addition of EPclin saved <euro>3,388 and gained 0.002 QALYs per patient. Combining guidelines with EPclin remained preferable in sensitivity analysis. Our study suggests that molecular markers can be sensibly combined with clinical guidelines to determine the risk profile of adjuvant breast cancer patients. Compared with the current German best practice (German-S3), combinations of EPclin with the St. Gallen, German-S3 or NCCN guideline and EPclin alone were dominant from the perspective of the German healthcare system.


Osteoarthritis Year in Review 2016: biomarkers (biochemical markers).
The aim of this "Year in Review" article is to summarize and discuss the implications of biochemical marker related articles published between the Osteoarthritis Research Society International (OARSI) 2015 Congress in Seattle and the OARSI 2016 Congress in Amsterdam. The PubMed/MEDLINE bibliographic database was searched using the combined keywords: 'biomarker' and 'osteoarthritis'. The PubMed/MEDLINE literature search was conducted using the Advanced Search Builder function (http://www.ncbi.nlm.nih.gov/pubmed/advanced). Over two hundred new biomarker-related papers were published during the literature search period. Some papers identified new biomarkers whereas others explored the biological properties and clinical utility of existing markers. There were specific references to several adipocytokines including leptin and adiponectin. ADAM Metallopeptidase with Thrombospondin Type 1 motif 4 (ADAMTS-4) and aggrecan ARGS neo-epitope fragment (ARGS) in synovial fluid (SF) and plasma chemokine (CeC motif) ligand 3 (CCL3) were reported as potential new knee biomarkers. New and refined proteomic technologies and novel assays including a fluoro-microbead guiding chip (FMGC) for measuring C-telopeptide of type II collagen (CTX-II) in serum and urine and a novel magnetic nanoparticle-based technology (termed magnetic capture) for collecting and concentrating CTX-II, were described this past year. There has been steady progress in osteoarthritis (OA) biomarker research in 2016. Several novel biomarkers were identified and new technologies have been developed for measuring existing biomarkers. However, there has been no "quantum leap" this past year and identification of novel early OA biomarkers remains challenging. During the past year, OARSI published a set of recommendations for the use of soluble biomarkers in clinical trials, which is a major step forward in the clinical use of OA biomarkers and bodes well for future OA biomarker development.


Assessing the relationship between HIV infection and cervical cancer in Côte d'Ivoire: a case-control study.
The association between HIV infection and invasive cervical cancer that has been reported may reflect differential prevalence of human papillomavirus (HPV) infection or uncontrolled confounding. We conducted a case-control study in a West African population to assess the relationship between HIV infection and invasive cervical cancer, taking into account HPV infection and other potential risk factors for cervical cancer. Women with invasive cervical cancer (cases) or normal cervical cytology (controls) were recruited in a hospital-based case-control study in Abidjan, Côte d'Ivoire. Odds ratios and 95% confidence intervals (CI) were estimated in logistic regression analyses controlling for important cofactors. HIV infection was noted in 22/132 (16.7%) cases and 10/120 (8.3%) controls (p = 0.048). High-risk HPV infection was detected in cervical tumor samples from 89.4% of case-participants and in cervical cytology samples in 31.1% of control-participants. In logistic regression analysis, HIV infection was associated with cervical cancer in women with HPV (OR 3.4; 95% CI 1.1-10.8). Among women aged <or= 40 years, risk factors for cervical cancer were high-risk HPV infection (OR 49.3; 95% CI 8.2-295.7); parity > 2 (OR 7.0; 95% CI 1.9-25.7) and HIV infection (OR 4.5; 95% CI 1.5-13.6). Among women aged > 40 years, high-risk HPV infection (OR 23.5; 95% CI 9.1-60.6) and parity > 2 (OR 5.5; 95% CI 2.3-13.4), but association with HIV infection was not statistically significant. These data support the hypothesis that HIV infection is a cofactor for cervical cancer in women with HPV infection, and, as in all populations, the need for promoting cervical screening in populations with high prevalence of HIV infection.


Electroactive polymer actuators as artificial muscles: are they ready for bioinspired applications?
Electroactive polymer (EAP) actuators are electrically responsive materials that have several characteristics in common with natural muscles. Thus, they are being studied as 'artificial muscles' for a variety of biomimetic motion applications. EAP materials are commonly classified into two major families: ionic EAPs, activated by an electrically induced transport of ions and/or solvent, and electronic EAPs, activated by electrostatic forces. Although several EAP materials and their properties have been known for many decades, they have found very limited applications. Such a trend has changed recently as a result of an effective synergy of at least three main factors: key scientific breakthroughs being achieved in some of the existing EAP technologies; unprecedented electromechanical properties being discovered in materials previously developed for different purposes; and higher concentration of efforts for industrial exploitation. As an outcome, after several years of basic research, today the EAP field is just starting to undergo transition from academia into commercialization, with significant investments from large companies. This paper presents a brief overview on the full range of EAP actuator types and the most significant areas of interest for applications. It is hoped that this overview can instruct the reader on how EAPs can enable bioinspired motion systems.


Cognitive Outcomes of Long-term Benzodiazepine and Related Drug (BDZR) Use in People Living With Mild to Moderate Alzheimer's Disease: Results From NILVAD.
Benzodiazepines and related drugs (BDZRs) have been associated with an increased risk of Alzheimer's disease (AD) in later life. Despite this, it remains unclear whether ongoing BDZR use may further accelerate cognitive decline in those diagnosed with mild to moderate AD. This study was embedded within NILVAD, a randomized controlled trial of nilvadipine in mild to moderate AD. Cognition was measured at baseline and 18 months using the Alzheimer Disease Assessment Scale, Cognitive Subsection (ADAS-Cog). We assessed predictors of long-term BDZR use and analyzed the effect of ongoing BDZR use on ADAS-Cog scores at 18 months. Additionally, the impact of BDZR use on adverse events, incident delirium, and falls over 18-month follow-up was assessed adjusting for relevant covariates. 448 participants with mild to moderate AD recruited from 23 academic centers in 9 European countries. Overall, 14% (62/448) were prescribed an ongoing BDZR for the study duration. Increasing total number of (non-BDZR) medications was associated with a greater likelihood of BDZR prescription (odds ratio 1.16, 95% confidence interval 1.05-1.29). At 18 months, BDZR use was not associated with greater cognitive decline on the ADAS-Cog controlling for baseline ADAS-Cog scores, age, gender, study arm, and other clinical covariates (β = 1.62, -1.34 to 4.56). However, ongoing BDZR use was associated with a greater likelihood of adverse events [incidence rate ratio (IRR) 1.19, 1.05-1.34], incident delirium (IRR 2.31, 1.45-3.68), and falls (IRR 1.66, 1.02-2.65) over 18 months that persisted after robust adjustment for covariates. This study found no effect of ongoing BDZR use on ADAS-Cog scores in those with mild to moderate AD over 18 months. However, ongoing use of these medications was associated with an increased risk of adverse events, delirium, and falls. Thus, BDZR use should be avoided where possible and deprescribing interventions should be encouraged in older adults with AD.


Early Health Shocks, Intra-household Resource Allocation and Child Outcomes.
An open question in the literature is whether families compensate or reinforce the impact of child health shocks. Discussions usually focus on one dimension of child investment. This paper examines multiple dimensions using household survey data on Chinese child twins whose average age is 11. We find that, compared with a twin sibling who did not suffer from negative early health shocks at ages 0-3, the other twin sibling who did suffer negative health shocks received RMB 305 more in terms of health investments, but received RMB 182 less in terms of educational investments in the 12 months prior to the survey. In terms of financial transfers over all dimensions of investment, the family acts as a net equalizer in response to early health shocks for children. We estimate a human capital production function and establish that, for this sample, early health shocks negatively affect child human capital, including health, education, and socioemotional skills. Compensating investments in health as measured by BMI reduce the adverse effects of health shocks by 50%, but exacerbate the adverse impact of shocks on educational attainment by 30%.


Silica-coated Gd(DOTA)-loaded protein nanoparticles enable magnetic resonance imaging of macrophages.
The molecular imaging of in vivo targets allows non-invasive disease diagnosis. Nanoparticles offer a promising platform for molecular imaging because they can deliver large payloads of imaging reagents to the site of disease. Magnetic resonance imaging (MRI) is often preferred for clinical diagnosis because it uses non-ionizing radiation and offers both high spatial resolution and excellent penetration. We have explored the use of plant viruses as the basis of for MRI contrast reagents, specifically Tobacco mosaic virus (TMV), which can assemble to form either stiff rods or spheres. We loaded TMV particles with paramagnetic Gd ions, increasing the ionic relaxivity compared to free Gd ions. The loaded TMV particles were then coated with silica maintaining high relaxivities. Interestingly, we found that when Gd(DOTA) was loaded into the interior channel of TMV and the exterior was coated with silica, the T1 relaxivities increased by three-fold from 10.9 mM-1 s-1 to 29.7 mM-1s-1 at 60 MHz compared to uncoated Gd-loaded TMV. To test the performance of the contrast agents in a biological setting, we focused on interactions with macrophages because the active or passive targeting of immune cells is a popular strategy to investigate the cellular components involved in disease progression associated with inflammation. In vitro assays and phantom MRI experiments indicate efficient targeting and imaging of macrophages, enhanced contrast-to-noise ratio was observed by shape-engineering (SNP > TMV) and silica-coating (Si-TMV/SNP > TMV/SNP). Because plant viruses are in the food chain, antibodies may be prevalent in the population. Therefore we investigated whether the silica-coating could prevent antibody recognition; indeed our data indicate that mineralization can be used as a stealth coating option to reduce clearance. Therefore, we conclude that the silica-coated protein-based contrast agent may provide an interesting candidate material for further investigation for in vivo delineation of disease through macrophage imaging.


Is migraine a lateralization defect?
Migraine often co-occurs with patent foramen ovale (PFO), and some people have suggested surgical closure as an efficient treatment for migraine. Prospective studies, however, do not report radical effect of PFO surgery on migraine. Here, we examined the hypothesis that PFO and migraine may cooccur as two independent manifestations of lateralization defect during embryonic development. We measured the absolute displacement of a midline structure, the pineal gland, on brain scans of 39 migraineurs and 26 controls. We found a significant asymmetry of the pineal gland in migraineurs compared with controls. Our data suggest that migraine's circadian component and its association with PFO may be linked to a lateralization defect during embryogenesis, which could be a result from abnormal serotonin regulation.


Compatibility between Clonostachys isolates with a view to mixed inocula for biocontrol.
To aid the development of compatible biocontrol inocula, a prescreening method for the prediction of compatibility of fungal antagonists was developed. Compatibility between 18 Clonostachys isolates with known antagonistic capabilities against Phytophthora palmivora was tested using intra- or interisolate pairings (dual cultures) on water agar plates, a hyphal interaction experiment and a modified double host-range experiment. Almost all inter- or intraisolate pairings of Clonostachys isolates showed growth inhibition zones and did not show free hyphal intermingling. A hyphal interaction experiment on water agar demonstrated that the aggressiveness of a Clonostachys isolate and its susceptibility to mycoparasitism were unrelated phenomena. However the level of aggressiveness and/or susceptibility of an isolate were largely dependant on the isolate with which it was challenged. The degree of growth-inhibition caused by an isolate was unrelated to the hyphal damaged it caused or received. In the double host-range experiment all possible pairs from four Clonostachys isolates were inoculated in different ratios (10 000-fold range) on plates precolonized with one of two P. palmivora isolates. The results showed that antagonistic capabilities of certain combinations were affected by the Clonostachys isolates. The primary host, P. palmivora, did not affect antagonistic capabilities; whereas inoculum ratio did. Of note, it was not possible to predict the outcome of the double host range on the basis of the results of the hyphal interaction experiment. In conclusion the competitive abilities of Clonostachys isolates depend on the partner with which they are applied and less on resource availability. The double host-range test as developed here might provide the most representative tool to date to test compatibility of fungal antagonists to be used in biocontrol inocula. However the link between the results of the double host-range test and field efficacy of biocontrol inocula remains to be investigated.


From glycerol to value-added products.
Today, industrial plants that produce glycerol are closing down and others are opening that use glycerol as a raw material, owing to the large surplus of glycerol formed as a by-product during the production of biodiesel. Research efforts to find new applications of glycerol as a low-cost feedstock for functional derivatives have led to the introduction of a number of selective processes for converting glycerol into commercially valued products. This Minireview describes a selection of such achievements and shows how glycerol will be a central raw material in future chemical industries.


The osmotic tolerance of boar spermatozoa and its usefulness as sperm quality parameter.
Predicting the fertility outcome of ejaculates is very important in the field of porcine reproduction. The aims of this study were to determine the effects of different osmotic treatments on boar spermatozoa and to correlate them with fertility and prolificacy, assessed as non-return rates within 60 days (NRR(60d)) of the first inseminations, and litter size (LS), respectively. Sperm samples (n=100) from one hundred healthy Piétrain boars were used to assess 48 treatments combining different osmolalities (ranged between 100 and 4000 mOsm kg(-1)), different compounds used to prepare anisotonic solutions, and two different modalities: return and non-return to isotonic conditions. Sperm quality was evaluated before and after applying the treatments on the basis of analyses of sperm viability, motility, morphology and percentages of acrosome-intact spermatozoa. Statistical analyses were performed using a one-way ANOVA and post hoc Tukey's test, linear regression analyses (Pearson correlation and multiple regression) and Jackknife cross-validation. Although three conventional parameters: sperm viability, sperm morphology and the percentages of acrosome-intact spermatozoa were significantly correlated with NRR(60d) and with LS, their respective osmotic tolerance parameters (defined for each parameter and treatment regarding with negative control) presented a higher Pearson coefficient with both fertility and prolificacy in three treatments (150 mOsm kg(-1) with non-return to isotonic conditions, 200 mOsm kg(-1) with return and 500 mOsm kg(-1) using sodium citrate and non-return to isotonic conditions). We conclude that osmotic resistance in sperm viability, sperm morphology and acrosome-intactness in the treatments mentioned above could be assessed along with classical parameters to better predict the fertilising ability of a given ejaculate.


Recommended Strategies for Physician Burnout, a Well-Recognized Escalating Global Crisis Among Neurologists.
Several indexes are used to classify physician burnout, with the Maslach Burnout Inventory currently being the most widely accepted. This index measures physician burnout based on emotional exhaustion, detachment from work, and lack of personal achievement. The overall percentage of physicians with burnout is estimated to be around 40%, but the proportion varies between specialties. Neurology currently has the second-highest rate of burnout and is projected to eventually take the top position. The purpose of this review is to provide a comprehensive overview focusing on the causes and ramifications of burnout and possible strategies for addressing the crisis. Several factors contribute to burnout among neurologist, including psychological trauma associated with patient care and a lack of respect compared to other specialties. Various interventions have been proposed for reducing burnout, and this article explores the feasibility of some of them. Burnout not only impacts the physician but also has adverse effects on the overall quality of patient care and places a strain on the health-care system. Burnout has only recently been recognized and accepted as a health crisis globally, and hence most of the proposed action plans have not been validated. More studies are needed to evaluate the long-term effects of such interventions.


Interleukin-13 protects against experimental autoimmune myocarditis by regulating macrophage differentiation.
We report here that interleukin (IL)-13 protects BALB/c mice from myocarditis, whether induced by peptide immunization or by viral infection. In contrast to mild disease in IL-4 knockout (KO) BALB/c mice, IL-13 KO BALB/c mice developed severe coxsackievirus B3 (CVB3)-induced autoimmune myocarditis and myocarditogenic peptide-induced experimental autoimmune myocarditis. Such severe disease was characterized by increased cardiac inflammation, increased total intracardiac CD45(+) leukocytes, elevated anti-cardiac myosin autoantibodies, and increased cardiac fibrosis. Echocardiography revealed that IL-13 KO mice developed severe dilated cardiomyopathy with impaired cardiac function and heart failure. Hearts of IL-13 KO mice had increased levels of the proinflammatory and profibrotic cytokines IL-1beta, IL-18, interferon-gamma, transforming growth factor-beta1, and IL-4 as well as histamine. The hallmark of the disease in IL-13 KO mice was the up-regulation of T-cell responses. CD4(+) T cells were increased in IL-13 KO hearts both proportionally and in absolute number. Splenic T cells from IL-13 KO mice were highly activated, and myosin stimulation additionally increased T-cell proliferation. CD4(+)CD25(+)Foxp3(+) regulatory T-cell numbers were decreased in the spleens of IL-13 KO mice. IL-13 deficiency led to decreased levels of alternatively activated CD206(+) and CD204(+) macrophages and increased levels of classically activated macrophages. IL-13 KO mice had increased caspase-1 activation, leading to increased production of both IL-1beta and IL-18. Therefore, IL-13 protects against myocarditis by modulating monocyte/macrophage populations and by regulating their function.


Loss of extracellular superoxide dismutase leads to acute lung damage in the presence of ambient air: a potential mechanism underlying adult respiratory distress syndrome.
The extracellular superoxide dismutase 3 (SOD3) is highly expressed in both blood vessels and lungs. In different models of pulmonary injury, SOD3 is reduced; however, it is unclear whether this contributes to lung injury. To study the role of acute SOD3 reduction in lung injury, the SOD3 gene was deleted in adult mice by using the Cre-Lox technology. Acute reduction of SOD3 led to a fivefold increase in lung superoxide, marked inflammatory cell infiltration, a threefold increase in the arterial-alveolar gradient, respiratory acidosis, histological changes similar to those observed in adult respiratory distress syndrome, and 85% mortality. Treatment with the SOD mimetic MnTBAP and intranasal administration of SOD-containing polyketal microparticles reduced mortality, prevented the histological alterations, and reduced lung superoxide levels. To understand how mice with the SOD3 embryonic deletion survived without lung injury, gene array analysis was performed. These data demonstrated the up-regulation of 37 genes and down-regulation of nine genes, including those involved in cell signaling, inflammation, and gene transcription in SOD3-/- mice compared with either mice with acute SOD3 reduction or wild-type controls. These studies show that SOD3 is essential for survival in the presence of ambient oxygen and that acute loss of this enzyme can lead to severe lung damage. Strategies either to prevent SOD3 inactivation or to augment its levels might prove useful in the treatment of acute lung injury.


Examination of moderators of expressive writing in patients with renal cell carcinoma: the role of depression and social support.
To identify groups most likely to benefit from an Expressive Writing (EW) intervention, we examined psychosocial variables as intervention moderators. We hypothesized that EW would be particularly effective for participants with high levels of depressive symptoms and social support at study entry. Patients (n = 277; 60.6% male) with kidney cancer were randomly assigned to either an expressive (EW) or neutral writing (NW) condition. Intervention outcomes included measures of depressive symptoms (CESD), cancer-related symptoms (MDASI), fatigue (BFI), and sleep disturbances (PSQI) assessed at baseline, 1, 4, and 10 months later. Moderators were measured at baseline. As hypothesized, depressive symptoms and social support moderated intervention efficacy. When examining both moderators simultaneously, EW appeared to be most effective in terms of cancer-related symptoms (p < 0.05) and depressive symptoms (p < 0.01) for participants with elevated depressive symptoms who received high levels of social support at baseline relative to their counterparts in the NW condition. Moreover, participants in EW with high levels of social support at baseline reported lower levels sleep disturbances (p = 0.005) than their counterparts in NW. Recognition of baseline depressive symptoms and social support as intervention moderators may lead to improved patient selection for EW interventions, as EW may be particularly beneficial regarding QOL outcomes for patients that have social support available including participants with depressive symptoms. EW may not be beneficial, or potentially even contraindicated, for participants lacking social support. Copyright © 2016 John Wiley & Sons, Ltd.


Tyrosine and tryptophan hydroxylases as therapeutic targets in human disease.
The ancient and ubiquitous monoamine signalling molecules serotonin, dopamine, norepinephrine, and epinephrine are involved in multiple physiological functions. The aromatic amino acid hydroxylases tyrosine hydroxylase (TH), tryptophan hydroxylase 1 (TPH1), and tryptophan hydroxylase 2 (TPH2) catalyse the rate-limiting steps in the biosynthesis of these monoamines. Genetic variants of TH, TPH1, and TPH2 genes are associated with neuropsychiatric disorders. The interest in these enzymes as therapeutic targets is increasing as new roles of these monoamines have been discovered, not only in brain function and disease, but also in development, cardiovascular function, energy and bone homeostasis, gastrointestinal motility, hemostasis, and liver function. Areas covered: Physiological roles of TH, TPH1, and TPH2. Enzyme structures, catalytic and regulatory mechanisms, animal models, and associated diseases. Interactions with inhibitors, pharmacological chaperones, and regulatory proteins relevant for drug development. Expert opinion: Established inhibitors of these enzymes mainly target their amino acid substrate binding site, while tetrahydrobiopterin analogues, iron chelators, and allosteric ligands are less studied. New insights into monoamine biology and 3D-structural information and new computational/experimental tools have triggered the development of a new generation of more selective inhibitors and pharmacological chaperones. The enzyme complexes with their regulatory 14-3-3 proteins are also emerging as therapeutic targets.


Chronic consumption of flavanol-rich cocoa improves endothelial function and decreases vascular cell adhesion molecule in hypercholesterolemic postmenopausal women.
Endothelial dysfunction characterizes many disease states including subclinical atherosclerosis. The consumption of flavanol-rich cocoa and cocoa-based products has been shown to improve endothelial function in both compromised and otherwise normal, healthy individuals when administered either acutely or over a period of several days, or weeks. Women experience increased risk for cardiovascular disease after menopause, which can be associated with endothelial dysfunction. Whether a flavanol-rich cocoa-based product can improve endothelial function in hypercholesterolemic postmenopausal women is not known. The purpose of the present study was to determine whether chronic dietary administration of flavanol-rich cocoa improves endothelial function and markers of cardiovascular health in hypercholesterolemic postmenopausal women. Thirty-two postmenopausal hypercholesterolemic women were randomly assigned to consume a high-flavanol cocoa beverage (high cocoa flavanols (CF)--446 mg of total flavanols), or a low-flavanol cocoa beverage (low CF--43 mg of total flavanols) for 6 weeks in a double-blind study (n=16 per group). Endothelial function was determined by brachial artery-reactive hyperemia. Plasma was analyzed for lipids (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol), hormones (follicle-stimulating hormone), total nitrate/nitrite, activation of cellular adhesion markers (vascular cell adhesion molecule 1, intercellular adhesion molecule 1, E-Selectin, P-Selectin), and platelet function and reactivity. Changes in these plasma markers were then correlated to brachial reactivity. Brachial artery hyperemic blood flow increased significantly by 76% (P<0.05 vs. baseline) after the 6-week cocoa intervention in the high CF group, compared with 32% in the low CF cocoa group (P=ns vs. baseline). The 2.4-fold increase in hyperemic blood flow with high CF cocoa closely correlated (r2=0.8) with a significant decrease (11%) in plasma levels of soluble vascular cell adhesion molecule-1. Similar responses were not observed after chronic use of low CF. There were no significant differences between high and low CF in other biochemical markers and parameters measured. This study is the first to identify beneficial vascular effects of flavanol-rich cocoa consumption in hypercholesterolemic postmenopausal women. In addition, our results suggest that reductions in plasma soluble vascular cell adhesion molecule-1 after chronic consumption of a flavanol-rich cocoa may be mechanistically linked to improved vascular reactivity.


Successful attenuation of humoral immunity to viral capsid and transgenic protein following AAV-mediated gene transfer with a non-depleting CD4 antibody and cyclosporine.
The ability of transient immunosuppression with a combination of a non-depleting anti-CD4 (NDCD4) antibody and cyclosporine (CyA) to abrogate immune reactivity to both adeno-associated viral vector (AAV) and its transgene product was evaluated. This combination of immunosuppressants resulted in a 20-fold reduction in the resulting anti-AAV8 antibody titres, to levels in naïve mice, following intravenous administration of 2 × 10(12) AAV8 vector particles per kg to immunocompetent mice. This allowed efficient transduction upon secondary challenge with vector pseudotyped with the same capsid. Persistent tolerance did not result, however, as an anti-AAV8 antibody response was elicited upon rechallenge with AAV8 without immunosuppression. The route of vector administration, vector dose, AAV serotype or the concomitant administration of adenoviral vector appeared to have little impact on the ability of the NDCD4 antibody and CyA combination to moderate the primary humoral response to AAV capsid proteins. The combination of NDCD4 and CyA also abrogated the humoral response to the transgene product, that otherwise invariably would occur, following intramuscular injection of AAV5, leading to stable transgene expression. These observations could significantly improve the prospects of using rAAV vectors for chronic disorders by allowing for repeated vector administration and avoiding the development of antibodies to the transgene product.


CuO-Coated and Cu2+-doped Co-modified P2-type Na2/3[Ni1/3Mn2/3]O2 for sodium-ion batteries.
Layered P2-type CuO-coated Na2/3[Ni1/3Mn2/3]O2 (NNMO@CuO) with excellent rate capability and cycling performance was investigated as a sodium-ion battery cathode material for the first time. The NNMO@CuO cathode material combines the advantages of CuO coating and Cu2+ doping. Transmission electron microscopy (TEM) images, TEM elemental line scan analysis and ex situ scanning electron microscopy (SEM) images show that CuO has been successfully coated on the particle surface uniformly, and that this CuO layer effectively suppresses the exfoliation of the metal oxide layers and unfavorable side reactions. Furthermore, Cu2+ is also partially incorporated into the host structure, according to the X-ray diffraction (XRD) patterns and refinement results. Although incorporated Cu2+ does not take part in the redox reactions of the battery cell, the refinement results indicate that the d-spacing of the Na+-ion diffusion layer is enlarged due to Cu2+ doping in the crystal structure, which results in better Na+ kinetics. Thus, the CuO-coated cathode material shows prominent cycling performance and rate capability. We believe that this CuO-coating and Cu2+-doping co-modification strategy provides a promising approach to designing advanced cathode materials for sodium-ion batteries.


Abnormal composition of hypertriglyceridemic very low density lipoprotein determines abnormal cell metabolism.
The metabolism of very low density lipoprotein (VLDL) from normolipemic (NTG) subjects, hypertriglyceridemic (HTG) subjects, and hypertriglyceridemic subjects treated with bezafibrate (BZ) was studied in cultured human skin fibroblasts. The binding, cell association, and proteolytic degradation of 125I-labeled lipoproteins and the capacity to regulate cellular sterol synthesis was determined with and without maximal stimulation of the lipoprotein by exogenous recombinant or plasmatic apolipoprotein (apo) E-3. The VLDL was separated into three density subfractions: I, II, and III. Multiple differences between HTG and NTG lipoproteins were found, which all reverted toward normal with therapy. Even in the presence of an optimal concentration of apo E-3, HTG-VLDL demonstrated 100% to 200% higher metabolic activities, indicating a better association or a better biological expression of apo E-3 at the surface of the lipoprotein. There was a strong and linear relationship between the cholesterol ester/protein ratios of the different VLDLs and their proteolytic degradations by the cells (r = 0.95). Thus, the composition/structure alterations of VLDL appear to determine their apo E-3-dependent cellular catabolism. In addition, HTG-VLDLs not enriched with apo E-3 exhibited a capacity to down-regulate cellular sterol synthesis independently of their uptake and degradation by the cells. This abnormality appeared to reflect the ability of the VLDL to donate cholesterol to the cells and was not observed in receptor-negative cells. Thus, HTG-VLDL is much more capable than NTG-VLDL of introducing cholesterol to cells by at least two mechanisms: 1) accelerated uptake and degradation and 2) direct transfer of cholesterol to the cells. Both processes are potentially atherogenic and are reversible when triglyceride-lowering therapy is instituted.


Skilled Nursing Facility Use and Hospitalizations in Heart Failure: A Community Linkage Study.
To examine the effect of skilled nursing facility (SNF) use on hospitalizations in patients with heart failure (HF) and to examine predictors of hospitalization in patients with HF admitted to a SNF. Olmsted County, Minnesota, residents with first-ever HF from January 1, 2000, through December 31, 2010, were identified, and clinical data were linked to SNF utilization data from the Centers for Medicare and Medicaid Services. Andersen-Gill models were used to determine the association between SNF use and hospitalizations and to determine predictors of hospitalization. Of 1498 patients with incident HF (mean ± SD age, 75±14 years; 45% male), 605 (40.4%) were admitted to a SNF after HF diagnosis (median follow-up, 3.6 years; range, 0-13.0 years). Of those with a SNF admission, 225 (37%) had 2 or more admissions. After adjustment for age, sex, ejection fraction, and comorbidities, SNF use was associated with a 50% increased risk of hospitalization compared with no SNF use (adjusted hazard ratio, 1.52; 95% CI, 1.31-1.76). In SNF users, arrhythmia, asthma, chronic kidney disease, and the number of activities of daily living requiring assistance were independently associated with an increased risk of hospitalization. Approximately 40% of patients with HF were admitted to a SNF at some point after diagnosis. Compared with SNF nonusers, SNF users were more likely to be hospitalized. Characteristics associated with hospitalization in SNF users were mostly noncardiovascular, including reduced ability to perform activities of daily living. These findings underscore the effect of physical functioning on hospitalizations in patients with HF in SNFs and the importance of strategies to improve physical functioning.


Lymph Node Cellular and Viral Dynamics in Natural Hosts and Impact for HIV Cure Strategies.
Combined antiretroviral therapies (cARTs) efficiently control HIV replication leading to undetectable viremia and drastic increases in lifespan of people living with HIV. However, cART does not cure HIV infection as virus persists in cellular and anatomical reservoirs, from which the virus generally rebounds soon after cART cessation. One major anatomical reservoir are lymph node (LN) follicles, where HIV persists through replication in follicular helper T cells and is also trapped by follicular dendritic cells. Natural hosts of SIV, such as African green monkeys and sooty mangabeys, generally do not progress to disease although displaying persistently high viremia. Strikingly, these hosts mount a strong control of viral replication in LN follicles shortly after peak viremia that lasts throughout infection. Herein, we discuss the potential interplay between viral control in LNs and the resolution of inflammation, which is characteristic for natural hosts. We furthermore detail the differences that exist between non-pathogenic SIV infection in natural hosts and pathogenic HIV/SIV infection in humans and macaques regarding virus target cells and replication dynamics in LNs. Several mechanisms have been proposed to be implicated in the strong control of viral replication in natural host's LNs, such as NK cell-mediated control, that will be reviewed here, together with lessons and limitations of in vivo cell depletion studies that have been performed in natural hosts. Finally, we discuss the impact that these insights on viral dynamics and host responses in LNs of natural hosts have for the development of strategies toward HIV cure.


Effectiveness of insoles used for the prevention of ulceration in the neuropathic diabetic foot: a systematic review.
Ulceration can be a debilitating and costly complication of the neuropathic diabetic foot. Insoles inserted into footwear are routinely used in clinical practice to help to prevent ulceration. AIM AND SCOPE OF THE REVIEW: This review evaluated the effectiveness of insoles used for the prevention of ulcer in the neuropathic diabetic foot. Databases were searched from inception to 2008, supplemented by hand searching of references and grey literature. Data extraction and methodological quality assessment were independently conducted by two reviewers following the recommendations of the Centre for Reviews and Dissemination. A total of five trials met the inclusion criteria: two randomised control trials (RCTs), two case control studies, and one follow-up study. The methodological quality of the majority of studies was poor. Omitted details regarding the generalisability of results made study comparison and inference to practice difficult. There is a small amount of limited evidence indicating that insoles are effective in reducing incidence of ulceration and reducing plantar peak pressures in the diabetic neuropathic foot. No study included economic analysis or patient-based outcome measures. Insoles appear of use for the prevention of neuropathic diabetic foot ulceration, although evidence is limited. Clinical recommendation regarding type and specification of insole is not possible at this time. There is an essential need for a large well-designed RCT comparing different types of commonly used insole for the prevention of ulceration in the diabetic neuropathic foot. Outcome measures should include patient perceptions of the effectiveness and cost-effectiveness analysis.


Lung Cancer: Preventable Disease.
Objective of the paper is to present lung cancer as preventable disease based on epidemiological, molecular and genomic data. Lung cancer is the most deadly malignancy around the world, both in male and female population. Vast majority of lung cancers (close to 90%) are directly caused by cigarette smoking, and thus present one of the most preventable deadly disease in humanity. Analysis of history of cigarette consumption and rise of lung cancer as world epidemics. Review of efforts to fight tobacco epidemics and how it influences incidence and prevalence of the lung cancer. Investigation of the effects of cigarette smoking on health and economic status of Bosnia and Hercegovina. Tobacco epidemics and lung cancer can be prevented. Goal is to exterminate cigarette smoking. That can be achieved only concerted effort by members of family, patients themselves, physicians, researchers, non-governmental organizations, political figures and society as a whole. In country like Bosnia and Herzegovina first step is to inform society about devastating effects of cigarette smoking. Best practices already exist and initial goal should be to start using them.


Increasing the expression of microRNA-126-5p in the temporal muscle can promote angiogenesis in the chronically ischemic brains of rats subjected to two-vessel occlusion plus encephalo-myo-synangiosis.
miR-126-5p plays an important role in promoting endothelial cell (EC) proliferation. We thus explored whether miR-126-5p can promote EC proliferation and angiogenesis in chronically ischemic brains (CIBs). Improved revascularization in moyamoya patients was correlated with upregulated miR-126-5p expression in the TM and DM. In vitro experiments showed that miR-126-5p promoted EC proliferation through the PI3K/Akt pathway. CIBs from the agomir group exhibited significantly higher p-Akt, VEGF, CD31 and eNOS expression compared with the control CIBs. The ICBP and the RCF were significantly better in the agomir compared with the control group. Increasing miR-126-5p expression in the TM can promote EC proliferation and angiogenesis in CIBs of 2VO+EMS rats through the PI3K/Akt pathway. We assessed the correlation between revascularization and miR-126-5p expression in the temporal muscle (TM) and dura mater (DM) of moyamoya patients. The effect of miR-126-5p on EC proliferation and downstream signaling pathways was explored in vitro. We established an animal model of two-vessel occlusion plus encephalo-myo-synangiosis (2VO+EMS), transfected the TM with miR-126-5p agomir/antagomir, compared the expression of miR-126-5p and relevant downstream cytokines in brain tissue among different groups, and investigated the improvement in cerebral blood perfusion (ICBP) and the recovery of cognitive function (RCF).


Aortic valve involvement in Behçet's disease. A clinical study of 9 patients.
To assess the clinical features, pathologic findings, postoperative results and the effects of immunosuppressive therapy in patients with Behçet's disease (BD). We reviewed the postoperative course of the 9 BD patients who underwent a total of 17 aortic valve replacement procedures with prosthetic valves. Histological examination of the aortic valve commonly revealed diffuse myxoid degeneration (75 percent). Of 17 valve replacement surgeries, 13 surgeries resulted in complications, such as detachment of the prosthetic valve with perivalvular leakage and dehiscence of the sternotomy wound, within an average of 5 months (range from 1 month to 14 months). The rate of prosthetic valve detachment was 76 percent (13 of 17 surgeries). Four of the 9 patients (44 percent) who underwent aortic valve replacement procedures died of heart failure or infection associated with the detachment of the prosthetic valve, and perivalvular leakage within an average of 9 months. Aortic insufficiency associated with dehiscence of the prosthetic valve developed in 11 of 12 surgical cases (92 percent) with a mechanical valve and 2 of 5 surgical cases (40 percent) with tissue valves. Thirteen of 15 surgeries (87 percent) which were not given postoperative immunosuppressive therapy developed complications, while none of 2 surgeries that used postoperative immunosuppressive therapy with prednisolone (1 mg/kg/day) and azathioprine (100 mg/day) had these complications. The rates of prosthetic valve detachment in BD involving aortic valve were higher than those of other diseases. Aortic valve involvement was also one of the poor prognostic factors in BD. Intensive postoperative immunosuppressive therapy and surgical methods may be important factors for postoperative results.


Overweight in late adolescence predicts development of severe liver disease later in life: A 39years follow-up study.
The increased prevalence of overweight has been suggested to contribute to the worldwide increase in liver diseases. We investigated if body mass index (BMI) in late adolescence predicts development of severe liver disease later in life. We performed a cohort study using data from 44,248 men (18-20years) conscribed to military service in Sweden between 1969 and 1970. Outcome data were collected from national registers to identify any diagnosis of severe liver disease (i.e., diagnosis of decompensated liver disease, cirrhosis or death in liver disease) until the end of 2009. A Cox regression model was applied using BMI as independent variable. The model was adjusted for use of alcohol, use of narcotics, smoking, high blood pressure and cognitive ability at time of conscription. During a follow-up period of a mean of 37.8years, 393 men were diagnosed with severe liver disease (mean time to diagnosis 24.7years). BMI (Hazard ratio [HR]=1.05 for each unit increase in BMI, 95% confidence interval [CI]: 1.01-1.09, p=0.008) and overweight (HR=1.64 for BMI 25-30 compared to BMI 18.5-22.5, 95% CI: 1.16-2.32, p=0.006) were associated with an increased risk of development of severe liver disease. Being overweight in late adolescence is a significant predictor of severe liver disease later in life in men. We investigated close to 45,000 Swedish men in their late teens enlisted for conscription in 1969-1970. After almost 40years of follow-up, we found that being overweight was a risk factor for developing severe liver disease, independent of established risk factors such as alcohol consumption.


Experimental estimate of a classicality witness via a single measurement.
The perception that quantum correlations can still appear in separable states has opened exciting new possibilities regarding their use as a resource in quantum information science. Quantifying such quantum correlations involves the complete knowledge of the system's state and numerical optimization procedures. Thus, it is natural to seek methods involving fewer measurements that indicate the nature of the correlations in a system. Here we propose a classicality witness that can be accurately estimated via statistics from a single measurement and perform an experiment to explore the utility of this witness for quantum states with different types of correlations.


Luminous fabric devices for wearable low-level light therapy.
In this paper, a flexible luminous fabric device was developed and investigated for wearable three-dimensionally fitted low-level light therapy. The fabric device exhibited excellent optical and thermal properties. Its optical power density and operating temperature were stable during usage for 10 hours. In vitro experiments demonstrated a significant increase in collagen production in human fibroblast irradiated by the fabric device, compared with the fibroblast without light irradiation. A series of tests were conducted for the safety of the fabric for human skin contact according to ISO standard ISO 10993-1:2003. The results showed that there was no potential hazard when the luminous fabrics were in direct contact with human skin.


How important is randomisation in a stepped wedge trial?
In cluster randomised trials, randomisation increases internal study validity. If enough clusters are randomised, an unadjusted analysis should be unbiased. If a smaller number of clusters are included, stratified or matched randomisation can increase comparability between trial arms. In addition, an adjusted analysis may be required; nevertheless, randomisation removes the possibility for systematically biased allocation and increases transparency. In stepped wedge trials, clusters are randomised to receive an intervention at different start times ('steps'), and all clusters eventually receive it. In a recent study protocol for a 'modified stepped wedge trial', the investigators considered randomisation of the clusters (hospital wards), but decided against it for ethical and logistical reasons, and under the assumption that it would not add much to the rigour of the evaluation. We show that the benefits of randomisation for cluster randomised trials also apply to stepped wedge trials. The biggest additional issue for stepped wedge trials in relation to parallel cluster randomised trials is the need to control for secular trends in the outcome. Analysis of stepped wedge trials can in theory be based on 'horizontal' or 'vertical' comparisons. Horizontal comparisons are based on measurements taken before and after the intervention is introduced in each cluster, and are unbiased if there are no secular trends. Vertical comparisons are based on outcome measurements from clusters that have switched to the intervention condition and those from clusters that have yet to switch, and are unbiased under randomisation since at any time point, which clusters are in intervention and control conditions will have been determined at random. Secular outcome trends are a possibility in many settings. Many stepped wedge trials are analysed with a mixed model, including a random effect for cluster and fixed effects for time period to account for secular trends, thereby combining both vertical and horizontal comparisons of intervention and control clusters. The importance of randomisation in a stepped wedge trial is that the effects of time can be estimated from the data, and bias from secular trends that would otherwise arise can be controlled for, provided the trends are correctly specified in the model.


A "tag-and-modify" approach to site-selective protein modification.
Covalent modification can expand a protein's functional capacity. Fluorescent or radioactive labeling, for instance, allows imaging of a protein in real time. Labeling with an affinity probe enables isolation of target proteins and other interacting molecules. At the other end of this functional spectrum, protein structures can be naturally altered by enzymatic action. Protein-protein interactions, genetic regulation, and a range of cellular processes are under the purview of these post-translational modifications. The ability of protein chemists to install these covalent additions selectively has been critical for elucidating their roles in biology. Frequently the transformations must be applied in a site-specific manner, which demands the most selective chemistry. In this Account, we discuss the development and application of such chemistry in our laboratory. A centerpiece of our strategy is a "tag-and-modify" approach, which entails sequential installation of a uniquely reactive chemical group into the protein (the "tag") and the selective or specific modification of this group. The chemical tag can be a natural or unnatural amino acid residue. Of the natural residues, cysteine is the most widely used as a tag. Early work in our program focused on selective disulfide formation in the synthesis of glycoproteins. For certain applications, the susceptibility of disulfides to reduction was a limitation and prompted the development of several methods for the synthesis of more stable thioether modifications. The desulfurization of disulfides and conjugate addition to dehydroalanine are two routes to these modifications. The dehydroalanine tag has since proven useful as a general precursor to many modifications after conjugate addition of various nucleophiles; phosphorylated, glycosylated, peptidylated, prenylated, and even mimics of methylated and acetylated lysine-containing proteins are all accessible from dehydroalanine. While cysteine is a useful tag for selective modification, unnatural residues present the opportunity for bio-orthogonal chemistry. Azide-, arylhalide-, alkyne-, and alkene-containing amino acids can be incorporated into proteins genetically and can be specifically modified through various transformations. These transformations often rely on metal catalysis. The Cu-catalyzed azide-alkyne addition, Ru-catalyzed olefin metathesis, and Pd-catalyzed cross-coupling are examples of such transformations. In the course of adapting these reactions to protein modification, we learned much about the behavior of these reactions in water, and in some cases entirely new catalysts were developed. Through a combination of these bio-orthogonal transformations from the panel of tag-and-modify reactions, multiple and distinct modifications can be installed on protein surfaces. Multiple modifications are common in natural systems, and synthetic access to these proteins has enabled study of their biological role. Throughout these investigations, much has been learned in chemistry and biology. The demands of selective protein modification have revealed many aspects of reaction mechanisms, which in turn have guided the design of reagents and catalysts that allow their successful deployment in water and in biological milieu. With this ability to modify proteins, it is now possible to interrogate biological systems with precision that was not previously possible.


Effects of neurotrophic factors and cell substrates on the differentiation of a sympathoadrenal progenitor cell line.
The detailed spatial organization of cytoskeletal proteins in an immortalized sympathoadrenal precursor cell line, termed MAH, was studied when the cells were grown on cellular substrates and when treated with combinations of recombinant nerve growth factor, ciliary neurotrophic factor and basic fibroblast growth factor. In response to growth factors, MAH cells expressed appropriate distributions of phosphorylated and non-phosphorylated neurofilaments, and dendrite and axon specific microtubule associated proteins. Sequential stages of maturation and axon formation were identified as the MAH cells established neuronal polarity and developed into sympathetic-like neurons. Combinations of the growth factors initiated growth associated protein-43 expression in processes and promoted the MAH cells to acquire sympathetic-like neuron characteristics with long, thin processes that branched and often terminated in elaborate growth cones. When treated with the three trophic factors, 15% of the MAH cells differentiated into sympathetic-like neurons, in contrast to less than 10% when cultured with ciliary neurotrophic factor plus nerve growth factor. An enhanced cholinergic phenotype was evident in the MAH cells when grown with ciliary neurotrophic factor. MAH cells also expressed neuron-specific markers when co-cultured on enriched substrates of smooth muscle, fibroblasts or Schwann cells. The results indicate that this sympathoadrenal cell lineage, carrying the v-myc oncogene, can express appropriate cytoskeletal markers in the process of neuronal differentiation when induced by neurotrophic factors or by specific cellular conditions in vitro.


Endoscopic disconnection of hypothalamic hamartomas: safety and feasibility of robot-assisted, thulium laser-based procedures.
Hypothalamic hamartomas (HH) may induce drug-resistant epilepsy (DRE), thereby requiring surgical treatment. Conventionally, treatment is aimed at removing the lesion, but a disconnection procedure has been shown to be safer and at least as effective. The thulium laser (Revolix) has been recently introduced in urological endoscopy because of its ability to deliver a smooth cut with good control of the extent of tissue damage. The authors sought to analyze the safety and efficacy of the thulium 2-μm laser applied through navigated, robot-assisted endoscopy in disconnection surgery for HHs. Twenty patients with HH who were drug resistant were treated during a 12-month period. Conventional disconnection by monopolar coagulation (endoscopic electrode) was performed in 13 patients, and thulium laser disconnection was performed in the remaining 7 patients. The endoscope was inserted into the ventricle contralateral to the attachment of the HH on the third ventricular wall. Results in terms of safety, efficacy, and ease of use of the instrument were analyzed. All 20 patients achieved a satisfactory postoperative Engel score (Classes I-III). At 12 months, the Engel class was I or II in 8 of 13 patients (61.5%) who underwent monopolar coagulation and in 6 of 7 patients (85.7%) who underwent laser disconnection (p = 0.04). Seven of 13 patients (53.8%) who underwent monopolar coagulator disconnection and 2 of 7 patients (28.6%) who underwent laser disconnection had immediate postoperative complications. At the 3-month follow-up, only 2 patients (15.4%) treated by coagulation still experienced mild surgery-related recent memory deficits. No complications persisted at the 12-month follow-up. The disconnection procedure is a safe and effective treatment strategy to treat drug-resistant epilepsy in patients with HHs. With the limitations of initial experience and a short-term follow-up, it appears that the thulium 2-μm laser has the technical features to replace the standard coagulation in this procedure.


The pathology of cutaneous leishmaniasis due to Leishmania major in Sudan.
The pathology of cutaneous leishmaniasis in Sudan, where the disease is caused by Leishmania major, was studied by light and electron microscopy. Lesions were classified into four distinct groups based on the ratio of different cell types, especially lymphocytes, macrophages, and plasma cells in the inflammatory infiltrate, and the formation of compact epithelioid granulomas or the presence of necrosis. In the lesions, there was a positive correlation between the number of lymphocytes and the number of activated macrophages and epithelioid cells. We suggest that the parasites are eliminated from the lesion by two processes: 1) a lytic mechanism in which parasites are lysed within activated macrophages and 2) necrosis of parasitized macrophages. Morphologic evidence for these two mechanisms of parasite elimination was detected by both light and electron microscopy. The evolution of the pathology of the lesions was followed by rebiopsy when the lesion had regressed in size under antileishmanial therapy.


A mouse model for Glut-1 haploinsufficiency.
Glut-1 deficiency syndrome (Glut-1 DS, OMIM #606777) is characterized by infantile seizures, developmental delay, acquired microcephaly and hypoglycorrhachia. It is caused by haploinsufficiency of the blood-brain barrier hexose carrier. Heterozygous mutations or hemizygosity of the GLUT-1 gene cause Glut-1 DS. We generated a heterozygous haploinsufficient mouse model by targeted disruption of the promoter and exon 1 regions of the mouse GLUT-1 gene. GLUT-1+/- mice have epileptiform discharges on electroencephalography (EEG), impaired motor activity, incoordination, hypoglycorrhachia, microencephaly, decreased brain glucose uptake as measured by positron emission tomography (PET) scan and decreased brain Glut-1 expression by western blot (66%). The GLUT-1+/- murine phenotype mimics the classical human presentation of Glut-1 DS. This GLUT-1+/- mouse model creates an opportunity to investigate Glut-1 function, to examine the pathophysiology of Glut-1 DS in vivo and to evaluate new treatment strategies.


Assessing the therapeutic efficacy of oxime therapies against percutaneous organophosphorus pesticide and nerve agent challenges in the Hartley guinea pig.
Given the rapid onset of symptoms from intoxication by organophosphate (OP) compounds, a quick-acting, efficacious therapeutic regimen is needed. A primary component of anti-OP therapy is an oxime reactivator to rescue OP-inhibited acetylcholinesterases. Male guinea pigs, clipped of hair, received neat applications of either VR, VX, parathion, or phorate oxon (PHO) at the 85(th) percentile lethal dose, and, beginning with presentation of toxicosis, received the human equivalent dose therapy by intramuscular injection with two additional follow-on treatments at 3-hr intervals. Each therapy consisted of atropine free base at 0.4 mg/kg followed by one of eight candidate oximes. Lethality rates were obtained at 24 hr after VR, VX and PHO challenges, and at 48 hr after challenge with parathion. Lethality rates among symptomatic, oxime-treated groups were compared with that of positive control (OP-challenged and atropine-only treated) guinea pigs composited across the test days. Significant (p ≤ 0.05) protective therapy was afforded by 1,1-methylene bis(4(hydroxyimino- methyl)pyridinium) dimethanesulfonate (MMB4 DMS) against challenges of VR (p ≤ 0.001) and VX (p ≤ 0.05). Lethal effects of VX were also significantly (p ≤ 0.05) mitigated by treatments with oxo-[[1-[[4-(oxoazaniumylmethylidene)pyridin-1-yl]methoxymethyl]pyridin-4-ylidene]methyl]azanium dichloride (obidoxime Cl2) and 1-(((4-(aminocarbonyl) pyridinio)methoxy)methyl)-2,4-bis((hydroxyimino)methyl)pyridinium dimethanesulfonate (HLö-7 DMS). Against parathion, significant protective therapy was afforded by obidoxime dichloride (p ≤ 0.001) and 1,1'-propane-1,3-diylbis{4-[(E)-(hydroxyimino)methyl]pyridinium} dibromide (TMB-4, p ≤ 0.01). None of the oximes evaluated was therapeutically effective against PHO. Across the spectrum of OP chemicals tested, the oximes that offered the highest level of therapy were MMB4 DMS and obidoxime dichloride.


Beyond verbal fluency: investigating the long-term effects of bilateral subthalamic (STN) deep brain stimulation (DBS) on language function in two cases.
Cognitive functioning has been described as largely impervious to chronic STN-DBS administered over 12-month periods. In relation to the domain of language, however, the effects of STN-DBS are yet to be thoroughly delineated. Verbal fluency tasks represent an almost exclusively applied index of linguistic proficiency relative to neuropsychological research within this population. Comprehensive investigations of the impact of STN-DBS on language function, however, have never been undertaken. The more precise elucidation of the role of the STN in the mediation of language processes, by way of assessments which probe language comprehension and production mechanisms, served as the primary focus of this research. Longitudinal analysis also afforded consideration of the way in which cognitive-linguistic circuits respond to STN-DBS over time. Bilateral STN-DBS primarily effected clinically reliable fluctuations (i.e., both improvements and declines) in performance in both subjects on tasks demanding cognitive-linguistic flexibility in the formulation and comprehension of complex language. Of particular note, both subjects demonstrated a cumulative increase in the proportion of reliable post-operative improvements achieved over time. The findings of this research lend support to models of subcortical participation in language which endorse a role for the STN, and suggest that bilateral STN-DBS may serve to enhance the proficiency of basal ganglia-thalamocortical linguistic circuits over time.


The relationship between social behavior and severity of language impairment.
The Teacher Behavior Rating Scale (C. H. Hart and C. C. Robinson, 1996) was used to compare the withdrawn and sociable behaviors of 41 children with specific language impairment (SLI) and 41 typically developing peers. Three subtypes of withdrawal (reticence, solitary-active, solitary-passive) and 2 subtypes of sociable behavior (prosocial, impulse control/likeability) were examined. Teachers rated children with SLI as exhibiting higher levels of reticence and solitary-passive withdrawal than typical children. Teachers also rated the children with SLI as demonstrating lower levels of both types of sociable behavior than typical children. The group with SLI was then separated into subgroups of children having more severe and less severe language impairment. These groupings did not differ on comparisons involving withdrawn behavior, except that girls with more severe receptive problems demonstrated higher levels of solitary-passive withdrawal than did girls with less severe language problems. Children with less severe receptive language impairment demonstrated higher levels of proficiency on both types of sociable behavior than their peers with more severe impairment. Children with more severe expressive problems also demonstrated poorer prosocial behavior--but not poorer impulse control/likeability--than children with less severe expressive problems.


The biomechanics of osteoarthritis: implications for therapy.
The pathophysiology of osteoarthritis (OA) has been extensively studied. However, the basic approach to therapy, which consists of pain relief and maintenance of function, has not changed for decades. At present, there are no nonsurgical methods that clearly interfere with the natural history of OA or provide prolonged pain palliation. Much of OA disease progression is mediated by aberrant biomechanical forces or through pathologic responses to those forces. As understanding of these mechanisms improves, novel therapeutic approaches are being studied that may provide prolonged reductions in loading of OA joints. These new therapies may ultimately be shown to retard disease progression and palliate pain. This article reviews some of these strategies.


Children's response to parental separation during operation desert storm.
Commonly held attitudes concerning the effects of parental wartime deployment on children have usually been guided by stereotype, rather than scientific data. To determine the effects of Operation Desert Storm on military children and their parents, the authors compared children and families with and without a deployed soldier-parent prior to and during Operation Desert Storm. Three hundred eighty-three children and the remaining caretaking parent completed self- and parent-report instruments concerning child and family functioning and life stressors. Children of deployed and nondeployed personnel were compared cross-sectionally, as well as longitudinally, using data collected prior to any knowledge of Operation Desert Storm. Children of deployed personnel experienced elevated self-reported symptom levels of depression, as did their parents. Likewise, families of deployed personnel reported significantly more intervening stressors, compared with children and families of nondeployed personnel. However, deployment per se rarely provoked pathological levels of symptoms in otherwise healthy children. Generally, the factors shaping differential outcomes among children of deployed personnel do not differ from the variables affecting outcomes of children of nondeployed parents. However, boys and younger children appear to be especially vulnerable to deployment effects, and increased monitoring of these children is warranted. Adequate treatment of children requires treatment of the effects of the deployment on other family members. For children showing more persistent or pervasive psychopathology, factors other than simple deployment should be considered.


The risks we dread: a social circle account.
What makes some risks dreadful? We propose that people are particularly sensitive to threats that could kill the number of people that is similar to the size of a typical human social circle. Although there is some variability in reported sizes of social circles, active contact rarely seems to be maintained with more than about 100 people. The loss of this immediate social group may have had survival consequences in the past and still causes great distress to people today. Therefore we hypothesize that risks that threaten a much larger number of people (e.g., 1000) will not be dreaded more than those that threaten to kill "only" the number of people typical for social circles. We found support for this hypothesis in 9 experiments using different risk scenarios, measurements of fear, and samples from different countries. Fear of risks killing 100 people was higher than fear of risks killing 10 people, but there was no difference in fear of risks killing 100 or 1000 people (Experiments 1-4, 7-9). Also in support of the hypothesis, the median number of deaths that would cause maximum level of fear was 100 (Experiments 5 and 6). These results are not a consequence of lack of differentiation between the numbers 100 and 1000 (Experiments 7 and 8), and are different from the phenomenon of "psychophysical numbing" that occurs in the context of altruistic behavior towards members of other communities rather than in the context of threat to one's own community (Experiment 9). We discuss several possible explanations of these findings. Our results stress the importance of considering social environments when studying people's understanding of and reactions to risks.


Long-term neuroplasticity effects of febrile seizures in the developing brain.
Febrile seizures (FS) are the most common seizure disorder in childhood, occurring in 2%-5% of children. Regarding the large number of children with FS, it is important to delineate whether early-life FS alters long-term neuroplasticity, especially the neurocognitive function and subsequent temporal lobe epilepsy (TLE). Recent epidemiological studies reassure that most FS do not adversely affect global intelligence and hippocampal function, such as memory. However, there are concerns regarding those children who experience FS during the first postnatal year, having prior developmental delay and pre- or peri-natal events. The epidemiological data do not support a causal relationship between FS and TLE. However, magnetic resonance imaging studies confirmed that prolonged and focal FS can occasionally produce acute hippocampal injury that evolves into atrophy. Moreover, the common coexistence of hippocampal sclerosis and asymmetric cortical dysgenesis in TLE patients argues for a 'double-hit' theory for TLE. Animal studies have revealed that the exposure of hippocampal neurons to FS early in life, particularly prolonged or frequently repetitive FS, or together with brain malformation, may lead to sustained dysfunction of these cells including long-term memory impairment or epileptogenesis, in spite of the absence of neuronal damage. Recent clinical and molecular genetic studies suggest that the relationship between FS and later epilepsy is frequently genetic, and there are a number of syndrome-specific genes for FS. However, these channelopathies account for a small proportion of FS cases. The clinical management, therefore, is based mainly on the phenotypic features of FS and the subsequent seizures.


Efficient entanglement criteria beyond Gaussian limits using Gaussian measurements.
We present a formalism to derive entanglement criteria beyond the Gaussian regime that can be readily tested by only homodyne detection. The measured observable is the Einstein-Podolsky-Rosen (EPR) correlation. Its arbitrary functional form enables us to detect non-Gaussian entanglement even when an entanglement test based on second-order moments fails. We illustrate the power of our experimentally friendly criteria for a broad class of non-Gaussian states under realistic conditions. We also show rigorously that quantum teleportation for continuous variables employs a specific functional form of EPR correlation.


Catabolism of 3'-azido-3'-deoxythymidine in hepatocytes and liver microsomes, with evidence of formation of 3'-amino-3'-deoxythymidine, a highly toxic catabolite for human bone marrow cells.
Metabolic studies in humans have demonstrated that 3'-azido-3'-deoxythymidine (AZT) is primarily eliminated as its 5'-O-glucuronide (GAZT). However, no detailed cellular metabolic studies have been reported on the complete catabolic fate of AZT at the hepatic site. Because the liver is probably the major site of AZT catabolism, the metabolism and transmembrane distribution of AZT were evaluated in freshly isolated rat hepatocytes, a model for the study at the cellular level of biosynthetic, catabolic, and transport phenomena in the liver. Following exposure of cells to 10 microM [3H]AZT, the predominant intracellular catabolite was GAZT, which reached a concentration of approximately 22 microM by 60 min. Additionally, under nonreducing conditions substantial levels of two previously unidentified AZT catabolites that were formed at the hepatic site and were distinct from any known anabolites or catabolites were also detected. These catabolites were identified as 3'-amino-3'-deoxythymidine (AMT) by fast atom bombardment mass spectrometry and 3'-amino-3'-deoxythymidine glucuronide (GAMT) through specific enzymatic hydrolysis. However, AMT was not a substrate for uridine 5'-diphosphoglucuronyltransferase and GAMT was found to be a reductive product of GAZT. Studies using rat and human liver microsomes demonstrated that the rate of formation of AMT and GAMT increased in the presence of NADPH, suggesting the involvement of a NADPH-dependent enzyme system. Studies using human hematopoietic progenitor cells demonstrated that AMT was 5- to 7-fold more toxic to human colony-forming units granulocyte-macrophage and burst-forming units erythroid than was AZT. This study provides the first detailed catabolic profile of AZT at the hepatic site and emphasizes the critical role that the liver plays in drug clearance. Formation of AMT, a highly toxic catabolite of AZT, raises a question regarding the role of AMT in the cytotoxic effects of AZT observed in patients.


Developing the concept of caring in nursing education.
Caring is a value-based concept in the nursing field and in education. Exact understanding of caring in education and developing this concept in nursing will result in the evolution of the position of nursing science and profession. The aim of this study was to attempt to develop the concept of caring in nursing education. This qualitative study was conducted in 2016 using directed content analysis. Participants were thirteen subjects (6 instructors and 7 senior and junior nursing students) who were selected using purposeful sampling method. Research environment was the Faculty of Nursing and Midwifery in Mashhad. Data collection method was semi-structured interviews for thirty to ninety minutes and sampling continued until data saturation. Interviews were conducted in Persian language and they were immediately transcribed and analyzed using MAXDA10 software. The text of interviews was reviewed several times. First, open codes were extracted, and after several reviews based on similarity in meaning, they were classified into subcategories and finally, similar subcategories were placed in main classes based on meaning. Results of this study led to the identification of four themes: 1, ethical and religious commitment, 2, development of knowing and cultural sensitivity, 3, soft assertion, 4, clear describing of objectives, expectations, and educational rules for students. Results of this study showed that the cultural and religious background of instructors affects their interaction with students. Instructors' commitment and compliance to values in interacting with students and other educational colleagues has an origin beyond ethical and human subjects and it is originated from their religious education and training.


The use of chemical actinometry for the evaluation of the light absorption efficiency in scattering photopolymerizable miniemulsions.
Oil-in-water miniemulsions containing a mixture of monomers as the dispersed organic phase have been shown recently to be promising media for the development of photoinitiated polymerization processes. Albeit a crucial factor for a successful application, the efficiency of light absorption by the photoinitiator in these highly scattering systems is difficult to evaluate. In this work, a well-characterized water insoluble chemical actinometer (DFIS) replaced the oil-soluble photoinitiator, and was used as a probe and a model for UV light absorption in miniemulsions of variable droplet sizes and organic phase compositions (i.e. at different levels of scattered light). In the first step, the photon flux absorbed by the actinometer was determined in model miniemulsions based on an inert solvent (ethyl acetate), at a low oil phase content (3.0-6.0 wt%). For these low to moderately scattering systems, the photon flux absorbed by the actinometer in the miniemulsions was comparable to that in a homogeneous solution of ethyl acetate. In the second step, the absorbed photon flux was investigated in photopolymerizable miniemulsions (a mixture of acrylate monomers as oil phase). Surprisingly, in spite of much higher scattering coefficients than those found for ethyl acetate based miniemulsions of otherwise the same composition, the photon flux absorbed by the actinometer in photopolymerizable miniemulsions showed only a small decreasing trend. Such a result may be considered favorable for the further development of applications of photopolymerizations in miniemulsions.


Acceptability and effectiveness of a strategy for the communication of the diagnosis of psychogenic nonepileptic seizures.
Communicating the diagnosis of psychogenic nonepileptic seizures (PNES) is a challenging task. This study was carried out to assess the acceptability and effectiveness of a new communication procedure consisting of a patient information leaflet and a communication strategy for neurologists. In a multicenter prospective study, 50 patients newly diagnosed with PNES were informed about the diagnosis by 10 different neurologists using the communication procedure. Follow-up data were gathered by telephone interview and completion of a questionnaire about symptom attributions (psychological/physical) and illness cognitions (Illness Perception Questionnaire-Revised, IPQ-R). Ninety-four percent of patients found the leaflet easy to understand. Ninety-four percent stated their questions were answered by the doctor; 70% got what they wanted from the consultation; only 4% reported feeling angry during the consultation. Eighty-six percent of patients acknowledged that psychological factors were at least contributing to their seizures. On the IPQ-R, "emotional" causes for the seizures were endorsed more commonly than "nonemotional" causes (p < 0.001). After 3 months, 14% of patients were seizure-free and 63% reported a >50% reduction in seizure frequency. We conclude that our procedure is acceptable and effectively communicates a psychological etiologic model for PNES.


5-HT1A-receptor agonist modified amygdala activity and amygdala-associated social behavior in a valproate-induced rat autism model.
Accumulating evidence suggests that dysfunction of the amygdala is related to abnormal fear processing, anxiety, and social behaviors noted in autistic spectrum disorders (ASDs). In addition, studies have shown that disrupted brain serotonin homeostasis is linked to ASD. With a valproate (VPA)-induced rat ASD model, we investigated the possible role of amygdala serotonin homeostasis in autistic phenotypes and further explored the underlying mechanism. We first discovered that the distribution of tryptophan hydroxylase immunoreactivity in the caudal raphe system was modulated on postnatal day (PD) 28 of the VPA-exposed offspring. Then, we found a significantly higher serotonin transporter availability in the amygdala of the VPA-exposed offspring on PD 56 by using single photon emission computed tomography and computed tomography co-registration following injection of (123)I-labeled 2-((2-(dimethylamino)methyl)phenyl)thio)-5-iodophenylamine((123)I[ADAM]). Furthermore, treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, increased social interaction and improved fear memory extinction in the VPA-exposed offspring. 8-OH-DPAT treatment also reversed the characteristics of miniature excitatory post-synaptic currents as well as paired pulse facilitation observed in lateral amygdala slices. These results provided further evidence to support the role of the amygdala in characteristic behavioral changes in the rat ASD model. The serotonergic projections that modulate the amygdala function might play a certain role in the development and treatment of behavioral symptoms exhibited in individuals with ASD.


Impact of a well-organized collaborative team approach on mortality in patients with ST-segment elevation myocardial infarction.
Fibrinolytic therapy remains a legitimate option for many patients presenting with acute ST-segment elevation myocardial infarction (STEMI). Shorter time- to- treatment for patients with STEMI administered fibrinolytic therapy has repeatedly been shown to reduce mortality. A well-organized collaborative team approach was implemented in April 2007. The purpose of this study was to examine the effect of implementing a well-organized collaborative team approach on the outcome in patients with acute STEMI treated with fibrinolysis. Sociodemographic, clinical, laboratory, and time interval data were prospectively collected on 109 consecutive patients (the study group) and 155 patients from the years 2005-2007 (the control group) retrospectively. A single-phone call was made to discuss case. Emergency department evaluation was bypassed for definitive case. An electrocardiogram was faxed to the on-call cardiologist for suspected case. Door-to-needle times were calculated as medians. Mortality was assessed by reviewing records of all patients visiting outpatient clinic. For the rest, information was obtained over the phone. Median door-to-needle times were compared using Mann-Whitney U test. The Fisher's exact test was used to compare 6-month mortalities. Improvements were seen in door-to- needle times in the study group regardless of time of presentation (reduced from 59 minutes to 29 minutes during off hours) (reduced from 35 minutes to 18 minutes during regular hours) (p<0.0001). Mortality was significantly reduced in the study group (2 deaths, 1.8%) compared with the control group (12 deaths, 7.7%, p=0.048). The mortality of patients presenting with acute STEMI treated with fibrinolytic therapy was significantly reduced after optimal hospital organization.


Addressing Climate Change Mitigation and Adaptation Together: A Global Assessment of Agriculture and Forestry Projects.
Adaptation and mitigation share the ultimate purpose of reducing climate change impacts. However, they tend to be considered separately in projects and policies because of their different objectives and scales. Agriculture and forestry are related to both adaptation and mitigation: they contribute to greenhouse gas emissions and removals, are vulnerable to climate variations, and form part of adaptive strategies for rural livelihoods. We assessed how climate change project design documents (PDDs) considered a joint contribution to adaptation and mitigation in forestry and agriculture in the tropics, by analyzing 201 PDDs from adaptation funds, mitigation instruments, and project standards [e.g., climate community and biodiversity (CCB)]. We analyzed whether PDDs established for one goal reported an explicit contribution to the other (i.e., whether mitigation PDDs contributed to adaptation and vice versa). We also examined whether the proposed activities or expected outcomes allowed for potential contributions to the two goals. Despite the separation between the two goals in international and national institutions, 37% of the PDDs explicitly mentioned a contribution to the other objective, although only half of those substantiated it. In addition, most adaptation (90%) and all mitigation PDDs could potentially report a contribution to at least partially to the other goal. Some adaptation project developers were interested in mitigation for the prospect of carbon funding, whereas mitigation project developers integrated adaptation to achieve greater long-term sustainability or to attain CCB certification. International and national institutions can provide incentives for projects to harness synergies and avoid trade-offs between adaptation and mitigation.


Metagenomic to evaluate norovirus genomic diversity in oysters: Impact on hexamer selection and targeted capture-based enrichment.
Human virus transmission through food consumption has been identified since many years and the international trade increases the risk of dissemination of viral pathogens. The development of metagenomic approach holds many promises for the surveillance of viruses in food and water. This work aimed to analyze norovirus diversity and to evaluate strain-dependent accumulation patterns in three oyster types by using a metagenomic approach. Different hexamer sets to prime cDNA were evaluated before capture-based approach to enhance virus reads recovery during deep sequencing. The study includes the use of technical replicates of artificially contaminated oysters and the analysis of multiple negatives controls. Results showed a clear impact of the hexamer set used for cDNA synthesis. A set of In-house designed (I-HD) hexamers, selected to lower mollusk amplification, gave promising results in terms of viral reads abundancy. However, the best correlation between CT values, thus concentrations, and number of reads was observed using random hexamers. Random hexamers also provided the highest numbers of reads and allowed the identification of sequence of different human enteric viruses. Regarding human norovirus, different genogroups and genotypes were identified among contigs longer than 500 bp. Two full genomes and six sequences longer than 3600 bases were obtained allowing a precise strain identification. The use of technical triplicates was found valuable to increase the chances to sequence viral strains present at low concentrations. Analyzing viral contamination in shellfish samples is quite challenging, however this work demonstrates that the recovery of full genome or long contigs, allowing clear identification of viral strains is possible.


Storm Event Suspended Sediment-Discharge Hysteresis and Controls in Agricultural Watersheds: Implications for Watershed Scale Sediment Management.
Within agricultural watersheds suspended sediment-discharge hysteresis during storm events is commonly used to indicate dominant sediment sources and pathways. However, availability of high-resolution data, qualitative metrics, longevity of records, and simultaneous multiwatershed analyses has limited the efficacy of hysteresis as a sediment management tool. This two year study utilizes a quantitative hysteresis index from high-resolution suspended sediment and discharge data to assess fluctuations in sediment source location, delivery mechanisms and export efficiency in three intensively farmed watersheds during events over time. Flow-weighted event sediment export was further considered using multivariate techniques to delineate rainfall, stream hydrology, and antecedent moisture controls on sediment origins. Watersheds with low permeability (moderately- or poorly drained soils) with good surface hydrological connectivity, therefore, had contrasting hysteresis due to source location (hillslope versus channel bank). The well-drained watershed with reduced connectivity exported less sediment but, when watershed connectivity was established, the largest event sediment load of all watersheds occurred. Event sediment export was elevated in arable watersheds when low groundcover was coupled with high connectivity, whereas in the grassland watershed, export was attributed to wetter weather only. Hysteresis analysis successfully indicated contrasting seasonality, connectivity and source availability and is a useful tool to identify watershed specific sediment management practices.


Borrelia in granuloma annulare, morphea and lichen sclerosus: a PCR-based study and review of the literature.
Morphea, granuloma annulare (GA) and lichen sclerosus et atrophicans (LSA) have also been suggested to be linked to Borrelia infection. Previous studies based on serologic data or detection of Borrelia by immunohistochemistry and polymerase chain reaction (PCR) reported contradictory results. Thus, we examined skin biopsies of morphea, GA and LSA by PCR to assess the prevalence of Borrelia DNA in an endemic area and to compare our results with data in the literature. Amplification of DNA sequences of Borrelia burgdorferi sensu lato by nested PCR from formalin-fixed and paraffin-embedded skin biopsies of morphea, GA and LSA, followed by automated sequencing of amplification products. PCR-based studies on Borrelia species in these disorders published until July 2009 were retrieved by a literature search. Borrelia DNA was detected in 3 of 112 skin biopsies (2.7%) including one of 49 morphea biopsies (2.0%), one of 48 GA biopsies (2.1%) and one of 15 LSA biopsies (6.6%). Amplification products belonged to B. burgdorferi sensu stricto in two cases available for sequence analysis. The results of our and most of other PCR-based studies do not argue for a significant association of B. burgdorferi sensu lato with morphea, GA, LSA.


Climate change threatens polar bear populations: a stochastic demographic analysis.
The polar bear (Ursus maritimus) depends on sea ice for feeding, breeding, and movement. Significant reductions in Arctic sea ice are forecast to continue because of climate warming. We evaluated the impacts of climate change on polar bears in the southern Beaufort Sea by means of a demographic analysis, combining deterministic, stochastic, environment-dependent matrix population models with forecasts of future sea ice conditions from IPCC general circulation models (GCMs). The matrix population models classified individuals by age and breeding status; mothers and dependent cubs were treated as units. Parameter estimates were obtained from a capture-recapture study conducted from 2001 to 2006. Candidate statistical models allowed vital rates to vary with time and as functions of a sea ice covariate. Model averaging was used to produce the vital rate estimates, and a parametric bootstrap procedure was used to quantify model selection and parameter estimation uncertainty. Deterministic models projected population growth in years with more extensive ice coverage (2001-2003) and population decline in years with less ice coverage (2004-2005). LTRE (life table response experiment) analysis showed that the reduction in lambda in years with low sea ice was due primarily to reduced adult female survival, and secondarily to reduced breeding. A stochastic model with two environmental states, good and poor sea ice conditions, projected a declining stochastic growth rate, log lambdas, as the frequency of poor ice years increased. The observed frequency of poor ice years since 1979 would imply log lambdas approximately - 0.01, which agrees with available (albeit crude) observations of population size. The stochastic model was linked to a set of 10 GCMs compiled by the IPCC; the models were chosen for their ability to reproduce historical observations of sea ice and were forced with "business as usual" (A1B) greenhouse gas emissions. The resulting stochastic population projections showed drastic declines in the polar bear population by the end of the 21st century. These projections were instrumental in the decision to list the polar bear as a threatened species under the U.S. Endangered Species Act.