Electrochemical paper-based devices: sensing approaches and progress toward practical applications.
Paper-based sensors offer an affordable yet powerful platform for field and point-of-care (POC) testing due to their self-pumping ability and utility for many different analytical measurements. When combined with electrochemical detection using small and portable electronics, sensitivity and selectivity of the paper devices can be improved over naked eye detection without sacrificing portability. Herein, we review how the field of electrochemical paper-based analytical devices (ePADs) has grown since it was introduced a decade ago. We start by reviewing fabrication methods relevant to ePADs with more focus given to the electrode fabrication, which is fundamental for electrochemical sensing. Multiple sensing approaches applicable to ePADs are then discussed and evaluated to present applicability, advantages and challenges associated with each approach. Recent applications of ePADs in the fields of clinical diagnostics, environmental testing, and food analysis are also presented. Finally, we discuss how the current ePAD technologies have progressed to meet the analytical and practical specifications required for field and/or POC applications, as well as challenges and outlook.


Hydrocarbonoclastic Alcanivorax Isolates Exhibit Different Physiological and Expression Responses to n-dodecane.
Autochthonous microorganisms inhabiting hydrocarbon polluted marine environments play a fundamental role in natural attenuation and constitute promising resources for bioremediation approaches. Alcanivorax spp. members are ubiquitous in contaminated surface waters and are the first to flourish on a wide range of alkanes after an oil-spill. Following oil contamination, a transient community of different Alcanivorax spp. develop, but whether they use a similar physiological, cellular and transcriptomic response to hydrocarbon substrates is unknown. In order to identify which cellular mechanisms are implicated in alkane degradation, we investigated the response of two isolates belonging to different Alcanivorax species, A. dieselolei KS 293 and A. borkumensis SK2 growing on n-dodecane (C12) or on pyruvate. Both strains were equally able to grow on C12 but they activated different strategies to exploit it as carbon and energy source. The membrane morphology and hydrophobicity of SK2 changed remarkably, from neat and hydrophilic on pyruvate to indented and hydrophobic on C12, while no changes were observed in KS 293. In addition, SK2 accumulated a massive amount of intracellular grains when growing on pyruvate, which might constitute a carbon reservoir. Furthermore, SK2 significantly decreased medium surface tension with respect to KS 293 when growing on C12, as a putative result of higher production of biosurfactants. The transcriptomic responses of the two isolates were also highly different. KS 293 changes were relatively balanced when growing on C12 with respect to pyruvate, giving almost the same amount of upregulated (28%), downregulated (37%) and equally regulated (36%) genes, while SK2 transcription was upregulated for most of the genes (81%) when growing on pyruvate when compared to C12. While both strains, having similar genomic background in genes related to hydrocarbon metabolism, retained the same capability to grow on C12, they nevertheless presented very different physiological, cellular and transcriptomic landscapes.


Relationship Between Depression and Stress Coping Ability Among Residents in Japan: A Two-Year Longitudinal Study.
Depression among medical residents is a critical issue. The early detection of depression and provision of appropriate care is necessary for fostering healthy conditions during clinical training. To investigate whether Sense of Coherence (SOC), an indicator of stress coping ability, could be a predictor of depression 2 years after the start of clinical training, we conducted a national longitudinal study. We distributed self-administered questionnaires to residents in 251 postgraduate educational hospitals just before the start of their clinical training. The questionnaire contained the Center for Epidemiologic Studies Depression (CES-D) scale (a screening tool for depression), the SOC scale, and demographic factors. After 2 years, we distributed questionnaires to residents who responded to the first survey. The second questionnaire contained the CES-D scale and questions about working conditions. We categorized respondents into three groups according to their SOC score and analyzed the relationship between SOC groups (low, middle, high) and depressive symptoms on the follow-up survey. In total, 1,738 of 2,935 residents (59.2%) responded to the first survey. Of these, 1,169 residents (67.3%) also responded to the follow-up survey. A total of 169 residents were excluded because they screened positive for depressive symptoms at the time of the first survey. On the follow-up survey, 187 residents (19.5%) had new-onset depressive symptoms: 33.3% in the low SOC group, 18.2% in the middle SOC group, and 11.4% in the high SOC group (P < 0.01). Compared with the high SOC group, the odds ratio for new-onset depressive symptoms in the low SOC group was 2.04 (95% confidence interval, 1.02 - 4.05) after adjusting for demographic factors, baseline CES-D score, and mean working time. SOC score is significantly associated with future depressive symptoms among residents after 2 years. Residents in the low SOC group had a 2-fold higher risk of future depressive symptoms than those in the high SOC group. The SOC scale might be a useful predictor of future depression and allow for the provision of appropriate support to residents during clinical training.


Genomic and physiological responses to strong selective pressure during late organogenesis: few gene expression changes found despite striking morphological differences.
Adaptations to a new environment, such as a polluted one, often involve large modifications of the existing phenotypes. Changes in gene expression and regulation during critical developmental stages may explain these phenotypic changes. Embryos from a population of the teleost fish, Fundulus heteroclitus, inhabiting a clean estuary do not survive when exposed to sediment extract from a site highly contaminated with polycyclic aromatic hydrocarbons (PAHs) while embryos derived from a population inhabiting a PAH polluted estuary are remarkably resistant to the polluted sediment extract. We exposed embryos from these two populations to surrogate model PAHs and analyzed changes in gene expression, morphology, and cardiac physiology in order to better understand sensitivity and adaptive resistance mechanisms mediating PAH exposure during development. The synergistic effects of two model PAHs, an aryl hydrocarbon receptor (AHR) agonist (β-naphthoflavone) and a cytochrome P4501A (CYP1A) inhibitor (α-naphthoflavone), caused significant developmental delays, impaired cardiac function, severe morphological alterations and failure to hatch, leading to the deaths of reference embryos; resistant embryos were mostly unaffected. Unexpectedly, patterns of gene expression among normal and moderately deformed embryos were similar, and only severely deformed embryos showed a contrasting pattern of gene expression. Given the drastic morphological differences between reference and resistant embryos, a surprisingly low percentage of genes, 2.24% of 6,754 analyzed, show statistically significant differences in transcript levels during late organogenesis between the two embryo populations. Our study demonstrates important contrasts in responses between reference and resistant natural embryo populations to synergistic effects of surrogate model PAHs that may be important in adaptive mechanisms mediating PAH effects during fish embryo development. These results suggest that statistically significant changes in gene expression of relatively few genes contribute to the phenotypic changes and large morphological differences exhibited by reference and resistant populations upon exposure to PAH pollutants. By correlating cardiac physiology and morphology with changes in gene expression patterns of reference and resistant embryos, we provide additional evidence for acquired resistance among embryos whose parents live at heavily contaminated sites.


In vitro evaluation of novel titania-containing borate bioactive glass scaffolds.
Titanium-containing borate bioactive glass scaffolds (0, 5, 15, and 20 mol %, identified as BRT0, BRT1, BRT3, and BRT4) with a microstructure similar to that of human trabecular bone were prepared and evaluated in vitro for potential bone loss applications in revision total knee arthroplasty (rTKA). Methyl thiazolyl tetrazolium (MTT) cell viability assays of scaffold ion release extracts revealed that BRT0 scaffolds (0 mol % titanium) inhibited cell proliferation and activity at day 14. At day 30, all scaffold extracts decreased cell proliferation and activity significantly. However, live/dead cell assay results demonstrated that degradation products from all the scaffolds had no inhibitory effect on cell viability. Significant bactericidal efficacies of BRT3 extracts against Escherishia coli (Gram-negative) and BRT1 extracts against Staphylococcus aureus and Staphylococcus epidermidis (both Gram-positive bacteria) were demonstrated. Finally, evaluation of the cell/bioactive glass surface interactions showed well-spread cells on the surface of the BRT3 glass discs and BRT1 and BRT3 scaffolds, when compared to BRT0 and BRT4 scaffolds. The results indicate that by changing the Ti4+ :B3+ ratio, the ion release and consequently cell proliferation could be improved. in vitro results in this study demonstrate that BRT3 scaffolds could be a promising candidate for addressing bone loss in rTKAs; however, in vivo studies would be required to evaluate the effect of a dynamic environment on the cell and tissue response to the fabricated scaffolds.


Preliminary evaluation of urinary soluble Met as a biomarker for urothelial carcinoma of the bladder.
Among genitourinary malignancies, bladder cancer (BCa) ranks second in both prevalence and cause of death. Biomarkers of BCa for diagnosis, prognosis and disease surveillance could potentially help prevent progression, improve survival rates and reduce health care costs. Among several oncogenic signaling pathways implicated in BCa progression is that of hepatocyte growth factor (HGF) and its cell surface receptor, Met, now targeted by 25 experimental anti-cancer agents in human clinical trials. The involvement of this pathway in several cancers is likely to preclude the use of urinary soluble Met (sMet), which has been correlated with malignancy, for initial BCa screening. However, its potential utility as an aid to disease surveillance and to identify patients likely to benefit from HGF/Met-targeted therapies provide the rationale for this preliminary retrospective study comparing sMet levels between benign conditions and primary BCa, and in BCa cases, between different disease stages. Normally voided urine samples were collected from patients with BCa (Total: 183; pTa: 55, pTis: 62, pT1: 24, pT2: 42) and without BCa (Total: 83) on tissue-procurement protocols at three institutions and sMet was measured and normalized to urinary creatinine. Normalized sMet values grouped by pathologic stage were compared using non-parametric tests for correlation and significant difference. ROC analyses were used to derive classification models for patients with or without BCa and patients with or without muscle-invasive BCa (MIBCa or NMIBCa). Urinary sMet levels accurately distinguished patients with BCa from those without (p<0.0001, area under the curve (AUC): 0.7008) with limited sensitivity (61%) and moderate specificity (76%), and patients with MIBCa (n=42) from those with NMIBCa (n=141; p<0.0001, AUC: 0.8002) with moderate sensitivity and specificity (76% and 77%, respectively) and low false negative rate (8%). Urinary sMet levels distinguish patients with BCa from those without, and patients with or without MIBCa, suggesting the potential utility of urinary sMet as a BCa biomarker for surveillance following initial treatment. Further studies are warranted to determine its potential value for prognosis in advanced disease, predicting treatment response, or identifying patients likely to benefit from Met-targeted therapies.


Impact of a synthetic cannabinoid (CP-47,497-C8) on protein expression in human cells: evidence for induction of inflammation and DNA damage.
Synthetic cannabinoids (SCs) are marketed worldwide as legal surrogates for marihuana. In order to predict potential health effects in consumers and to elucidate the underlying mechanisms of action, we investigated the impact of a representative of the cyclohexylphenols, CP47,497-C8, which binds to both cannabinoid receptors, on protein expression patterns, genomic stability and on induction of inflammatory cytokines in human lymphocytes. After treatment of the cells with the drug, we found pronounced up-regulation of a variety of enzymes in nuclear extracts which are involved in lipid metabolism and inflammatory signaling; some of the identified proteins are also involved in the endogenous synthesis of endocannabinoids. The assumption that the drug causes inflammation is further supported by results obtained in additional experiments with cytosols of LPS-stimulated lymphocytes which showed that the SC induces pro-inflammatory cytokines (IL12p40 and IL-6) as well as TNF-α. Furthermore, the proteome analyses revealed that the drug causes down-regulation of proteins which are involved in DNA repair. This observation provides an explanation for the formation of comets which was seen in single-cell gel electrophoresis assays and for the induction of micronuclei (which reflect structural and numerical chromosomal aberrations) by the drug. These effects were seen in experiments with human lymphocytes which were conducted under identical conditions as the proteome analysis. Taken together, the present findings indicate that the drug (and possibly other structurally related SCs) may cause DNA damage and inflammation in directly exposed cells of consumers.


The problem of auto-correlation in parasitology.
Explaining the contribution of host and pathogen factors in driving infection dynamics is a major ambition in parasitology. There is increasing recognition that analyses based on single summary measures of an infection (e.g., peak parasitaemia) do not adequately capture infection dynamics and so, the appropriate use of statistical techniques to analyse dynamics is necessary to understand infections and, ultimately, control parasites. However, the complexities of within-host environments mean that tracking and analysing pathogen dynamics within infections and among hosts poses considerable statistical challenges. Simple statistical models make assumptions that will rarely be satisfied in data collected on host and parasite parameters. In particular, model residuals (unexplained variance in the data) should not be correlated in time or space. Here we demonstrate how failure to account for such correlations can result in incorrect biological inference from statistical analysis. We then show how mixed effects models can be used as a powerful tool to analyse such repeated measures data in the hope that this will encourage better statistical practices in parasitology.


COVID-19: Uncertainties from Conception to Birth.
Scientific information on the impact of the new coronavirus (SARS-CoV-2) on the health of pregnant women, fetuses and newborns is considered of limited confidence, lacking good-quality evidence, and drawing biased conclusions. As a matter of fact, the initial impressions that the evolution of COVID-19 was no different between pregnant and non-pregnant women, and that SARS-CoV-2 was not vertically transmitted, are confronted by the documentation of worsening of the disease during pregnancy, poor obstetric outcomes, and the possibility of vertical transmission. The present article aims to compile the data available on the association of COVID-19 and reproductive events, from conception to birth.


Liquid-phase decomposition mechanism for bis(triaminoguanidinium) azotetrazolate (TAGzT).
This work provides new insights for the liquid-phase decomposition of bis(triaminoguanidinium) azotetrazolate (TAGzT). The liquid-phase decomposition process was investigated using a combined experimental and computational approach. Sub-milligram samples of TAGzT were heated at rates of about 2000 K s-1 to a set temperature (230 to 260 °C) where liquid-phase decomposition occurred under isothermal conditions. Fourier transform infrared (FTIR) spectroscopy and time-of-flight mass spectrometry (ToFMS) were used to acquire transmittance spectra and mass spectra of the evolved gas-phase species from the rapid thermolysis, respectively. FTIR spectroscopy was also used to acquire the transmittance spectra of the condensate and residue formed from the decomposition. N2, NH3, HCN, N2H4, triaminoguanidine and 3-azido-1,2,4-triazol-4-ide anion were identified as products of liquid-phase decomposition. Quantum chemical calculations were used for confirming the identity of the species observed in experiments and for identifying elementary chemical reactions that formed these species. Based on the calculated free energy barriers of these elementary reactions, important reaction pathways were identified for the formation of each of the product species.


Radiofrequency ablation of the great saphenous vein in an elderly patient with co-morbid disease.
An 86-year-old male patient with hypertension, Parkinsonism, benign prostatic hyperplasia, cataract and chronic obstructive pulmonary disease had a history of coronary bypass surgery in two veins due to anterior myocardial infarction one year earlier. He presented with pain and feelings of paresthesia below the knee of his left leg, and had fallen twice. He had used compressions and venoprotective medication for two years and had also received physiotherapy but it had not alleviated the symptoms. He had varicose dilatations in the left leg and pigmentation and a recovered venous ulcer scar were present on the medial malleolus. The patient was classed as grade 4 according to the CEAP classification. Because there was no deficiency in the superficial femoral and popliteal veins, the patient was taken for endovenous ablation. He had no pain or sensation of heaviness in the legs on postoperative day 10, and the first, third and sixth months of check up. Endovenous ablation is a procedure that increases the quality of life and comfort in elderly patients, with minimal pain. Radiofrequency catheter procedures have proven to be more successful in patients of all age groups than procedures such as standard surgery and foam therapy.


Promoter diversity in multigene transformation.
Multigene transformation (MGT) is becoming routine in plant biotechnology as researchers seek to generate more complex and ambitious phenotypes in transgenic plants. Every nuclear transgene requires its own promoter, so when coordinated expression is required, the introduction of multiple genes leads inevitably to two opposing strategies: different promoters may be used for each transgene, or the same promoter may be used over and over again. In the former case, there may be a shortage of different promoters with matching activities, but repetitious promoter use may in some cases have a negative impact on transgene stability and expression. Using illustrative case studies, we discuss promoter deployment strategies in transgenic plants that increase the likelihood of successful and stable multiple transgene expression.


GVHD-associated, inflammasome-mediated loss of function in adoptively transferred myeloid-derived suppressor cells.
Myeloid-derived suppressor cells (MDSCs) are a naturally occurring immune regulatory population associated with inhibition of ongoing inflammatory responses. In vitro generation of MDSCs from bone marrow has been shown to enhance survival in an acute model of lethal graft-versus-host disease (GVHD). However, donor MDSC infusion only partially ameliorates GVHD lethality. In order to improve the potential therapeutic benefit and ultimately survival outcomes, we set out to investigate the fate of MDSCs after transfer in the setting of acute GVHD (aGVHD). MDSCs transferred to lethally irradiated recipients of allogeneic donor hematopoietic grafts are exposed to an intense inflammatory environment associated with aGVHD, which we now show directly undermines their suppressive capacity. Under a conditioning regimen and GVHD inflammatory settings, MDSCs rapidly lose suppressor function and their potential to inhibit GVHD lethality, which is associated with their induced conversion toward a mature inflammasome-activated state. We find even brief in vitro exposure to inflammasome-activating mediators negates the suppressive potential of cultured murine and human-derived MDSCs. Consistent with a role for the inflammasome, donor MDSCs deficient in the adaptor ASC (apoptosis-associated speck-like protein containing a CARD), which assembles inflammasome complexes, conferred improved survival of mice developing GVHD compared with wild-type donor MDSCs. These data suggest the use of MDSCs as a therapeutic approach for preventing GVHD and other systemic inflammatory conditions will be more effective when combined with approaches limiting in vivo MDSC inflammasome activation, empowering MDSCs to maintain their suppressive potential.


A Precision Microbiome Approach Using Sucrose for Selective Augmentation of Staphylococcus epidermidis Fermentation against Propionibacterium acnes.
Acne dysbiosis happens when there is a microbial imbalance of the over-growth of Propionibacterium acnes (P. acnes) in the acne microbiome. In our previous study, we demonstrated that Staphylococcus epidermidis (S. epidermidis, a probiotic skin bacterium) can exploit glycerol fermentation to produce short-chain fatty acids (SCFAs) which have antimicrobial activities to suppress the growth of P. acnes. Unlike glycerol, sucrose is chosen here as a selective fermentation initiator (SFI) that can specifically intensify the fermentation activity of S. epidermidis, but not P. acnes. A co-culture of P. acnes and fermenting S. epidermidis in the presence of sucrose significantly led to a reduction in the growth of P. acnes. The reduction was abolished when P. acnes was co-cultured with non-fermenting S. epidermidis. Results from nuclear magnetic resonance (NMR) analysis revealed four SCFAs (acetic acid, butyric acid, lactic acid, and succinic acid) were detectable in the media of S. epidermidis sucrose fermentation. To validate the interference of S. epidermidis sucrose fermentation with P. acnes, mouse ears were injected with both P. acnes and S. epidermidis plus sucrose or phosphate buffered saline (PBS). The level of macrophage-inflammatory protein-2 (MIP-2) and the number of P. acnes in ears injected with two bacteria plus sucrose were considerably lower than those in ears injected with two bacteria plus PBS. Our results demonstrate a precision microbiome approach by using sucrose as a SFI for S. epidermidis, holding future potential as a novel modality to equilibrate dysbiotic acne.


Quantitative variation in plasma angiotensin-I converting enzyme activity shows allelic heterogeneity in the ABO blood group locus.
Angiotensin-I converting enzyme (ACE) occupies a pivotal role in cardiovascular homeostasis. Major loci for plasma ACE have been identified at ACE on Chromosome 17 and at ABO on Chromosome 9. We sought to characterise the genetic architecture of plasma ACE at finer resolution in two populations. We carried out a GWAS in 1810 individuals of Japanese ethnicity; this identified signals at ACE and ABO that together accounted for nearly half of the population variability of the trait. We conducted measured haplotype analysis at the ABO locus in 1425 members of 248 British families using haplotypes of three SNPs, which together tagged the alleles responsible for the principal blood group antigens A1, A2, B and O. Type O alleles were associated with intermediate plasma ACE activity compared to Type A1 alleles (in whom plasma ACE activity was ∼36% lower) and Type B alleles (in whom plasma ACE activity was ∼36% higher). We demonstrated heterogeneity among A alleles: A2 alleles were associated with plasma ACE activity that was very similar to the O alleles. Variation at ACE accounted for 35% of the trait variance, and variation at ABO accounted for 15%. A further 10% could be ascribed to polygenic effects.


Maximizing smoking cessation in clinical practice: pharmacologic and behavioral interventions.
Clinicians are in a unique position to reduce cardiovascular morbidity and mortality by helping their patients quit smoking. At each visit, clinicians should document smoking status, provide strong and clear advice to quit, and recommend and prescribe pharmacotherapy for patients who are motivated to quit, which can double the odds of success. Effective pharmacotherapies include nicotine replacement, bupropion, and varenicline, which was recently approved by the Food and Drug Administration. Behavioral counseling to develop a quit plan and extended follow-up are critical to maximize quit rates but are rarely provided by clinicians due to time constraints and lack of expertise. As an alternative, the authors recommend referral to telephone quitlines that provide no-cost behavioral counseling by specialists. Hospitals should implement systemwide procedures to ensure that smokers are identified at admission and trained staff is available to provide smoking cessation consults that include a minimum of 20 minutes of inpatient counseling with follow-up for at least 1 month.


Restorative justice as social justice for victims of gendered violence: a standpoint feminist perspective.
This article provides an overview of restorative justice as a process and examines its relevance to women who have been victimized by physical and sexual abuse. The starting point is the justice system with its roots in adversarial, offender-oriented practices of obtaining justice. The widespread dissatisfaction by battered women and rape victims and their advocates with the current system of mandatory law enforcement opens the door for consideration of alternative forms of dealing with domestic violence. Restorative justice strategies, as argued here, have several major advantages. Like social work, these strategies are solution-based rather than problem-based processes, give voice to marginalized people, and focus on healing and reconciliation. Moreover, restorative justice offers an avenue through which the profession of social work can re-establish its historic role in criminal justice. The four models most relevant to women's victimization are victim-offender conferencing, family group conferencing, healing circles, and community reparations. Each model is examined separately from a feminist standpoint. The discussion is informed by insights from the teachings of standpoint feminist theory and social work values, especially social justice.


Novel mechanism of gene transfection by low-energy shock wave.
Extracorporeal shock wave (SW) therapy has been studied in the transfection of naked nucleic acids into various cell lines through the process of sonoporation, a process that affects the permeation of cell membranes, which can be an effect of cavitation. In this study, siRNAs were efficiently transfected into primary cultured cells and mouse tumor tissue via SW treatment. Furthermore SW-induced siRNA transfection was not mediated by SW-induced sonoporation, but by microparticles (MPs) secreted from the cells. Interestingly, the transfection effect of the siRNAs was transferable through the secreted MPs from human umbilical vein endothelial cell (HUVEC) culture medium after treatment with SW, into HUVECs in another culture plate without SW treatment. In this study, we suggest for the first time a mechanism of gene transfection induced by low-energy SW through secreted MPs, and show that it is an efficient physical gene transfection method in vitro and represents a safe therapeutic strategy for site-specific gene delivery in vivo.


Feedback control in planarian stem cell systems.
In planarian flatworms, the mechanisms underlying the activity of collectively pluripotent adult stem cells (neoblasts) and their descendants can now be studied from the level of the individual gene to the entire animal. Flatworms maintain startling developmental plasticity and regenerative capacity in response to variable nutrient conditions or injury. We develop a model for cell dynamics in such animals, assuming that fully differentiated cells exert feedback control on neoblast activity. Our model predicts a number of whole organism level and general cell biological and behaviours, some of which have been empirically observed or inferred in planarians and others that have not. As previously observed empirically we find: 1) a curvilinear relationship between external food and planarian steady state size; 2) the fraction of neoblasts in the steady state is constant regardless of planarian size; 3) a burst of controlled apoptosis during regeneration after amputation as the number of differentiated cells are adjusted towards their homeostatic/steady state level. In addition our model describes the following properties that can inform and be tested by future experiments: 4) the strength of feedback control from differentiated cells to neoblasts (i.e. the activity of the signalling system) and from neoblasts on themselves in relation to absolute number depends upon the level of food in the environment; 5) planarians adjust size when food level reduces initially through increased apoptosis and then through a reduction in neoblast self-renewal activity; 6) following wounding or excision of differentiated cells, different time scales characterize both recovery of size and the two feedback functions; 7) the temporal pattern of feedback controls differs noticeably during recovery from a removal or neoblasts or a removal of differentiated cells; 8) the signaling strength for apoptosis of differentiated cells depends upon both the absolute and relative deviations of the number of differentiated cells from their homeostatic level; and 9) planaria prioritize resource use for cell divisions. We offer the first analytical framework for organizing experiments on planarian flatworm stem cell dynamics in a form that allows models to be compared with quantitative cell data based on underlying molecular mechanisms and thus facilitate the interplay between empirical studies and modeling. This framework is the foundation for studying cell migration during wound repair, the determination of homeostatic levels of differentiated cells by natural selection, and stochastic effects.


Morphoanatomical studies of Uncaria tomentosa and Uncaria guianensis bark and leaves.
The genus Uncaria Schreber (Rubiaceae) includes species that are widely distributed in tropical areas. The inner bark of the stems and leaves of two native species of South America, Uncaria tomentosa (Willd. ex Roemer & Schultes) DC., and Uncaria guianensis (Aublet) J. F. Gmelin, "cat's claw" are used in either folk medicine or in procuring phytotherapeutic drugs. These species contain about sixty active substances which are being tested widely for possible medicinal value. The following applications are considered: peptic ulcer, rheumatism, tumours, antiinflammatory effect, inflammation, diabetes and as general tonic. Currently, Uncaria tomentosa is in demand as tea, tablets or capsules in more than 30 countries outside Perú, as well as inside the country. Pharmacognosy studies are required to determine the comparative morphoanatomical and micrographic features for identification and quality control purposes. Several microscopic parameters, including phloem fibers, calcium oxalate crystals, starch granules, trichomes, and foliar architecture should be considered. The aim of our work is to analyse comparative morphoanatomical and micrographic features which might provide assistance in the identification, analysis and standardization of Uncaria tomentosa (Willd. ex Roemer & Schultes) DC. and Uncaria guianensis (Aublet) J. F. Gmelin stem bark and leaves in order to obtain phytotherapeutic drugs, and of the crude drug as well.


Future life expectancy in 35 industrialised countries: projections with a Bayesian model ensemble.
Projections of future mortality and life expectancy are needed to plan for health and social services and pensions. Our aim was to forecast national age-specific mortality and life expectancy using an approach that takes into account the uncertainty related to the choice of forecasting model. We developed an ensemble of 21 forecasting models, all of which probabilistically contributed towards the final projections. We applied this approach to project age-specific mortality to 2030 in 35 industrialised countries with high-quality vital statistics data. We used age-specific death rates to calculate life expectancy at birth and at age 65 years, and probability of dying before age 70 years, with life table methods. Life expectancy is projected to increase in all 35 countries with a probability of at least 65% for women and 85% for men. There is a 90% probability that life expectancy at birth among South Korean women in 2030 will be higher than 86·7 years, the same as the highest worldwide life expectancy in 2012, and a 57% probability that it will be higher than 90 years. Projected female life expectancy in South Korea is followed by those in France, Spain, and Japan. There is a greater than 95% probability that life expectancy at birth among men in South Korea, Australia, and Switzerland will surpass 80 years in 2030, and a greater than 27% probability that it will surpass 85 years. Of the countries studied, the USA, Japan, Sweden, Greece, Macedonia, and Serbia have some of the lowest projected life expectancy gains for both men and women. The female life expectancy advantage over men is likely to shrink by 2030 in every country except Mexico, where female life expectancy is predicted to increase more than male life expectancy, and in Chile, France, and Greece where the two sexes will see similar gains. More than half of the projected gains in life expectancy at birth in women will be due to enhanced longevity above age 65 years. There is more than a 50% probability that by 2030, national female life expectancy will break the 90 year barrier, a level that was deemed unattainable by some at the turn of the 21st century. Our projections show continued increases in longevity, and the need for careful planning for health and social services and pensions. UK Medical Research Council and US Environmental Protection Agency.


A Novel Self-Emulsifying Drug Delivery System (SEDDS) Based on VESIsorb® Formulation Technology Improving the Oral Bioavailability of Cannabidiol in Healthy Subjects.
Cannabidiol (CBD), a phytocannabinoid compound of Cannabis sativa, shows limited oral bioavailability due to its lipophilicity and extensive first-pass metabolism. CBD is also known for its high intra- and inter-subject absorption variability in humans. To overcome these limitations a novel self-emulsifying drug delivery system (SEDDS) based on VESIsorb® formulation technology incorporating CBD, as Hemp-Extract, was developed (SEDDS-CBD). The study objective was to evaluate the pharmacokinetic profile of SEDDS-CBD in a randomized, double-blind, cross-over design in 16 healthy volunteers under fasted conditions. As reference formulation, the same Hemp-Extract diluted with medium-chain triglycerides (MCT-CBD) was used. CBD dose was standardized to 25 mg. Pharmacokinetic parameters were analyzed from individual concentration-time curves. Single oral administration of SEDDS-CBD led to a 4.4-fold higher Cmax and a 2.85-/1.70-fold higher AUC0-8h/AUC0-24h compared to the reference formulation. Tmax was substantially shorter for SEDDS-CBD (1.0 h) compared to MCT-CBD (3.0 h). Subgroup analysis demonstrated a higher bioavailability in women compared to men. This difference was seen for MCT-CBD while SEDDS-CBD mitigated this gender effect. Overall, SEDDS-CBD showed a significant improvement for all determined pharmacokinetic parameters: increased CBD plasma values (Cmax), favorably enhanced bioavailability (AUC) and fast absorption (Tmax). No safety concerns were noted following either administration.


Examining the global health arena: strengths and weaknesses of a convention approach to global health challenges.
The article comprises a conceptual framework to analyze the strengths and weaknesses of a global health convention. The analyses are inspired by Lawrence Gostin's suggested Framework Convention on Global Health. The analytical model takes a starting-point in events tentatively following a logic sequence: Input (global health funding), Processes (coordination, cooperation, accountability, allocation of aid), Output (definition of basic survival needs), Outcome (access to health services), and Impact (health for all). It then examines to what degree binding international regulations can create order in such a sequence of events. We conclude that a global health convention could be an appropriate instrument to deal with some of the problems of global health. We also show that some of the tasks preceding a convention approach might be to muster international support for supra-national health regulations, negotiate compromises between existing stakeholders in the global health arena, and to utilize WHO as a platform for further discussions on a global health convention.


A controlled trial of transcutaneous electrical nerve stimulation (TENS) and exercise for chronic low back pain.
A number of treatments are widely prescribed for chronic back pain, but few have been rigorously evaluated. We examined the effectiveness of transcutaneous electrical nerve stimulation (TENS), a program of stretching exercises, or a combination of both for low back pain. Patients with chronic low back pain (median duration, 4.1 years) were randomly assigned to receive daily treatment with TENS (n = 36), sham TENS (n = 36), TENS plus a program of exercises (n = 37), or sham TENS plus exercises (n = 36). After one month no clinically or statistically significant treatment effect of TENS was found on any of 11 indicators of outcome measuring pain, function, and back flexion; there was no interactive effect of TENS with exercise. Overall improvement in pain indicators was 47 percent with TENS and 42 percent with sham TENS (P not significant). The 95 percent confidence intervals for group differences excluded a major clinical benefit of TENS for most outcomes. By contrast, after one month patients in the exercise groups had significant improvement in self-rated pain scores, reduction in the frequency of pain, and greater levels of activity as compared with patients in the groups that did not exercise. The mean reported improvement in pain scores was 52 percent in the exercise groups and 37 percent in the nonexercise groups (P = 0.02). Two months after the active intervention, however, most patients had discontinued the exercises, and the initial improvements were gone. We conclude that for patients with chronic low back pain, treatment with TENS is no more effective than treatment with a placebo, and TENS adds no apparent benefit to that of exercise alone.


Associations between anxious-depressed symptoms and cardiovascular risk factors in a longitudinal childhood study.
To examine the influence of anxious/depressed scores on cardiovascular risk factors throughout childhood. Data from the Western Australian Pregnancy Cohort (Raine) Study, a study of 2900 pregnancies recruited between 1989 and 1991, were used. Anxious-depressed scores (derived from the Childhood Behavior Checklist), body mass index (BMI) and blood pressure were measured at 5 (n=1681), 8 (n=1697), 10 (n=1575) and 14 (n=1386) years. At age 14 depressive symptom scores (Beck Depression Inventory for Youth), anxious-depressed scores (Youth Self-Report (YSR) and Teacher Report Form (TRF)) and fasting lipid, glucose and insulin were also available. Cross sectional and longitudinal analyses were conducted. At age 14, girls with higher anxious-depressed scores had higher BMI (p≤ 0.005) and homeostasis model assessment-estimated insulin resistance (p≤ 0.0001). This equated to a difference of 0.6 kg/m(2) and 0.3 units in predicted BMI and HOMA-IR respectively (top 5% vs. score of zero). Boys with higher anxious-depressed scores had lower systolic blood pressure trajectories (p=0.024). Depressive scores appear to have differing influences on BMI, homeostasis model assessment-estimated insulin resistance and systolic blood pressure in boys and girls. Paradoxically boys with higher anxious-depressed scores had lower blood pressure throughout childhood.


Active Brownian particles: mapping to equilibrium polymers and exact computation of moments.
It is well known that the path probabilities of Brownian motion correspond to the equilibrium configurational probabilities of flexible Gaussian polymers, while those of active Brownian motion correspond to in-extensible semiflexible polymers. Here we investigate the properties of the equilibrium polymer that corresponds to the trajectories of particles acted on simultaneously by both Brownian and active noise. Through this mapping we can see interesting crossovers in the mechanical properties of the polymer with changing contour length. The polymer end-to-end distribution exhibits Gaussian behaviour for short lengths, which changes to the form of semiflexible filaments at intermediate lengths, to finally go back to a Gaussian form for long contour lengths. By performing a Laplace transform of the governing Fokker-Planck equation of the active Brownian particle, we discuss a direct method to derive exact expressions for all the moments of the relevant dynamical variables, in arbitrary dimensions. These are verified via numerical simulations and used to describe interesting qualitative features such as, for example, dynamical crossovers. Finally we discuss the kurtosis of the ABP's position, which we compute exactly, and show that it can be used to differentiate between active Brownian particles and the active Ornstein-Uhlenbeck process.


The California Health Interview Survey 2001: translation of a major survey for California's multiethnic population.
The cultural and linguistic diversity of the U.S. population presents challenges to the design and implementation of population-based surveys that serve to inform public policies. Information derived from such surveys may be less than representative if groups with limited or no English language skills are not included. The California Health Interview Survey (CHIS), first administered in 2001, is a population-based health survey of more than 55,000 California households. This article describes the process that the designers of CHIS 2001 underwent in culturally adapting the survey and translating it into an unprecedented number of languages: Spanish, Chinese, Vietnamese, Korean, and Khmer. The multiethnic and multilingual CHIS 2001 illustrates the importance of cultural and linguistic adaptation in raising the quality of population-based surveys, especially when the populations they intend to represent are as diverse as California's.


Extended source pyramid wave-front sensor for the human eye.
We describe a new wave-front sensor based on the previously proposed pyramid sensor. This new sensor uses an extended source instead of a point-like source avoiding in this manner the oscillation of the pyramid. After an introductory background the sensor functioning is described. Among other possible optical testing uses, we apply the sensor to measure the wave-front aberration of the human eye. An experimental system built to test this specific application is described. Results obtained both in an articficial eye and in a real eye are presented. A discussion about the sensor characteristics, the experimental results and future work prospects is also included.


Scaffold topologies. 2. Analysis of chemical databases.
We have systematically enumerated graph representations of scaffold topologies for up to eight-ring molecules and four-valence atoms, thus providing coverage of the lower portion of the chemical space of small molecules (Pollock et al. J. Chem. Inf. Model., this issue). Here, we examine scaffold topology distributions for several databases: ChemNavigator and PubChem for commercially available chemicals, the Dictionary of Natural Products, a set of 2742 launched drugs, WOMBAT, a database of medicinal chemistry compounds, and two subsets of PubChem, "actives" and DSSTox comprising toxic substances. We also examined a virtual database of exhaustively enumerated small organic molecules, GDB (Fink et al. Angew. Chem., Int. Ed. 2005, 44, 1504-1508), and we contrast the scaffold topology distribution from these collections to the complete coverage of up to eight-ring molecules. For reasons related, perhaps, to synthetic accessibility and complexity, scaffolds exhibiting six rings or more are poorly represented. Among all collections examined, PubChem has the greatest scaffold topological diversity, whereas GDB is the most limited. More than 50% of all entries (13 000 000+ actual and 13 000 000+ virtual compounds) exhibit only eight distinct topologies, one of which is the nonscaffold topology that represents all treelike structures. However, most of the topologies are represented by a single or very small number of examples. Within topologies, we found that three-way scaffold connections (3-nodes) are much more frequent compared to four-way (4-node) connections. Fused rings have a slightly higher frequency in biologically oriented databases. Scaffold topologies can be the first step toward an efficient coarse-grained classification scheme of the molecules found in chemical databases.


Ischemia-Modified Albumin, Creatinine, And Paraoxonase-1 Levels in Serum of Patients Undergoing Intravenous Contrast-Enhanced Computed Tomography and Its Association with Contrast-Induced Nephropathy.
Following contrast-enhanced computed tomography (CECT) contrast-induced nephropathy (CIN) may occur in patients with renal insufficiency or diabetes. Creatinine, the most common marker of CIN, may not be an accurate measure of damage and is affected by many non-renal factors. Our aim was to evaluate ischemia-modified albumin (IMA) as an early CIN marker and correlate it with paraoxonase-1 (PON-1) and creatinine before and after CECT. Forty-eight adult patients scheduled for intravenous CECT, regardless of indication or body region for CECT, were included in this prospective study. Venous blood samples were obtained 12-24 hours before and after contrast media (CM) administration. Ischemia-modified albumin and PON-1 were estimated using methods described by Bar-Or et al. and Dantoine et.al., respectively. Creatinine was estimated on an automated analyzer. Significant differences in IMA (P < 0.001) and PON-1 (P < 0.001) levels were found between pre- and post-CECT samples, while the difference for creatinine was not significant (p = 0.073). No correlation was found between IMA and PON-1 or IMA and creatinine in either the pre- or post-CECT samples. After CM administration patients are subjected to oxidative stress and/or ischemia, as revealed by elevated IMA and decreased PON-1 levels; however, creatinine levels, most commonly estimated to assess reduced renal function, did not reflect the condition accurately. IMA may be a sensitive marker for CIN but further studies are required to confirm its usefulness.


Plant species composition and biofuel yields of conservation grasslands.
Marginal croplands, such as those in the Conservation Reserve Program (CRP), have been suggested as a source of biomass for biofuel production. However, little is known about the composition of plant species on these conservation grasslands or their potential for ethanol production. Our objective was to assess the potential of CRP and other conservation grasslands for biofuel production, describing the relationships of plant species richness and tall native C4 prairie grass abundance with plant chemical composition and the resulting potential ethanol yield. We determined plant species composition and diversity at multiple scales with the modified Whittaker plot technique, aboveground biomass, plant chemical composition, and potential ethanol yield at 34 sites across the major ecological regions of the northeastern USA. Conservation grasslands with higher numbers of plant species had lower biomass yields and a lower ethanol yield per unit biomass compared with sites with fewer species. Thus, biofuel yield per unit land area decreased by 77% as plant species richness increased from 3 to 12.8 species per m2. We found that, as tall native C4 prairie grass abundance increased from 1.7% to 81.6%, the number of plant species decreased and aboveground biomass per unit land area and ethanol yield per unit biomass increased resulting in a 500% increased biofuel yield per unit land area. Plant species richness and composition are key determinants of biomass and ethanol yields from conservation grasslands and have implications for low-input high-diversity systems. Designing systems to include a large proportion of species with undesirable fermentation characteristics could reduce ethanol yields.


Multisource Evaluation of Surgeon Behavior Is Associated With Malpractice Claims.
We merged direct, multisource, and systematic assessments of surgeon behavior with malpractice claims, to analyze the relationship between surgeon 360-degree reviews and malpractice history. Previous work suggests that malpractice claims are associated with a poor physician-patient relationship, which is likely related to behaviors captured by 360-degree review. We hypothesize that 360-degree review results are associated with malpractice claims. Surgeons from 4 academic medical centers covered by a common malpractice carrier underwent 360-degree review in 2012 to 2013 (n = 385). Matched, de-identified reviews and malpractice claims data were available for 264 surgeons from 2000 to 2015. We analyzed 23 questions, highlighting positive and negative behaviors within the domains of education, excellence, humility, openness, respect, service, and teamwork. Regression analysis with robust standard error was used to assess the potential association between 360-degree review results and malpractice claims. The range of claims among the 264 surgeons was 0 to 8, with 48.1% of surgeons having at least 1 claim. Multiple positive and negative behaviors were significantly associated with the risk of having malpractice claims (P < 0.05). Surgeons in the bottom decile for several items had an increased likelihood of having at least 1 claim. Surgeon behavior, as assessed by 360-degree review, is associated with malpractice claims. These findings highlight the importance of teamwork and communication in exposure to malpractice. Although the nature of malpractice claims is complex and multifactorial, the identification and modification of negative physician behaviors may mitigate malpractice risk and ultimately result in the improved quality of patient care.


A functional portrait of Med7 and the mediator complex in Candida albicans.
Mediator is a multi-subunit protein complex that regulates gene expression in eukaryotes by integrating physiological and developmental signals and transmitting them to the general RNA polymerase II machinery. We examined, in the fungal pathogen Candida albicans, a set of conditional alleles of genes encoding Mediator subunits of the head, middle, and tail modules that were found to be essential in the related ascomycete Saccharomyces cerevisiae. Intriguingly, while the Med4, 8, 10, 11, 14, 17, 21 and 22 subunits were essential in both fungi, the structurally highly conserved Med7 subunit was apparently non-essential in C. albicans. While loss of CaMed7 did not lead to loss of viability under normal growth conditions, it dramatically influenced the pathogen's ability to grow in different carbon sources, to form hyphae and biofilms, and to colonize the gastrointestinal tracts of mice. We used epitope tagging and location profiling of the Med7 subunit to examine the distribution of the DNA sites bound by Mediator during growth in either the yeast or the hyphal form, two distinct morphologies characterized by different transcription profiles. We observed a core set of 200 genes bound by Med7 under both conditions; this core set is expanded moderately during yeast growth, but is expanded considerably during hyphal growth, supporting the idea that Mediator binding correlates with changes in transcriptional activity and that this binding is condition specific. Med7 bound not only in the promoter regions of active genes but also within coding regions and at the 3' ends of genes. By combining genome-wide location profiling, expression analyses and phenotyping, we have identified different Med7p-influenced regulons including genes related to glycolysis and the Filamentous Growth Regulator family. In the absence of Med7, the ribosomal regulon is de-repressed, suggesting Med7 is involved in central aspects of growth control.


Expression patterns of cell wall-modifying genes from banana during fruit ripening and in relationship with finger drop.
Few molecular studies have been devoted to the finger drop process that occurs during banana fruit ripening. Recent studies revealed the involvement of changes in the properties of cell wall polysaccharides in the pedicel rupture area. In this study, the expression of cell-wall modifying genes was monitored in peel tissue during post-harvest ripening of Cavendish banana fruit, at median area (control zone) and compared with that in the pedicel rupture area (drop zone). To this end, three pectin methylesterase (PME) and seven xyloglucan endotransglycosylase/hydrolase (XTH) genes were isolated. The accumulation of their mRNAs and those of polygalaturonase, expansin, and pectate lyase genes already isolated from banana were examined. During post-harvest ripening, transcripts of all genes were detected in both zones, but accumulated differentially. MaPME1, MaPG1, and MaXTH4 mRNA levels did not change in either zone. Levels of MaPME3 and MaPG3 mRNAs increased greatly only in the control zone and at the late ripening stages. For other genes, the main molecular changes occurred 1-4 d after ripening induction. MaPME2, MaPEL1, MaPEL2, MaPG4, MaXTH6, MaXTH8, MaXTH9, MaEXP1, MaEXP4, and MaEXP5 accumulated highly in the drop zone, contrary to MaXTH3 and MaXTH5, and MaEXP2 throughout ripening. For MaPG2, MaXET1, and MaXET2 genes, high accumulation in the drop zone was transient. The transcriptional data obtained from all genes examined suggested that finger drop and peel softening involved similar mechanisms. These findings also led to the proposal of a sequence of molecular events leading to finger drop and to suggest some candidates.


The effects of acupuncture after thyroid surgery: A randomized, controlled trial.
Acupuncture is a safe and well-tolerated treatment for pain relief. Previous studies supported the effectiveness of several acupuncture techniques for postoperative pain. The aim of this randomized, controlled trial was to evaluate the efficacy of acupuncture in reducing pain after thyroid surgery. We randomized 121 patients to a control group (undergoing only standard postoperative analgesic treatment with acetaminophen) and an acupuncture group, undergoing also either electroacupuncture (EA) or traditional acupuncture (TA). Pain was measured according to intraoperative remifentanil use, acetaminophen daily intake, Numeric Rating Scale (NRS), and McGill Pain Questionnaire on postoperative days (POD) 1-3. Acupuncture group required less acetaminophen than controls at POD 2 (P = .01) and 3 (P = .016). EA patients required less remifentanil (P = .032) and acetaminophen than controls at POD 2 (P = .004) and 3 (P = .008). EA patients showed a trend toward better NRS and McGill scores from POD 1 to 3 compared with controls. EA patients had a lower remifentanil requirement and better NRS and McGill scores than TA patients. No differences occurred between TA patients and controls. Acupuncture may be effective in reducing pain after thyroid surgery. EA is more useful; TA achieves no significant effects.


A preliminary study for constructing a bioartificial liver device with induced pluripotent stem cell-derived hepatocytes.
Bioartificial liver systems, designed to support patients with liver failure, are composed of bioreactors and functional hepatocytes. Immunological rejection of the embedded hepatocytes by the host immune system is a serious concern that crucially degrades the performance of the device. Induced pluripotent stem (iPS) cells are considered a desirable source for bioartificial liver systems, because patient-derived iPS cells are free from immunological rejection. The purpose of this paper was to test the feasibility of a bioartificial liver system with iPS cell-derived hepatocyte-like cells. Mouse iPS cells were differentiated into hepatocyte-like cells by a multi-step differentiation protocol via embryoid bodies and definitive endoderm. Differentiation of iPS cells was evaluated by morphology, PCR assay, and functional assays. iPS cell-derived hepatocyte-like cells were cultured in a bioreactor module with a pore size of 0.2 μm for 7 days. The amount of albumin secreted into the circulating medium was analyzed by ELISA. Additionally, after a 7-day culture in a bioreactor module, cells were observed by a scanning electron microscope. At the final stage of the differentiation program, iPS cells changed their morphology to a polygonal shape with two nucleoli and enriched cytoplasmic granules. Transmission electron microscope analysis revealed their polygonal shape, glycogen deposition in the cytoplasm, microvilli on their surfaces, and a duct-like arrangement. PCR analysis showed increased expression of albumin mRNA over the course of the differentiation program. Albumin and urea production was also observed. iPS-Heps culture in bioreactor modules showed the accumulation of albumin in the medium for up to 7 days. Scanning electron microscopy revealed the attachment of cell clusters to the hollow fibers of the module. These results indicated that iPS cells were differentiated into hepatocyte-like cells after culture for 7 days in a bioreactor module with a pore size of 0.2 μm. We consider the combination of a bioreactor module with a 0.2-μm pore membrane and embedded hepatocytes differentiated from iPS cells to be a promising option for bioartificial liver systems. This paper provides the basic concept and preliminary data for an iPS cell-oriented bioartificial liver system.PACS code: 87. Biological and medical physics, 87.85.-d Biomedical engineering, 87.85.Lf Tissue engineering, 87.85.Tu Modeling biomedical systems.


Feeding on dispersed vs. aggregated particles: The effect of zooplankton feeding behavior on vertical flux.
Zooplankton feeding activity is hypothesized to attenuate the downward flux of elements in the ocean. We investigated whether the zooplankton community composition could influence the flux attenuation, due to the differences of feeding modes (feeding on dispersed vs. aggregated particles) and of metabolic rates. We fed 5 copepod species-three calanoid, one harpacticoid and one poecilamastoid-microplankton food, in either dispersed or aggregated form and measured rates of respiration, fecal pellet production and egg production. Calanoid copepods were able to feed only on dispersed food; when their food was introduced as aggregates, their pellet production and respiration rates decreased to rates observed for starved individuals. In contrast, harpacticoids and the poecilamastoid copepod Oncaea spp. were able to feed only when the food was in the form of aggregates. The sum of copepod respiration, pellet production and egg production rates was equivalent to a daily minimum carbon demand of ca. 10% body weight-1 for all non-feeding copepods; the carbon demand of calanoids feeding on dispersed food was 2-3 times greater, and the carbon demand of harpacticoids and Oncaea spp. feeding on aggregates was >7 times greater, than the resting rates. The zooplankton species composition combined with the type of available food strongly influences the calculated carbon demand of a copepod community, and thus also the attenuation of vertical carbon flux.


Examination of migraine management in emergency departments.
Despite advances in treatment, patients with migraine have been underdiagnosed and undertreated, specifically in emergency departments. In addition, great variability exists with respect to the diagnosis, management and treatment of migraine patients in emergency departments. In particular, migraine-specific treatments, including serotonin receptor agonists, appear to be rarely used. To examine the diagnosis and management of migraine patients within Ontario emergency departments. A prospective survey was designed to inquire how emergency physicians diagnose and manage patients with migraine. Questions focused on the use of serotonin receptor agonists, the rationale behind their use or nonuse, and acute headache protocols. The survey also inquired about the use of International Classification Of Headache Disorders-2 criteria in diagnosing migraine by emergency physicians, medication prescribed on discharge, and referrals made to outpatient specialists. These surveys were distributed to and anonymously completed by emergency physicians in several departments in Ontario. Migraine-specific treatments were underused in emergency departments. Furthermore, many departments lacked headache protocols and, often, migraine-specific treatment was not included in the few departments with protocols. Diagnosis and management of migraines can be improved within emergency departments, and patients can be more effectively channelled toward appropriate outpatient care.


Macrodomain-containing proteins are new mono-ADP-ribosylhydrolases.
ADP-ribosylation is an important post-translational protein modification (PTM) that regulates diverse biological processes. ADP-ribosyltransferase diphtheria toxin-like 10 (ARTD10, also known as PARP10) mono-ADP-ribosylates acidic side chains and is one of eighteen ADP-ribosyltransferases that catalyze mono- or poly-ADP-ribosylation of target proteins. Currently, no enzyme is known that reverses ARTD10-catalyzed mono-ADP-ribosylation. Here we report that ARTD10-modified targets are substrates for the macrodomain proteins MacroD1, MacroD2 and C6orf130 from Homo sapiens as well as for the macrodomain protein Af1521 from archaebacteria. Structural modeling and mutagenesis of MacroD1 and MacroD2 revealed a common core structure with Asp102 and His106 of MacroD2 implicated in the hydrolytic reaction. Notably, MacroD2 reversed the ARTD10-catalyzed, mono-ADP-ribose-mediated inhibition of glycogen synthase kinase 3β (GSK3β) in vitro and in cells, thus underlining the physiological and regulatory importance of mono-ADP-ribosylhydrolase activity. Our results establish macrodomain-containing proteins as mono-ADP-ribosylhydrolases and define a class of enzymes that renders mono-ADP-ribosylation a reversible modification.


Occurrence and genetic typing of infectious hematopoietic necrosis virus in Kamchatka, Russia.
Infectious hematopoietic necrosis virus (IHNV) is a well known rhabdoviral pathogen of salmonid fish in North America that has become established in Asia and Europe. On the Pacific coast of Russia, IHNV was first detected in hatchery sockeye from the Kamchatka Peninsula in 2001. Results of virological examinations of over 10,000 wild and cultured salmonid fish from Kamchatka during 1996 to 2005 revealed IHNV in several sockeye salmon Oncorhynchus nerka populations. The virus was isolated from spawning adults and from juveniles undergoing epidemics in both hatchery and wild sockeye populations from the Bolshaya watershed. No virus was detected in 2 other watersheds, or in species other than sockeye salmon. Genetic typing of 8 virus isolates by sequence analysis of partial glycoprotein and nucleocapsid genes revealed that they were genetically homogeneous and fell within the U genogroup of IHNV. In phylogenetic analyses, the Russian IHNV sequences were indistinguishable from the sequences of North American U genogroup isolates that occur throughout Alaska, British Columbia, Washington, and Oregon. The high similarity, and in some cases identity, between Russian and North American IHNV isolates suggests virus transmission or exposure to a common viral reservoir in the North Pacific Ocean.


Embedding the dynamics of a single delay system into a feed-forward ring.
We investigate the relation between the dynamics of a single oscillator with delayed self-feedback and a feed-forward ring of such oscillators, where each unit is coupled to its next neighbor in the same way as in the self-feedback case. We show that periodic solutions of the delayed oscillator give rise to families of rotating waves with different wave numbers in the corresponding ring. In particular, if for the single oscillator the periodic solution is resonant to the delay, it can be embedded into a ring with instantaneous couplings. We discover several cases where the stability of a periodic solution for the single unit can be related to the stability of the corresponding rotating wave in the ring. As a specific example, we demonstrate how the complex bifurcation scenario of simultaneously emerging multijittering solutions can be transferred from a single oscillator with delayed pulse feedback to multijittering rotating waves in a sufficiently large ring of oscillators with instantaneous pulse coupling. Finally, we present an experimental realization of this dynamical phenomenon in a system of coupled electronic circuits of FitzHugh-Nagumo type.


Monitoring the randomized trials of the Women's Health Initiative: the experience of the Data and Safety Monitoring Board.
Data Safety Monitoring Committees (DSMB) for large, long-term randomized trials of agents in common use face challenging problems especially when the emerging data indicate unanticipated effects. The DSMB for the Women's Health Initiative Clinical Trials, on observing early indication of a surprising adverse cardiovascular effect of post-menopausal hormones, spent several years deliberating what recommendations it should make. This paper describes the dilemmas faced by the DSMB and the considerations it made over the course of its existence. The paper concludes with some recommendations for other DSMBs.


Surgical pathology of spinal schwannoma: has the nerve of its origin been preserved or already degenerated during tumor growth?
This study was aimed to understand ultrastructural pathology of nerves of tumor origin of spinal schwannomas, which has not been reported so far, in order to understand the mechanism of the postoperative functional restoration after the nerve transection. From 13 patients who underwent sacrifice of an affected nerve root at total removal of spinal schwannomas (C2 conus), the proximal (spinal cord side, n = 12) and distal (dorsal root ganglion side, n = 10) stumps of the nerves of the tumor origin were collected and examined by light and electron microscope, followed by morphometric analysis (n = 9). Almost all of affected nerves at both proximal and distal to the lesion were composed of well-preserved myelin sheath and axons with mild disturbance of endo- and perineurial structures at light microscopic level except one case, which showed severe fibrosis. Electron-microscopically, regenerated axons with thin myelin were found in part in the proximal and distal nerves with few macrophages in three cases. The area of nerves (mm2), density of myelinated axons (axons/mm2) and total number of myelinated axons in the proximal stump (0.552 +/- 0.430, 10,400 +/- 5,240 and 5,480 +/- 4,790) was approximately 70%, 80% and 60%, respectively, of those in the distal stump (0.765 +/- 0.333, 12,400 +/- 5,180 and 9,970 +/- 8,630). This data combined with no permanent deficits after nerve transection suggest that the nerves of tumor origin are in the processes of slowly progressed deterioration with repeated degeneration and regeneration/remyelination, and the postoperative rapid recovery from the transient neurological deficit may be explained by functional compensation by the adjacent non-affected nerves with slow tumor growth.


Improved rural access to care: dimensions of best practice.
This article describes the processes and outcomes of an action research project targeted at describing 'best practice' as experienced by interdisciplinary rural health projects funded by the Quentin N. Burdick Program for Rural Interdisciplinary Training, a Federally funded training grant competition in the USA. Each of 15 rural interdisciplinary health training projects across the areas of mental health, chronic disease, diabetes, minority health, and geriatrics was used to build a qualitative case study representing best practice experiences in projects focused on improving rural access to care. Across these programs, best practice is seen in the integrated dimensions of connections, community, and culture. In the USA, academic institutions build meaningful authentic connections with rural communities as they work together in meeting community needs, while demonstrating sensitivity and respect for cultural perspectives. Implications are offered in the context of higher education, health care delivery, and Federal initiatives within the USA.


Distinguishing between benign and malignant melanocytic nevi by in vivo multiphoton microscopy.
Monitoring of atypical nevi is an important step in early detection of melanoma, a clinical imperative in preventing the disease progression. Current standard diagnosis is based on biopsy and histopathologic examination, a method that is invasive and highly dependent upon physician experience. In this work, we used a clinical multiphoton microscope to image in vivo and noninvasively melanocytic nevi at three different stages: common nevi without dysplastic changes, dysplastic nevi with structural and architectural atypia, and melanoma. We analyzed multiphoton microscopy (MPM) images corresponding to 15 lesions (five in each group) both qualitatively and quantitatively. For the qualitative analysis, we identified the morphologic features characteristic of each group. MPM images corresponding to dysplastic nevi and melanoma were compared with standard histopathology to determine correlations between tissue constituents and morphology and to evaluate whether standard histopathology criteria can be identified in the MPM images. Prominent qualitative correlations included the morphology of epidermal keratinocytes, the appearance of nests of nevus cells surrounded by collagen fibers, and the structure of the epidermal-dermal junction. For the quantitative analysis, we defined a numerical multiphoton melanoma index (MMI) based on three-dimensional in vivo image analysis that scores signals derived from two-photon excited fluorescence, second harmonic generation, and melanocyte morphology features on a continuous 9-point scale. Indices corresponding to common nevi (0-1), dysplastic nevi (1-4), and melanoma (5-8) were significantly different (P < 0.05), suggesting the potential of the method to distinguish between melanocytic nevi in vivo.


Student attitudes to dentistry in South African dental schools.
The present study investigated student motives for choosing dentistry in five South African dental schools. An attitude questionnaire was complied and administered to all entering students at these schools. The study population comprised 161 students, 92 males and 69 females. Results indicate that in spite of the changing student populations at all universities, the motives for studying dentistry remain essentially the same. Similarities in attitudes to dentistry tend to outweigh differences. Similarities are shown with respect to service, the need for status, independence and financial security. Differences are reflected in the contradictions between service and status, service and regular working hours, service and financial security. The question these findings raise, is how and to what extent students selected for training, based on their current motivation and attitudes will best adapt to changes in the practice of dentistry, health policies, and increased population demands.


Dissemination of Chlamydia trachomatis chronic genital tract infection in gamma interferon gene knockout mice.
Mice (C57BL/6), treated with progesterone and infected intravaginally with the mouse pneumonitis strain of Chlamydia trachomatis (MoPn), acquired genital tract disease that ascended from the endocervix to the uterine horns, oviducts, and ovaries in a temporal fashion before the occurrence of spontaneous microbiological resolution by about 28 days after infection. Surprisingly, dissemination of MoPn in small numbers to draining lymph nodes, the peritoneal cavity, spleen, liver, kidneys, and lungs occurred in normal mice during the early stages of disease (7 to 14 days) in a portion of infected animals but resolved from these tissues, by microbiological criteria, prior to resolution of genital tract involvement. In contrast, gamma interferon knockout (IFN-gamma KO) mice exhibited dissemination of infection to a greater extent and for longer periods in a variety of tissues, and a portion of infected IFN-gamma KO mice failed to microbiologically resolve their genital tract disease. By comparison, C57BL/6 SCID mice uniformly failed to resolve their genital tract disease and exhibited high levels of dissemination to all tissues tested for extended (50-day) periods of times. Interestingly, although IFN-gamma KO mice failed to completely clear organisms from their genital tracts, they exhibited an attenuated infection indistinguishable from that of heterozygous littermates when challenged 112 days after primary infection. These data support a role for IFN-gamma in containing dissemination of MoPn from the genital tract to extragenital sites and in the microbiological resolution of infection. Data also indicate that IFN-gamma is not required for modulating reinfections, which normally follow a shorter and less dramatic course.


Self organizing motor maps for color-mapped image re-indexing.
Palette re-ordering is an effective approach for improving the compression of color-indexed images. If the spatial distribution of the indexes in the image is smooth, greater compression ratios may be obtained. As is already known, obtaining an optimal re-indexing scheme is not a trivial task. In this paper, we provide a novel algorithm for palette re-ordering problem making use of a motor map neural network. Experimental results show the real effectiveness of the proposed method both in terms of compression ratio and zero-order entropy of local differences. Also, its computational complexity is competitive with previous works in the field.


Simulation of near-field scanning optical microscopy using a plasmonic gap probe.
Imaging by near-field scanning optical microscopy (NSOM) with a plasmonic gap probe (PGP) is simulated to confirm the operation of the recently proposed PGP. The simulations demonstrate that the probe works in illumination, collection-reflection and collection mode, and that is it not necessary to vibrate the probe tip in order to remove background noise. The resolution of the scanned image is also shown to be approximately equal to the diameter of the probe tip. Furthermore, the throughput of the probe is much higher than conventional aperture probes providing similar resolution. The proposed probe thus has the advantages of both aperture probes and scattering probes, and is expected to have excellent characteristics for use as a scanning probe for NSOM.


Predicting wellness among rural older Australians: a cross- sectional study.
Prior research on older people's wellbeing and quality of life has lacked clarity and consistency. Research examining older people's health has tended to use these different terms and measurement tools interchangeably, which might explain why the evidence is somewhat mixed. There is a paucity of research that uses the multi-dimensional construct of wellness in rural older people. Addressing both limitations, this study seeks to make a unique contribution to knowledge testing an ecological model of wellness that includes intrapersonal factors, interpersonal processes, institutional factors, community factors and public policy. Six rural case study sites were chosen across two Australian sites, the states of Queensland and Victoria. A community saturation recruitment strategy was utilised. Telephone surveys were conducted with community-dwelling rural older people (n=266) aged ≥65 years across the sites. The central variable of the study was wellness as measured by the Perceived Wellness Survey. The ecological model developed included the following intrapersonal factors: physical and mental health, loneliness and social demographic characteristics (age, sex, marital status and financial capability). Interpersonal factors included a measure of social and community group participation, social network size and support provided. Institutional factors were measured by series of questions devised around the resource base environment and access to amenities and services. A hierarchical regression analysis was conducted to determine which variables in the model predict wellness. The results showed that a combination of intrapersonal factors (physical health, mental health, loneliness and financial capability) and interpersonal factors (size of social network and community participation) predicted wellness. However, institutional factors, the resource base environment, and access to amenities and services, contributed only marginally to the model. Community factors, including the personal and physical characteristics of community, also only made a marginal contribution. The study identified the usefulness of using an integrated model of measurement in wellness. This model recognised the interrelated physical, social and economic influences that impact on rural older people throughout their life course. The study found that physical health made the greatest contribution to perceived wellness, followed by mental health. These findings support a body of research that has found that rural older people experience poorer health outcomes than those in urban areas. Lower levels of loneliness were also a strong predictor of perceived wellness, thus supporting research that has examined the impact of loneliness on physical and mental health. The presence of social capital, as measured by social network size, and the degree of community participation, were also predictors of perceived wellness. Overall, the findings of the present study implications for policy as well as subsequent strategies designed to increase the capacity of wellness in rural older people. Such strategies need to consider the contribution of a range of factors.


Brief report: Repetitive behaviours in Greek individuals with autism spectrum disorder.
The main objective of this study was to examine the factor structure of restricted repetitive behaviours (RRBs) in a sample of 205 Greek individuals with Autism Spectrum Disorder (ASD), using the Repetitive Behavior Scale-Revised (RBS-R). Results show that the structure of RRBs in this Greek sample can be described using a 2-factor solution. The current study provides further, cross-cultural support for the distinction between a "high-order" factor reflecting compulsions, rituals, sameness, and restricted behaviours (CRSRB) and a "low-order" factor reflecting stereotyped movements and self-injurious behaviours (SSIB). These factors are most likely located at the top of the RRB structural hierarchy and represent general, independent constructs of ASD behaviours that can be identified not only across studies but also across cultures.


Effect of helper and/or cytotoxic T-lymphocyte depletion on low-dose streptozocin-induced diabetes in C57BL/6J mice.
The low-dose streptozocin (STZ) model of diabetes has been reported to involve direct STZ beta-cytotoxicity and/or immunologically mediated beta-cell destruction. Because the T-lymphocyte dependency of such a model is controversial, we further assessed the role of T-lymphocytes by determining the occurrence and magnitude of hyperglycemia as well as the pancreatic insulin contents in both STZ-injected nude C57BL/6J male mice and STZ-injected euthymic C57BL/6J male mice selectively depleted in helper and/or cytotoxic T-lymphocytes with monoclonal antibodies (MoAbs). The effectiveness of MoAb treatment was assessed in lymph node cells by flow-microfluorometry analysis and in spleen cells by concanavalin A stimulation, allospecific cytotoxic T-lymphocyte activity, and T-lymphocyte lymphokine production. Sixteen days after the first STZ injection, hyperglycemia (plasma glucose greater than 200 mg/dl) occurred in significantly fewer helper T-lymphocyte-depleted mice (P less than .005) or helper and cytotoxic T-lymphocyte-depleted mice (P less than .001) than in non-MoAb-treated mice. However, a progressive increase in the number of mice with hyperglycemia ensued in all MoAb-treated groups, and 2 mo after STZ was administered, the prevalence of hyperglycemia, mean plasma glucose levels, and pancreatic insulin contents did not differ significantly from the values obtained in the non-MoAb-treated animals. Similarly, STZ-injected C57BL/6J male nude mice developed hyperglycemia that was associated with a marked decrease in pancreatic insulin contents on a time course comparable with that of STZ-injected euthymic C57BL/6J male mice depleted in helper or in helper and cytotoxic T-lymphocytes by MoAbs.(ABSTRACT TRUNCATED AT 250 WORDS)


The I2C family from the wilt disease resistance locus I2 belongs to the nucleotide binding, leucine-rich repeat superfamily of plant resistance genes.
Characterization of plant resistance genes is an important step in understanding plant defense mechanisms. Fusarium oxysporum f sp lycopersici is the causal agent of a vascular wilt disease in tomato. Genes conferring resistance to plant vascular diseases have yet to be described molecularly. Members of a new multigene family, complex I2C, were isolated by map-based cloning from the I2 F. o. lycopersici race 2 resistance locus. The genes show structural similarity to the group of recently isolated resistance genes that contain a nucleotide binding motif and leucine-rich repeats. Importantly, the presence of I2C antisense transgenes abrogated race 2 but not race 1 resistance in otherwise normal plants. Expression of the complete sense I2C-1 transgene conferred significant but partial resistance to F. o. lycopersici race 2. All members of the I2C gene family have been mapped genetically and are dispersed on three different chromosomes. Some of the I2C members cosegregate with other tomato resistance loci. Comparison within the leucine-rich repeat region of I2C gene family members shows that they differ from each other mainly by insertions or deletions.


Sphingosine-1-phosphate enhances satellite cell activation in dystrophic muscles through a S1PR2/STAT3 signaling pathway.
Sphingosine-1-phosphate (S1P) activates a widely expressed family of G protein-coupled receptors, serves as a muscle trophic factor and activates muscle stem cells called satellite cells (SCs) through unknown mechanisms. Here we show that muscle injury induces dynamic changes in S1P signaling and metabolism in vivo. These changes include early and profound induction of the gene encoding the S1P biosynthetic enzyme SphK1, followed by induction of the catabolic enzyme sphingosine phosphate lyase (SPL) 3 days later. These changes correlate with a transient increase in circulating S1P levels after muscle injury. We show a specific requirement for SphK1 to support efficient muscle regeneration and SC proliferation and differentiation. Mdx mice, which serve as a model for muscular dystrophy (MD), were found to be S1P-deficient and exhibited muscle SPL upregulation, suggesting that S1P catabolism is enhanced in dystrophic muscle. Pharmacological SPL inhibition increased muscle S1P levels, improved mdx muscle regeneration and enhanced SC proliferation via S1P receptor 2 (S1PR2)-dependent inhibition of Rac1, thereby activating Signal Transducer and Activator of Transcription 3 (STAT3), a central player in inflammatory signaling. STAT3 activation resulted in p21 and p27 downregulation in a S1PR2-dependent fashion in myoblasts. Our findings suggest that S1P promotes SC progression through the cell cycle by repression of cell cycle inhibitors via S1PR2/STAT3-dependent signaling and that SPL inhibition may provide a therapeutic strategy for MD.


An international meta-analysis confirms the association of BNC2 with adolescent idiopathic scoliosis.
Adolescent idiopathic scoliosis (AIS) is a common spinal deformity with the prevalence of approximately 3%. We previously conducted a genome-wide association study (GWAS) using a Japanese cohort and identified a novel locus on chromosome 9p22.2. However, a replication study using multi-population cohorts has not been conducted. To confirm the association of 9p22.2 locus with AIS in multi-ethnic populations, we conducted international meta-analysis using eight cohorts. In total, we analyzed 8,756 cases and 27,822 controls. The analysis showed a convincing evidence of association between rs3904778 and AIS. Seven out of eight cohorts had significant P value, and remaining one cohort also had the same trend as the seven. The combined P was 3.28 × 10-18 (odds ratio = 1.19, 95% confidence interval = 1.14-1.24). In silico analyses suggested that BNC2 is the AIS susceptibility gene in this locus.


First report of the isolation and molecular characterization of Rickettsia amblyommii and Rickettsia felis in Central America.
During 2010, 15 adult ticks, identified as Amblyomma cajennense, were collected from horses in Cahuita and Turrialba districts, whereas 7 fleas, identified as Ctenocephalides felis, were collected from a dog in San Jose city, Costa Rica. In the laboratory, three A. cajennense specimens, two from Cahuita and one from Turrialba, were individually processed for rickettsial isolation in cell culture, as was a pool of seven fleas. Rickettsiae were successfully isolated and established in Vero cell culture from the three ticks and from a pool of seven fleas in C6/36 cell culture. The three tick isolates were genotypically identified as Rickettsia amblyommii, and the flea isolate was identified as Rickettsia felis through DNA sequencing of portions of the rickettsial genes gltA, ompA, and ompB of each isolate. In addition, other seven ticks were shown to contain rickettsial DNA. Polymerase chain reaction products of at least two of these ticks were sequenced and also showed to correspond to R. amblyommii. Overall, 66.7% (10/15) of the A. cajennense adult ticks were found to be infected with rickettsiae. This is the first report of a successful isolation in cell culture of R. amblyommii and R. felis from Central America.


Divergent modulation of clinical measures of volitional and reflexive motor behaviors following serotonergic medications in human incomplete spinal cord injury.
Incomplete spinal cord injury (SCI) can result in profound impairments in volitional strength and reflex excitability, which contribute to loss of function. Human and animal models suggest that disruption of endogenous monoaminergic input, particularly serotonin (5-HT), from supraspinal centers contributes to this impaired motor function following SCI. In the present study, we investigated the effects of 5-HT medications on motor function in individuals with chronic (>1 year) SCI. Clinical measures of strength, spasticity/spasms, and walking ability were assessed in 12 individuals with chronic incomplete SCI following acute administration of either 8 mg cyproheptadine, a 5-HT antagonist, or 10 mg escitalopram, a selective 5-HT reuptake inhibitor (SSRI), in a double-blinded, randomized, crossover fashion. Results indicated that 5-HT medications modulated both volitional and reflexive behaviors with little change in walking performance; 5-HT antagonist medications depressed clinical measures of strength and spasticity/spasms, whereas SSRIs augmented both strength and spasticity/spasms. These changes are consistent with the dysregulation of 5-HT sensitive spinal neurons following SCI. This understanding may augment clinicians' awareness of the motor consequences of 5-HT medications.


Lyme disease: resolution of a serous retinal detachment and chorioretinal folds after antibiotic therapy.
Ocular manifestations of Lyme disease are uncommon. There has not been a documented case of serous retinal detachment and chorioretinal folds because of Lyme disease that have resolved after only antibiotic treatment. A 69-year-old white man with a history of recent tick bites presented with a gradual decrease in visual acuity in the left eye. Initial visual acuity was 3/200 in the left eye. Examination revealed an inferior, serous, macula-off retinal detachment. Chorioretinal folds were also noted. Lyme screening antibody test (enzyme-linked immunosorbent assay) was positive and a confirmatory Western blot was immunoglobulin M negative and immunoglobulin G positive. Oral amoxicillin (500 mg 3 times daily for 2 weeks) was given followed by intravenous ceftriaxone (2 g daily for 4 weeks). After two weeks of ceftriaxone, fundus examination and ultrasonography showed complete reattachment of the macula and periphery, and only mild residual chorioretinal folds remained on fluorescein angiogram. We suggest that Borrelia burgdorferi infection led to choroidal inflammation with secondary chorioretinal folds and a serous retinal detachment, which resolved with antibiotic therapy alone. This supports the suspicion of an intraocular infection, perhaps involving the choroid, as opposed to a secondary autoimmune reaction.


Tumoral calcinosis and epidural lipomatosis of the lumbar spine.
Lumbar spinal tumoral calcinosis and spinal epidural lipomatosis are rare conditions. We present a 70-year-old female patient with serology negative spondyloarthropathy who developed paresis due to tumoral calcinosis in the left facet joint between L5 and S1 levels and spinal epidural lipomatosis at L5 and S1 levels. Surgery was performed to excise the lesions en bloc. Neural decompression was provided. Neurological symptoms improved after surgery. Here, we report the first serology negative spondyloarthropathy case that had concomitant development of tumoral calcinosis and spinal epidural lipomatosis.


Quantification of Epicardial Fat by Cardiac CT Imaging.
The aim of this work is to introduce and design image processing methods for the quantitative analysis of epicardial fat by using cardiac CT imaging.Indeed, epicardial fat has recently been shown to correlate with cardiovascular disease, cardiovascular risk factors and metabolic syndrome. However, many concerns still remain about the methods for measuring epicardial fat, its regional distribution on the myocardium and the accuracy and reproducibility of the measurements.In this paper, a method is proposed for the analysis of single-frame 3D images obtained by the standard acquisition protocol used for coronary calcium scoring. In the design of the method, much attention has been payed to the minimization of user intervention and to reproducibility issues.In particular, the proposed method features a two step segmentation algorithm suitable for the analysis of epicardial fat. In the first step of the algorithm, an analysis of epicardial fat intensity distribution is carried out in order to define suitable thresholds for a first rough segmentation. In the second step, a variational formulation of level set methods - including a specially-designed region homogeneity energy based on Gaussian mixture models- is used to recover spatial coherence and smoothness of fat depots.Experimental results show that the introduced method may be efficiently used for the quantification of epicardial fat.


Purified Betacyanins from Hylocereus undatus Peel Ameliorate Obesity and Insulin Resistance in High-Fat-Diet-Fed Mice.
Natural bioactive compounds in food have been shown to be beneficial in preventing the development of obesity, diabetes, and other metabolic diseases. Increasing evidence indicates that betacyanins possess free-radical-scavenging and antioxidant activities, suggesting their beneficial effects on metabolic disorders. The main objective of this study was to isolate and identify the betaycanins from Hylocereus undatus (white-fleshed pitaya) peel and evaluate their ability to ameliorate obesity, insulin resistance, and hepatic steatosis in high-fat-diet (HFD)-induced obese mice. The purified pitaya peel betacyanins (PPBNs) were identified by liquid chromatography/tandem mass spectrometry (LC/MS/MS), and the male C57BL/6 mice were fed a low-fat diet, HFD, or HFD supplemented with PPBNs for 14 weeks. Our results showed that the white-fleshed pitaya peel contains 14 kinds of betacyanins and dietary PPBNs reduced HFD-induced body weight gain and ameliorated adipose tissue hypertrophy, hepatosteatosis, glucose intolerance, and insulin resistance. Moreover, the hepatic gene expression analysis indicated that PPBN supplementation increased the expression levels of lipid-metabolism-related genes (AdipoR2, Cpt1a, Cpt1b, Acox1, PPARγ, Insig1, and Insig2) and FGF21-related genes (β-Klotho and FGFR1/2) but decreased the expression level of Fads2, Fas, and FGF21, suggesting that the protective effect of PPBNs might be associated with the induced fatty acid oxidation, decreased fatty acid biosynthesis, and alleviated FGF21 resistance.


Brain activity during stepping: a novel MRI-compatible device.
Little is known about the impact of supraspinal centers on the control of human locomotion. Analyzing brain activity can help to clarify their impact and to improve the effects of locomotor training. A fMRI-compatible pneumatic robotic device is presented that can generate freely programmable, highly repetitive periodic active and passive leg movements comprised by hip, knee, and ankle joint displacements. Forces of up to 400N can be applied to each foot while the subject is lying in a supine position. Magnetic interference of the device with the magnetic field of the scanner is measurable, but does not affect the image quality as obtained by a usual image analysis procedure. In a first experiment, brain activity of one healthy subject was acquired during nine different gait-like movement conditions. Brain activity in the somatosensory and motor function related areas increased more when the subject actively moved the legs than when the legs were passively moved by the device. In almost all conditions, mean head motion could be limited to 2mm within the duration of one fMRI scan by a specifically developed head and trunk fixation system. Based on these results, it is concluded that our device will significantly contribute to a better understanding of human locomotor control and related therapeutic effects in spinal cord injured and stroke patients, and thereby, to improve training approaches.


Do malaria control interventions reach the poor? A view through the equity lens.
Malaria, more than any other disease of major public health importance in developing countries, disproportionately affects poor people, with 58% of malaria cases occurring in the poorest 20% of the world's population. If malaria control interventions are to achieve their desired impact, they must reach the poorest segments of the populations of developing countries. Unfortunately, a growing body of evidence from benefit-incidence analyses has demonstrated that many public health interventions that were designed to aid the poor are not reaching their intended target. For example, the poorest 20% of people in selected developing countries were as much as 2.5 times less likely to receive basic public health services as the least-poor 20%. In the field of malaria control, a small number of studies have begun to shed light on differences by wealth status of malaria burden and of access to treatment and prevention services. These early studies found no clear difference in fever incidence based on wealth status, but did show significant disparities in both the consequences of malaria and in the use of malaria prevention and treatment services. Further study is needed to elucidate the underlying factors that contribute to these disparities, and to examine possible inequities related to gender, social class, or other factors. To achieve impact and overcome such inequities, malaria control efforts must begin to incorporate approaches relevant to equity in program design, implementation, and monitoring and evaluation.


Intranasal triamcinolone and growth velocity.
Inadequate designs and conflicting results from previous studies prompted the US Food and Drug Administration to publish guidelines for the design of clinical trials evaluating the effects of orally inhaled and intranasal corticosteroids on the growth of children. This study conformed to these guidelines to evaluate the effect of triamcinolone acetonide aqueous nasal spray (TAA-AQ) on the growth of children with perennial allergic rhinitis (PAR). This randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluated the effect of once-daily TAA-AQ (110 μg) on the growth velocity (GV) of children aged 3-9 years with PAR by using stadiometry at baseline (4-6 months), during treatment (12 months), and at follow-up (2 months). Hypothalamus-pituitary-adrenal (HPA) axis function was assessed by measuring urinary cortisol levels. Details of adverse events were recorded. Of 1078 subjects screened, 299 were randomized, and 216 completed the study (placebo, 107; TAA-AQ, 109). In the primary analysis (modified intent-to-treat: placebo, 133; TAA-AQ, 134), least-squares mean GV during treatment was lower in the TAA-AQ group (5.65 cm/year) versus placebo (6.09 cm/year). The difference (-0.45 cm/year; 95% confidence interval: -0.78 to -0.11; P = .01), although clinically nonsignificant, was evident within 2 months of treatment and stabilized thereafter. At follow-up, the GV approached baseline (6.70 cm/year) in the TAA-AQ group (6.59 cm/year) and decreased slightly in the placebo group (5.89 cm/year vs 6.06 cm/year at baseline). No HPA axis suppression was observed. By using rigorous Food and Drug Administration-recommended design elements, this study detected a small, statistically significant effect of TAA-AQ on the GV of children with PAR.