Assessing the micro-scale environment using Google Street View: the Virtual Systematic Tool for Evaluating Pedestrian Streetscapes (Virtual-STEPS).
Altering micro-scale features of neighborhood walkability (e.g., benches, sidewalks, and cues of social disorganization or crime) could be a relatively cost-effective method of creating environments that are conducive to active living. Traditionally, measuring the micro-scale environment has required researchers to perform observational audits. Technological advances have led to the development of virtual audits as alternatives to observational field audits with the enviable properties of cost-efficiency from elimination of travel time and increased safety for auditors. This study examined the reliability of the Virtual Systematic Tool for Evaluating Pedestrian Streetscapes (Virtual-STEPS), a Google Street View-based auditing tool specifically designed to remotely assess micro-scale characteristics of the built environment. We created Virtual-STEPS, a tool with 40 items categorized into 6 domains (pedestrian infrastructure, traffic calming and streets, building characteristics, bicycling infrastructure, transit, and aesthetics). Items were selected based on their past abilities to predict active living and on their feasibility for a virtual auditing tool. Two raters performed virtual and field audits of street segments in Montreal neighborhoods stratified by the Walkscore that was used to determine the 'walking-friendliness' of a neighborhood. The reliability between virtual and field audits (n = 40), as well as inter-rater reliability (n = 60) were assessed using percent agreement, Cohen's Kappa statistic, and the Intra-class Correlation Coefficient. Virtual audits and field audits (excluding travel time) took similar amounts of time to perform (9.8 versus 8.2 min). Percentage agreement between virtual and field audits, and for inter-rater agreement was 80% or more for the majority of items included in the Virtual-STEPS tool. There was high reliability between virtual and field audits with Kappa and ICC statistics indicating that 20 out of 40 (50.0%) items had almost perfect agreement and 13 (32.5%) items had substantial agreement. Inter-rater reliability was also high with 17 items (42.5%) with almost perfect agreement and 11 (27.5%) items with substantial agreement. Virtual-STEPS is a reliable tool. Tools that measure the micro-scale environment are important because changing this environment could be a relatively cost-effective method of creating environments that are conducive to active living.


The translational regulator FMRP controls lipid and glucose metabolism in mice and humans.
The Fragile X Mental Retardation Protein (FMRP) is a widely expressed RNA-binding protein involved in translation regulation. Since the absence of FMRP leads to Fragile X Syndrome (FXS) and autism, FMRP has been extensively studied in brain. The functions of FMRP in peripheral organs and on metabolic homeostasis remain elusive; therefore, we sought to investigate the systemic consequences of its absence. Using metabolomics, in vivo metabolic phenotyping of the Fmr1-KO FXS mouse model and in vitro approaches, we show that the absence of FMRP induced a metabolic shift towards enhanced glucose tolerance and insulin sensitivity, reduced adiposity, and increased β-adrenergic-driven lipolysis and lipid utilization. Combining proteomics and cellular assays, we highlight that FMRP loss increased hepatic protein synthesis and impacted pathways notably linked to lipid metabolism. Mapping metabolomic and proteomic phenotypes onto a signaling and metabolic network, we predicted that the coordinated metabolic response to FMRP loss was mediated by dysregulation in the abundances of specific hepatic proteins. We experimentally validated these predictions, demonstrating that the translational regulator FMRP associates with a subset of mRNAs involved in lipid metabolism. Finally, we highlight that FXS patients mirror metabolic variations observed in Fmr1-KO mice with reduced circulating glucose and insulin and increased free fatty acids. Loss of FMRP results in a widespread coordinated systemic response that notably involves upregulation of protein translation in the liver, increased utilization of lipids, and significant changes in metabolic homeostasis. Our study unravels metabolic phenotypes in FXS and further supports the importance of translational regulation in the homeostatic control of systemic metabolism.


A Review of Ruthenium Complexes Activities on Breast Cancer Cells.
Cancer is one of the main causes of death worldwide. Breast cancer is the most prevalent type of cancer in women and the leading cause of cancer deaths due to its high metastasis to the lymph nodes, lungs bones and brain. Interactions with the stromal microenvironment surrounding tumor cells facilitate tumor cell migration and invasion of tissues and dissemination to other organs, to form metastasis. The development of antitumor metal-based drugs was originated with the discovery of cisplatin, however, its severe side effects represent a limitation for its clinical use. Ruthenium (Ru) complexes with different ligands have been successfully studied as promising antitumor drugs. In this review, we focused on the effects of Ru complexes on breast cancer cells and their impact on different steps of the metastatic process.


Regional migratory osteoporosis.
Regional migratory osteoporosis (RMO) is an uncommon disease characterised by a migrating arthralgia involving the weight bearing joints of the lower limb. The typical imaging findings on radiographs, magnetic resonance imaging, computed tomography and bone scintigraphy are described and illustrated. Men in their fifth and sixth decades of life are most commonly affected. The most common presentation is with proximal to distal spread in the lower limb. The world literature has been reviewed which has revealed 63 documented cases of regional osteoporosis or bone marrow oedema with migratory symptoms. Most of these cases have not been labelled as RMO and therefore the condition is probably under-diagnosed. The radiology of RMO is indistinguishable from transient osteoporosis of the hip (TOH) except for the migratory symptoms and the two conditions are likely to be part of the same spectrum of disease. Systemic osteoporosis is a more recently recognised accompanying feature that hints at an underlying aetiology and an approach to the management of this condition.


Building a cascade detector and its applications in automatic target detection.
A hierarchical classifier (cascade) is proposed for target detection. In building an optimal cascade we considered three heuristics: (1) use of a frontier-following approximation, (2) controlling error rates, and (3) weighting. Simulations of synthetic data with various underlying distributions were carried out. We found that a weighting heuristic is optimal in terms of both computational complexity and error rates. We initiate a systematic comparison of several potential heuristics that can be utilized in building a hierarchical model. A range of discussions regarding the implications and the promises of cascade architecture as well as of techniques that can be integrated into this framework is provided. The optimum heuristic--weighting algorithms--was applied to an IR data set. It was found that these algorithms outperform some state-of-the-art approaches that utilize the same type of simple classifier.


Unintended consequences: abortion training in the years after Roe v Wade.
The US Supreme Court's 1973 Roe v Wade decision had clear implications for American women's reproductive rights and physician ability to carry out patient choices. Its effect on physician abortion training was less apparent. In an effort to increase patient access to abortions after Roe, provision shifted from hospitals to nonhospital clinics. However, these procedures and patients were taken out of the medical education realm, and physicians became vulnerable to intimidation. The consequent provider shortage created an unexpected barrier to abortion access. Medical Students for Choice was founded in 1993 to increase abortion-training opportunities for medical students and residents. Its mission ensures that motivated medical students will learn and a growing number of physicians will commit to comprehensive abortion provision.


Influence of age on the efficacy of electroconvulsive therapy in major depression: a retrospective study.
Several variables have been studied as possible predictors for the efficacy of ECT, results from the few studies assessing the influence of age on the efficacy of ECT were inconsistent. In older patients suffering from severe depression, ECT is often the treatment of choice, therefore, investigating the influence of age on ECT response is considered relevant. At two depression units, 141 patients meeting DSM-IV criteria for major depression and scores of at least 18 on the 17-item Hamilton Rating Scale for Depression (HAM-D) were treated with bilateral ECT, twice weekly. Clinical evaluation of depressive symptoms was performed each week; scores on the HAM-D were obtained 1-3 days prior to ECT and 1-3 days after termination of the ECT course. The primary outcome criterion was defined a priori as the mean change on the HAM-D score. The influence of age on mean change on the HAM-D score was analyzed with multiple linear regression analysis, adjusted for three covariables: center, duration of the index episode and presence of psychotic features. Age as a continuous variable had no significant effect on the efficacy of ECT as measured by mean change on the HAM-D score (SE 0.057, p=0.84). The disproportionate distribution of patients among the three age groups appears to be the major limitation of the present study. This study suggests that the efficacy of ECT in elderly depressed patients is at least equal to that in younger depressed patients.


Intra-articular Autologous Conditioned Plasma Injections Provide Safe and Efficacious Treatment for Knee Osteoarthritis: An FDA-Sanctioned, Randomized, Double-blind, Placebo-controlled Clinical Trial.
Platelet-rich plasma (PRP) injections have become an intriguing treatment option for osteoarthritis (OA), particularly OA of the knee. Despite the plethora of PRP-related citations, there is a paucity of high-level evidence that is comparable, cohort specific, dose controlled, injection protocol controlled, and double-blinded. To determine the safety and efficacy of leukocyte-poor PRP autologous conditioned plasma (ACP) for knee OA treatment through a feasibility trial regulated by the US Food and Drug Administration (FDA). Randomized controlled trial; Level of evidence, 1. In accordance with FDA protocol, patient selection was based on strict inclusion/exclusion criteria; 114 patients were screened, and 30 were ultimately included in the study. These patients were randomized to receive either ACP (n = 15) or saline placebo (n = 15) for a series of 3 weekly injections. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores served as the primary efficacy outcome measure. Patients were followed for 1 year. No adverse events were reported for ACP administration. Furthermore, the results demonstrated no statistically significant difference in baseline WOMAC scores between the 2 groups. However, in the ACP group, WOMAC scores at 1 week were significantly decreased compared with baseline scores, and the scores for this group remained significantly lower throughout the study duration. At the study conclusion (12 months), subjects in the ACP group had improved their overall WOMAC scores by 78% from their baseline score, compared with 7% for the placebo group. ACP is safe and provides quantifiable benefits for pain relief and functional improvement with regard to knee OA. No adverse events were reported for ACP administration. After 1 year, WOMAC scores for the ACP subjects had improved by 78% from their baseline score, whereas scores for the placebo control group had improved by only 7%. Other joints affected with OA may also benefit from this treatment.


Oxidative stress, telomere shortening, and DNA methylation in relation to low-to-moderate occupational exposure to welding fumes.
Evidence suggests that exposure to welding fumes is a risk factor for lung cancer. We examined relationships between low-to-moderate occupational exposure to particles from welding fumes and cancer-related biomarkers for oxidative stress, changes in telomere length, and alterations in DNA methylation. We enrolled 101 welders and 127 controls (all currently nonsmoking men) from southern Sweden. We performed personal sampling of respirable dust and measured 8-oxodG concentrations in urine using a simplified liquid chromatography tandem mass spectrometry method. Telomere length in peripheral blood was measured by quantitative polymerase chain reaction. Methylation status of 10 tumor suppressor genes was determined by methylation-sensitive high-resolution melting analysis. All analyses were adjusted for age, body mass index, previous smoking, passive smoking, current residence, and wood burning stove/boiler at home. Welders were exposed to respirable dust at 1.2 mg/m(3) (standard deviation, 3.3 mg/m(3); range, 0.1-19.3), whereas control exposures did not exceed 0.1 mg/m(3) (P < 0.001). Welders and controls did not differ in 8-oxodG levels (β = 1.2, P = 0.17) or relative telomere length (β = -0.053, P = 0.083) in adjusted models. Welders showed higher probability of adenomatous polyposis coli (APC) methylation in the unadjusted model (odds ratio = 14, P = 0.014), but this was not significant in the fully adjusted model (P = 0.052). Every working year as a welder was associated with 0.0066 units shorter telomeres (95% confidence interval -0.013 to -0.00053, P = 0.033). Although there were no clear associations between concentrations of respirable dust and the biomarkers, there were modest signs of associations between oxidative stress, telomere alterations, DNA methylation, and occupational exposure to low-to-moderate levels of particles.


Molecular Subtypes of Breast Cancers from Myanmar Women: A Study of 91 Cases at Two Pathology Centers
Background: Breast cancer is the most common cancer in Myanmar women. Revealing the hormonal receptor status, human epidermal growth factor receptor 2 (HER2) and Ki-67 expression is useful for estimating patient prognosis as well as determination of treatment strategy. However, immunohistochemical features and classification of molecular subtypes in breast cancers from Myanmar remain unknown. Methods: The clinicopathological features of 91 breast cancers from Myanmar women were examined. Immunohistochemistry was performed on tissue specimens with antibodies to estrogen receptor (ER), progesterone receptor (PgR), HER2, Ki-67, cytokeratin (CK)5/6 and CK14. Immunohistochemistry-based molecular subtyping was conducted. Results: Breast cancers in Myanmar women were relatively large, high grade with frequent metastatic lymph nodes. Of the 91 patients, tumors with ER positive, PgR positive, and HER2 positive were 57.1%, 37.4%, and 28.6%, respectively. The most prevalent subtype was luminal B (HER2-) (39.6%), followed by HER2 (22.0%), triple negative (TN)-basal-like (12.1%), luminal A (11.0%), TN-null (8.8%) and luminal B (HER2+) (6.6%). The mean Ki-67 expression of 91 cases was 33.9% (33.9% ± 19.2%) and the median was 28% (range; 4%-90%). The mean Ki-67 expression of luminal A, luminal B, HER2 and TN-basal-like/ null was 7%, 30%, 40%, and 57%/43%, respectively. A higher Ki-67 expression significantly correlated with a higher grade, larger size and higher stage of malignancy. Conclusions: We, for the first time, investigated the histopathological features of breast cancers from Myanmar women. Myanmar breast cancers appeared to be aggressive in nature, as evidenced by high frequency of poor-prognosis subtypes with high level of Ki-67 expression.


Bmp signaling exerts opposite effects on cardiac differentiation.
The importance for Bmp signaling during embryonic stem cell differentiation into myocardial cells has been recognized. The question when and where Bmp signaling in vivo regulates myocardial differentiation has remained largely unanswered. To identify when and where Bmp signaling regulates cardiogenic differentiation. Here we have observed that in zebrafish embryos, Bmp signaling is active in cardiac progenitor cells prior to their differentiation into cardiomyocytes. Bmp signaling is continuously required during somitogenesis within the anterior lateral plate mesoderm to induce myocardial differentiation. Surprisingly, Bmp signaling is actively repressed in differentiating myocardial cells. We identified the inhibitory Smad6a, which is expressed in the cardiac tissue, to be required to inhibit Bmp signaling and thereby promote expansion of the ventricular myocardium. Bmp signaling exerts opposing effects on myocardial differentiation in the embryo by promoting as well as inhibiting cardiac growth.


Variability analysis of SAR from 20 MHz to 2.4 GHz for different adult and child models using finite-difference time-domain.
This paper deals with the variability of body models used in numerical dosimetry studies. Six adult anthropomorphic voxel models have been collected and used to build 5-, 8- and 12-year-old children using a morphing method respecting anatomical parameters. Finite-difference time-domain calculations of a specific absorption rate (SAR) have been performed for a range of frequencies from 20 MHz to 2.4 GHz for isolated models illuminated by plane waves. A whole-body-averaged SAR is presented as well as the average on specific tissues such as skin, muscles, fat or bones and the average on specific parts of the body such as head, legs, arms or torso. Results point out the variability of adult models. The standard deviation of whole-body-averaged SAR of adult models can reach 40%. All phantoms are exposed to the ICNIRP reference levels. Results show that for adults, compliance with reference levels ensures compliance with basic restrictions, but concerning children models involved in this study, the whole-body-averaged SAR goes over the fundamental safety limits up to 40%.


Energy concentration and amino acid digestibility in high-protein canola meal, conventional canola meal, and soybean meal fed to growing pigs.
Two experiments were conducted to determine DE and ME and the standardized ileal digestibility (SID) of CP and AA in 2 sources of high-protein canola meal (CM-HP1 and CM-HP2), conventional canola meal (CM-CV), and soybean meal (SBM) fed to growing pigs. In Exp. 1, 40 barrows (51.5 ± 4.0 kg initial BW) were housed in metabolism cages and randomly allotted to 1 of 5 diets with 8 replicate pigs per diet. A corn-based diet (97.4% corn) and 4 diets that contained both corn and each of the 3 sources of canola meal or SBM were formulated. Feces and urine were collected for 5 d after a 5-d adaptation period. The DE and ME were 3,347 and 3,268 kcal/kg in corn, 3,312 and 2,893 kcal/kg in CM-HP1, 3,627 and 3,346 kcal/kg in CM-HP2, 2,798 and 2,492 kcal/kg in CM-CV, and 4,000 and 3,796 kcal/kg in SBM, respectively. Values for DE and ME were greater (P< 0.05) in SBM than in all other ingredients, but DE and ME were greater (P < 0.05) in corn and the 2 high-protein canola meals than in CM-CV. The DE and ME were also greater (P< 0.05) in CM-HP2 than in CM-HP1. In Exp. 2, 10 barrows (65.3 ± 10.4 kg initial BW) were equipped with a T-cannula in the distal ileum and randomly allotted to a replicated 5 × 5 Latin square design with 5 diets and 5 periods in each square. A N-free diet and 4 corn starch-based diets that contained CM-HP1, CM-HP2, CM-CV, or SBM as the sole source of AA were formulated. Each period lasted 7 d and ileal digesta were collected on d 6 and 7 of each period. The SID of CP and all AA except Pro were greater (P < 0.05) in SBM than in the 3 sources of canola meal. With the exception of His and Lys, no differences in SID of indispensable AA were observed among the 3 sources of canola meal. The SID of His and Lys were greater (P < 0.05) in CM-HP1 and CM-HP2 than in CM-CV and the SID of CP was greater (P < 0.05) in CM-HP2 than in CM-CV, but no differences in the SID of indispensable AA were observed between CM-HP1 and CM-HP2. In conclusion, the 2 high-protein canola meals used in this experiment have ME values that are not different from corn but greater than in CM-CV. The SID of most AA is greater in SBM than in canola meals, but SID of His and Lys are greater in high-protein canola meals than in CM-CV. As a consequence, high-protein canola meals supply more ME and SID of AA for growing pigs than CM-CV.


Association of non-wheezing lower respiratory tract illnesses in early life with persistently diminished serum IgE levels. Group Health Medical Associates.
The role of lower respiratory tract illnesses (LRIs) in the development of allergies is not well understood. The relation of wheezing and non-wheezing LRIs to serum IgE levels and atopy was studied in 888 children. Total serum IgE levels were measured at birth, nine months and six years of age; and interferon gamma production by blood mononuclear cells was measured at birth and nine months. Atopy was determined by skin prick tests at age six. Wheezing and non-wheezing LRIs up to age three were diagnosed by a physician. Cord serum IgE levels were similar between all LRI groups and the no LRI group. Children who had wheezing LRIs until the age of three had IgE levels at nine months and at six years within normal ranges for age. In contrast, children who had a non-wheezing LRI before the nine month IgE sample had lower IgE levels at nine months and six years (geometric mean 1.8 IU/ml and 9.9 IU/ml, respectively) compared with children who had no LRIs (3.9 IU/ml and 38.3 IU/ml, respectively). Children who had non-wheezing LRIs after the nine month IgE sample had normal nine month IgE levels (3.2 IU/ml) but decreased IgE levels at six years of age (15.7 IU/ml). Children with more than one non-wheezing LRI before the age of three were less likely to be atopic than those with no LRI (odds radio 0.2). Interferon gamma production was higher in the non-wheezing LRI group at nine months than in the no LRI or wheezing LRI groups. Non-wheezing LRIs are associated with subsequent depression of IgE levels and reduced skin test reactivity.


Mortality, recruitment and change of desert tree populations in a hyper-arid environment.
Long-term vegetation changes in hyper-arid areas have long been neglected. Mortality, recruitment and change in populations of the ecologically and culturally important and drought persistent Acacia tortilis and Balanites aegyptiaca are therefore estimated in the Eastern Desert of Egypt, and are related to the primary agents of change, water conditions and human intervention. A change analysis using high-resolution Corona images (1965) in combination with field data (2003) is the basis for recruitment, mortality and change estimates. For assessing the influence of water conditions on patterns in recruitment and survival, different types of generalized linear models are tested. The overall trend in population size in that part of the Eastern Desert studied here is negative. At some sites this negative trend is alarming, because the reduction in mature trees is substantial (>50%) at the same time as recruitment is nearly absent. At a few sites there is a positive trend and better recruitment. Frequent observations of sprouting in saplings indicate that this is an important mechanism to increase their persistence. It is the establishment itself that seems to be the main challenge in the recruitment process. There are indications that hydrological variables and surface water in particular can explain some of the observed pattern in mortality, but our results indicate that direct human intervention, i.e., charcoal production, is the main cause of tree mortality in the Eastern Desert.


Language skills of school-aged children prenatally exposed to antiepileptic drugs.
Fetal exposure to some antiepileptic drugs (AEDs) carries increased risk of major birth defects, and may be associated with reduced intellectual abilities. The impact on language remains unclear. This study aimed to investigate the impact of fetal AED exposure on language skills. Women with epilepsy and their children were recruited to this observational study through the Australian Pregnancy Register for Women with Epilepsy and Allied Disorders. Language skills of 102 AED-exposed children were assessed using the Clinical Evaluation of Language Fundamentals, fourth edition (CELF-4). Assessments were conducted blind to drug. Maternal epilepsy, pregnancy, and medical histories were obtained from prospectively collected records. Mean CELF-4 Core Language scores of children exposed to sodium valproate in monotherapy (mean 91.5, SD 17.5) or polytherapy (mean 73.4, SD = 22.3) were significantly below the standardized test mean of 100 (p < 0.05). Mean language scores of children exposed to carbamazepine or lamotrigine monotherapy, or polytherapy without sodium valproate, were not significantly different from normal. First-trimester sodium valproate dose was negatively correlated with language scores, and significantly predicted language scores after controlling for other group differences. Fetal exposure to sodium valproate increases the risk of language impairment. This should be taken into account when making treatment decisions for women with epilepsy of childbearing age.


Evaluation of liquid ingestion after bariatric surgery.
Bariatric surgery is an effective treatment for obesity; however, after surgery the patient may have difficulty in swallowing liquid and solid foods. To evaluate liquid ingestion in patients who had undergone bariatric surgery. We studied 43 volunteers with normal body mass index (BMI) (BMI: 18.5-24.9 kg/m²), 55 subjects with class III obesity (BMI: >40.0 kg/m²), and 48 subjects with bariatric surgery for treatment of class III obesity. The method chosen for evaluation was the water swallowing test. The subjects drank in triplicate 50 mL of water while being precisely timed and the number of swallows were counted. There was no difference between subjects with normal BMI and subjects with class III obesity. During the first 2 months after bariatric surgery the patients showed an increase in the time needed to drink the entire volume, in the number of swallows, and in the inter-swallow interval, and a decrease in the volume swallowing capacity (volume/swallowing) and swallowing flow rate (volume swallowed/second). After 2 months, the results of the swallowing measurements moved in the direction of normal values. Bariatric surgery may cause more intense alterations of liquid bolus swallowing within 2 months after the procedure, which moved to normal values after this time.


Triglyceride and cholesterol metabolism in primary hypertriglyceridemia.
To determine mechanisms of elevated plasma triglycerides (TG) in patients with primary hypertriglyceridemias, simultaneous studies were carried out on kinetics of very low density lipoprotein-triglycerides (VLDL-TG) and synthesis of cholesterol and bile acids. Sixteen hypertriglyceridemic patients with familial combined hyperlipidemia (FCHL) and 12 patients with poorly classified, primary hypertriglyceridemia were studied, and their results were compared to a series of normal and obese subjects previously studied in our laboratory. The mean value for transport (synthesis) of VLDL-TG in patients with FCHL was about twice normal. Although the upper normal synthesis rates overlapped with transport rates of some patients with FCHL, it appeared that the major cause of hypertriglyceridemia in FCHL was an elevated production of VLDL-TG. However, the height of the plasma TG in FCHL patients also was influenced by individual clearance capacities for VLDL-TG, and fractional clearance rates in several seemed particularly low. Synthesis rates for cholesterol and/or bile acids were high in several patients with FCHL, suggesting simultaneous overproduction of VLDL-TG and sterols; however, increased synthesis of both was not observed in all the patients. Most patients with poorly classified hypertriglyceridemia had over-production of VLDL-TG, but an apparent reduction in clearance was common. In these patients, increased synthesis of cholesterol and bile acids was infrequent. Our results indicate that abnormally high production of VLDL-TG seemed to be the major factor in causing primary hypertriglyceridemia, but that clearance capacity can play an important role in determining the the severity of the TG elevation.


Activation of factor XII by tobacco glycoprotein.
A glycoprotein of mol wt ca. 18,000 daltons isolated from cured tobacco leaves (TGP-L) and from cigarette smoke condensate (TGP-CSC) activated factor XII in normal human plasma in vitro as measured by (a) shortening of the partial thromboplastin time, (b) shortening of the lysis time of euglobulin clots, and (c) generation of kinin activity. These effects were not demonstrable in plasma deficient in factor XII. The capacity of TGP-L and TGP-CSC to activate factor XII was shown to depend on the presence of rutin, a substance chemically similar to quercetin and ellagic acid, which are known activators of factor XII. Rutin and rutin coupled to bovine serum albumin, but not bovine serum albumin alone, were also demonstrated to activate factor XII. The presence in cigarette smoke of material that is both allergenic and capable of activating factor XII of the intrinsic pathway of coagulatin may be important to the pathogenesis of cardiovascular and pulmonary disease associated with cigarette smoking.


Phosphorylation of the heat shock-related protein, HSP20, mediates cyclic nucleotide-dependent relaxation.
Cyclic nucleotide-dependent relaxation of vascular smooth muscle is associated with increases in the phosphorylation of the small heat shock-related protein, HSP20. To determine whether phosphorylated HSP20 directly mediates relaxation, we used gene transfection and protein transduction of HSP20 analogues. Rat mesangial cells were transfected with constructs containing wild-type HSP20-enhanced green fluorescent protein (EGFP), phosphorylation site mutated HSP20 (S16A-HSP20-EGFP), or EGFP alone. Contractile properties were determined on a silicone polymer substrata. In the presence of serum, EGFP-vector transfected control cells and S16A-HSP20 transfected cells formed wrinkles on the polymer (contracted). Activation of cyclic nucleotide signaling pathways in the EGFP-vector transfected control cells led to a time-dependent decrease in the wrinkles (relaxation). The S16A-HSP20 transfected cells were refractory to cyclic nucleotide-dependent relaxation. Cells overexpressing the wild-type HSP20 did not form wrinkles on the polymer in response to serum (refractory to contraction). Treatment of precontracted strips of intact bovine carotid artery smooth muscle with synthetic peptides containing HIV-trans-activating transcriptional activator and a phosphopeptide motif of HSP20 led to dose-dependent relaxation. These data provide evidence that phosphorylated HSP20 has a direct role in smooth muscle relaxation and that small phosphopeptide motifs of HSP20 can mimic the effects of the entire molecule.


Organic molecule-based photothermal agents: an expanding photothermal therapy universe.
Over the last decade, organic photothermal therapy (PTT) agents have attracted increasing attention as a potential complement for, or alternative to, classical drugs and sensitizers involving inorganic nanomaterials. In this tutorial review, we provide a structured description of the main classes of organic photothermal agents and their characteristics. Representative agents that have been studied in the context of photothermal therapy since 2000 are summarized and recent advances in using PTT agents to address various cancers indications are highlighted.


Co-spray dried resveratrol and budesonide inhalation formulation for reducing inflammation and oxidative stress in rat alveolar macrophages.
Oxidative stress is instrumental in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). Novel therapeutic strategies that target macrophages, based on the use of antioxidant compounds, could be explored to improve corticosteroid responses in COPD patients. In this study, inhalable microparticles containing budesonide (BD) and resveratrol (RES) were prepared and characterized. This approach was undertaken to develop a multi-drug inhalable formulation with anti-oxidant and anti-inflammatory activities for treatment of chronic lung diseases. The inhalable microparticles containing different ratios of BD and RES were prepared by spray drying. The physico-chemical properties of the formulations were characterized in terms of surface morphology, particle size, physical and thermal stability. Additionally, in vitro aerosol performances of these formulations were evaluated with the multi-stage liquid impinger (MSLI) at 60 and 90 l/min, respectively. The cytotoxicity effect of the formulations was evaluated using rat alveolar macrophages. The biological responses of alveolar macrophages in terms of cytokine expressions, nitric oxide (NO) production and free radical scavenging activities were also tested. The co-spray dried (Co-SD) microparticles of all formulations exhibited morphologies appropriate for inhalation administration. Analysis of the deposition profiles showed an increase in aerosol performance proportional to BD concentration. Cell viability assay demonstrated that alveolar macrophages could tolerate a wide range of RES and BD concentrations. In addition, RES and BD were able to decrease the levels of tumour necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in lipopolysaccharide (LPS) induced alveolar macrophages. This study has successfully established the manufacture of Co-SD formulations of RES and BD with morphology and aerosol properties suitable for inhalation drug delivery, negligible in vitro toxicity and enhanced efficacy to control inflammation and oxidative stress in LPS-induced alveolar macrophages.


Replication and extension of association between common genetic variants in SIM1 and human adiposity.
Haplo-insufficiency of the bHLH (basic helix-loop-helix) transcription factor single-minded 1 (SIM1) causes severe obesity in mice and humans. We hypothesized that common genetic variations in/near SIM1 could exert more subtle effects on its function and associate with human adiposity. First, SIM1 coding regions were sequenced in severely obese subjects, and two common nonsynonymous single-nucleotide polymorphisms (nsSNPs) in complete linkage disequilibrium (LD) were identified: Pro352Thr (rs3734354) and Ala371Val (rs3734355). We next carried out a SNP association study of five adiposity traits (BMI, % body fat, abdominal visceral and subcutaneous fat, and leptin concentrations) in 1,699 whites and 1,173 blacks. TagSNPs covering SIM1 and nearby conserved regions, and the only common nsSNP in SIM1's binding partner aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) (Gly679Ser/rs4072568), were investigated. The effects of rs3734355/4 on SIM1 activity were tested using an in vitro reporter assay. We replicated previous observations that homozygosity for the 371Val allele was associated with higher BMI in white males (P = 0.003). Together with previous findings in white males (combined n = 3,479), BMI was increased by 1.10 kg/m(2) in 371Val homozygotes (95% confidence interval (CI): 0.25-1.95 kg/m(2), P = 0.01). In vitro, the 352Thr-371Val haplotype impaired SIM1 transcriptional activity by 22% (P < 0.0001). TagSNP analysis of SIM1 revealed two SNPs in the 3' region (rs9390322 and rs7746743) and another in intron 5 (rs3734353) to be significantly associated with various adiposity measures in ethnicity- and sex-specific manners after multiple testing correction. In white males, rs4072568 in ARNT2 was also associated with BMI (P = 9 × 10(-4)) and % body fat (P = 0.001). Our findings implicate heritable defects of the SIM1-ARNT2 axis in the predisposition to human obesity.


High performance asymmetric V2O5-SnO2 nanopore battery by atomic layer deposition.
Here we report the high performance and cyclability of an asymmetric full cell nanopore battery, comprised of V2O5 as the cathode and prelithiated SnO2 as the anode, with integrated nanotubular Pt current collectors underneath each nanotubular storage electrode, confined within an anodized aluminium oxide (AAO) nanopore. Enabled by atomic layer deposition (ALD), this coaxial nanotube full cell is fully confined within a high aspect ratio nanopore (150 nm in diameter, 50 μm in length), with an ultra-small volume of about 1 fL. By controlling the amount of lithium ion prelithiated into the SnO2 anode, we can tune the full cell output voltage in the range of 0.3 V to 3 V. When tested as a massively parallel device (∼2 billion cm-2), this asymmetric nanopore battery array displays exceptional rate performance and cyclability: when cycled between 1 V and 3 V, capacity retention at the 200C rate is ∼73% of that at 1C, and at 25C rate only 2% capacity loss occurs after more than 500 charge/discharge cycles. With the increased full cell output potential, the asymmetric V2O5-SnO2 nanopore battery shows significantly improved energy and power density over the previously reported symmetric cell, 4.6 times higher volumetric energy and 5.2 times higher power density - an even more promising indication that controlled nanostructure designs employing nanoconfined environments with large electrode surface areas present promising directions for future battery technology.


Auditory imagery and the poor-pitch singer.
The vocal imitation of pitch by singing requires one to plan laryngeal movements on the basis of anticipated target pitch events. This process may rely on auditory imagery, which has been shown to activate motor planning areas. As such, we hypothesized that poor-pitch singing, although not typically associated with deficient pitch perception, may be associated with deficient auditory imagery. Participants vocally imitated simple pitch sequences by singing, discriminated pitch pairs on the basis of pitch height, and completed an auditory imagery self-report questionnaire (the Bucknell Auditory Imagery Scale). The percentage of trials participants sung in tune correlated significantly with self-reports of vividness for auditory imagery, although not with the ability to control auditory imagery. Pitch discrimination was not predicted by auditory imagery scores. The results thus support a link between auditory imagery and vocal imitation.


Facile synthesis of magnetic covalent organic frameworks for the hydrophilic enrichment of N-glycopeptides.
Protein glycosylations play important roles in various biological processes and in the disease progression of organisms. The development of specific enrichment materials and strategies before mass spectrometric analysis was a prerequisite to glycoproteomic analysis due to the difficulty caused by substoichiometric levels of glycoproteins. In this work, novel magnetic covalent organic frameworks (denoted as Fe3O4@TpPa-1) were first developed using only a two-step solvothermal reaction and then applied in the hydrophilic enrichment of glycopeptides. Sea urchin-type composites with super-paramagnetic properties were constructed by in situ growth of TpPa-1 covalent organic frameworks on the surface of magnetic nanoparticles. A total of 37 and 22 glycopeptides could be easily detected from IgG and HRP digests, respectively, by hydrophilic enrichment with the newly developed materials. An ultralow detection limit (28 fmol), satisfactory selectivity and high recovery could be achieved using Fe3O4@TpPa-1. The material's excellent enrichment performance was also demonstrated using glycopeptide analysis in real complex samples. Within three independent replicates, 228 glycopeptides corresponding to 114 glycoproteins could be detected from human serum digests, which is better than the performance obtained by commercial HILIC materials. The results suggest that covalent organic frameworks show potential for application in glycoproteomic studies.


Zoledronic acid in the management of mesothelioma - a feasibility study (Zol-A Trial): study protocol for a randomised controlled trial.
Nitrogen containing bisphosphonates such as zoledronic acid (ZA) are known to contain certain anti-cancer properties. These have been investigated in the past in various cancers such as breast, prostate and colon. ZA in particular has shown promising results in pre-clinical studies. We propose a multicentre double-blind randomised controlled feasibility study to assess the recruitment and acceptability of ZA/placebo alongside chemotherapy in malignant pleural mesothelioma (MPM). Patients will be recruited for a 13-month period from October 2016 to November 2017. Eligible patients will be identified via the regional mesothelioma multidisciplinary team meeting. Those who receive chemotherapy will be randomised to receive either ZA or placebo alongside their chemotherapy. Those who decline chemotherapy will be offered to join the trial on the non-randomised open-labelled arm of the trial. Patients will receive a maximum of six cycles of ZA/placebo, at three-weekly cycles. All patients will be followed up for six months from randomisation. Semi-structured interviews to gather data on acceptability of trial procedures, tolerability of ZA and other relevant information will take place after the participants have completed their six cycles of treatment. For a better understanding about non-participation in mesothelioma trials we also aim to interview those who decline to take part in the trial. The qualitative and quantitative data gathered in this feasibility trial will hopefully pave the way to designing a robust full phase III trial to investigate the potential synergistic effect of ZA and current standard treatment for MPM, cisplatin-pemetrexed combination chemotherapy. ISRCTN Registry, ISRCTN45536692 . Registered on 9 August 2016. EudraCT no. 2015-004433-26.


Alcohol septal ablation for hypertrophic cardiomyopathy: indications and technique.
Alcohol septal ablation for the treatment of hypertrophic cardiomyopathy has been the subject of great interest, and the number of procedures performed is increasing despite an absence of randomized trial data. Although straightforward in concept, alcohol septal ablation may be considerably more difficult in actual practice. To optimize the results and prevent complications, the anatomy of the septal arcade architecture must be understood and the anatomic relationship between the septal artery and the specific portion of the septum to be ablated must be carefully delineated. For the latter, during the procedure, an echocardiographic contrast medium injection into the septal artery of interest is essential. Selection of the volume and amount of alcohol to be injected varies depending on the size and distribution of the septal artery. Specific complications such as conduction defects, hemodynamic compromise, ventricular arrhythmias, and inadequate gradient reduction can be minimized by specific technical approaches. After ablation, protocols are needed for periprocedural guidelines because some complications may occur late during the next several days. For optimal results, patients need to be selected after catheter assessment and combined echocardiography and angiography, and ablation techniques need to be scientific and rigorous.


Effects of the solvents on bond strength of resin bonded porcelain.
Clinical trials of porcelain veneers for chairside colour modifications may require the use of a trial resin with various colours of tints. The bond strength effects of four different solvents used for removal of trial resin from etched porcelain specimens were investigated. Fifty-six porcelain specimens were fabricated, flattened by a metallurgically standard method, etched with hydrofluoric acid and silane treated. The specimens were divided into four groups at random. The trial resin material was cleaned with different solvents prior to bonding of a dual cure resin composite button. After bonding the specimens were stored in water at 37 degrees C for 7 days. Shear bond strength results were as follows: acetone (control) group, 12.9+/-2.9 MPa; ethanol group, 15.1+/-4.6 MPa; methanol group, 11.5+/-2.9 MPa; methylene chloride group, 11.3+/-2.4 MPa. No significant differences were measured (ANOVA, P>0.05). The results indicated that the resin-porcelain bond strengths were not affected by the type of solvent used to remove trial resin. This procedure is recommended for clinical cases when resin composite is used for the try-in of etched porcelain bonded restorations.


An Investigation of O-Demethyl Tramadol/Tramadol Ratio for Cytochrome P450 2D6 Phenotyping: The CYTRAM Study.
Cytochrome P450 2D6 (CYP2D6) gene polymorphisms influence the exposure to tramadol (T) and its pharmacologically active metabolite, O-demethyl tramadol (O-dT). Tramadol has been considered as a candidate probe drug for CYP2D6 phenotyping. The objective of the CYTRAM study was to investigate the value of plasma O-dT/T ratio for CYP2D6 phenotyping. European adult patients who received IV tramadol after surgery were included. CYP2D6 genotyping was performed and subjects were classified as extensive (EM), intermediate (IM), poor (PM), or ultra-rapid (UM) CYP2D6 metabolizers. Plasma concentrations of tramadol and O-dT were determined at 24 h and 48 h. The relationship between O-dT/T ratio and CYP2D6 phenotype was examined in both a learning and a validation group. Genotype data were obtained in 301 patients, including 23 PM (8%), 117 IM (39%), 154 EM (51%), and 7 UM (2%). Tramadol trough concentrations at 24 h were available in 297 patients. Mean value of O-dT/T ratio was significantly lower in PM than in non-PM individuals (0.061 ± 0.031 versus 0.178 ± 0.09, p < 0.01). However, large overlap was observed in the distributions of O-dT/T ratio between groups. Statistical models based on O-dT/T ratio failed to identify CYP2D6 phenotype with acceptable sensitivity and specificity. Those results suggest that tramadol is not an adequate probe drug for CYP2D6 phenotyping.


A meta-selective-C-H alkenylation of phenol-derivatives employing a traceless organosilicon template.
A traceless organosilicon template-directed meta-selective-C-H alkenylation of phenols was realized with good yields and high selectivities. The template was readily removable through F--promoted O-Si cleavage under extremely mild conditions or recyclable through a p-TSA catalyzed process. The product was successfully applied in the preparation of a series of meta-alkenylated aromatic compounds.


Neural Progenitors Adopt Specific Identities by Directly Repressing All Alternative Progenitor Transcriptional Programs.
In the vertebrate neural tube, a morphogen-induced transcriptional network produces multiple molecularly distinct progenitor domains, each generating different neuronal subtypes. Using an in vitro differentiation system, we defined gene expression signatures of distinct progenitor populations and identified direct gene-regulatory inputs corresponding to locations of specific transcription factor binding. Combined with targeted perturbations of the network, this revealed a mechanism in which a progenitor identity is installed by active repression of the entire transcriptional programs of other neural progenitor fates. In the ventral neural tube, sonic hedgehog (Shh) signaling, together with broadly expressed transcriptional activators, concurrently activates the gene expression programs of several domains. The specific outcome is selected by repressive input provided by Shh-induced transcription factors that act as the key nodes in the network, enabling progenitors to adopt a single definitive identity from several initially permitted options. Together, the data suggest design principles relevant to many developing tissues.


Cross-cultural differences in processing of architectural ranking: evidence from an event-related potential study.
Visual object identification is modulated by perceptual experience. In a cross-cultural ERP study we investigated whether cultural expertise determines how buildings that vary in their ranking between high and low according to the Western architectural decorum are perceived. Two groups of German and Chinese participants performed an object classification task in which high- and low-ranking Western buildings had to be discriminated from everyday life objects. ERP results indicate that an early stage of visual object identification (i.e., object model selection) is facilitated for high-ranking buildings for the German participants, only. At a later stage of object identification, in which object knowledge is complemented by information from semantic and episodic long-term memory, no ERP evidence for cultural differences was obtained. These results suggest that the identification of architectural ranking is modulated by culturally specific expertise with Western-style architecture already at an early processing stage.


Deep learning-assisted co-registration of full-spectral autofluorescence lifetime microscopic images with H&E-stained histology images.
Autofluorescence lifetime images reveal unique characteristics of endogenous fluorescence in biological samples. Comprehensive understanding and clinical diagnosis rely on co-registration with the gold standard, histology images, which is extremely challenging due to the difference of both images. Here, we show an unsupervised image-to-image translation network that significantly improves the success of the co-registration using a conventional optimisation-based regression network, applicable to autofluorescence lifetime images at different emission wavelengths. A preliminary blind comparison by experienced researchers shows the superiority of our method on co-registration. The results also indicate that the approach is applicable to various image formats, like fluorescence in-tensity images. With the registration, stitching outcomes illustrate the distinct differences of the spectral lifetime across an unstained tissue, enabling macro-level rapid visual identification of lung cancer and cellular-level characterisation of cell variants and common types. The approach could be effortlessly extended to lifetime images beyond this range and other staining technologies.


Persistent delivery of factor IX in mice: gene therapy for hemophilia using implantable microcapsules.
Severe hemophilia B is a life-threatening, life long condition caused by absence of or defective coagulation factor IX. Gene therapy could provide an alternative treatment to repeated injection of plasma-derived concentrate or recombinant factor IX. We have previously described the use of implantable microcapsules containing recombinant myoblasts to deliver human factor IX in mice. This study reports the generation of improved myoblast-specific expression vectors. Mouse myoblast clones transfected with the various vectors secreted factor IX in vitro, at rates between 70 and 1000 ng/10(6) cells/day. The recombinant myoblast clones were then encapsulated and implanted into mice. Immunocompetent mice implanted with encapsulated myoblasts had up to 65 ng of factor IX per milliliter in their plasma for up to 14 days, after which antibodies to human factor IX became detectable, and this coincided with decreased factor IX in mouse plasma. In immunodeficient mice, however, factor IX delivery was maintained at a constant level for at least 6 weeks (end of experiment). Interestingly, the highest-secreting myoblast clone in vitro did not deliver the highest level of hFIX in vivo. This discrepancy observed between performance in vitro and in vivo may have important implications for the development of gene therapy protocols based on recombinant cells.


A concept analysis of nursing overtime.
To report a concept analysis of nursing overtime. Economic constraints have resulted in hospital restructuring with the aim of reducing costs. These processes often target nurse staffing (the largest organizational expense) by increasing usage of alternative staffing strategies including overtime hours. Overtime is a multifaceted, poorly defined, and indiscriminately used concept. Analysis of nursing overtime is an important step towards development and propagation of appropriate staffing strategies and rigorous research. Concept analysis. The search of electronic literature included indexes, grey literature, dictionaries, policy statements, contracts, glossaries and ancestry searching. Sources included were published between 1993-2012; dates were chosen in relation to increases in overtime hours used as a result of the healthcare structuring in the early 1990s. Approximately 65 documents met the inclusion criteria. Walker and Avant's methodology guided the analysis. Nursing overtime can be defined by four attributes: perception of choice or control over overtime hours worked; rewards or lack thereof; time off duty counts equally as much as time on duty; and disruption due to a lack of preparation. Antecedents of overtime arise from societal, organizational, and individual levels. The consequences of nursing overtime can be positive and negative, affecting organizations, nurses, and the patients they care for. This concept analysis clarifies the intricacies surrounding nursing overtime with recommendations to advance nursing research, practice, and policies. A nursing-specific middle-range theory was proposed to guide the understanding and study of nursing overtime.


Participatory development and pilot testing of iChoose: an adaptation of an evidence-based paediatric weight management program for community implementation.
To describe the identification, adaptation, and testing of an evidence-based pediatric weight management program for a health disparate community. A community advisory board (CAB) of decision-makers and staff from local health care, public health, and recreation organizations engaged with academic partners to select an evidence-based program (EBP) for local implementation. Three EBPs were identified (Traffic Light, Bright Bodies, Golan and colleagues Home Environmental Model) and each EBP was rated on program characteristics, implementation and adaptation, and adoptability. Following selection of the EBP that was rated highest, the POPS-CAB made adaptations based on the program principles described in peer-reviewed publications. The adapted intervention, iChoose, was then pilot tested in 3 iterative phases delivered initially by research partners, then co-delivered by research and community partners, then delivered by community partners. The RE-AIM framework was used to plan and evaluate the iChoose intervention across all waves with assessments at baseline, post program (3 months), and follow-up (6 months). Bright Bodies rated highest on program characteristics and adoptability (p's < 0.05), while Home Environmental Model rated highest on implementation factors (p < 0.05). Qualitatively, the selection focused on important program characteristics and on matching those characteristics to the potential to fit within the community partner services. The adapted program-iChoose-had 18% reach and with participants that were representative of the target population on age, gender, ethnicity, and race. Effectiveness was demonstrated by modest, but significant reductions in BMI z-scores at post-program compared to baseline (MΔ = - 0.047; t = - 2.11, p = 0.046). This decrease returned to values similar to baseline 3 months (MΔ = 0.009) after the program was completed. Implementation fidelity was high and implementation fidelity did not differ between community or research delivery agents. The process to help organizations identify and select evidence-based programs appropriate for their community led to consensus on a single EBP. While iChoose was successful in initiating changes in BMI z-scores, could be implemented in a low resource community with fidelity, it was insufficient to lead to sustained child BMI z-scores. In response to these data, maintenance of program effects and delivery are the current focus of the CBPR team.


Global patterns in monthly activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus: a systematic analysis.
Influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus are the most common viruses associated with acute lower respiratory infections in young children (<5 years) and older people (≥65 years). A global report of the monthly activity of these viruses is needed to inform public health strategies and programmes for their control. In this systematic analysis, we compiled data from a systematic literature review of studies published between Jan 1, 2000, and Dec 31, 2017; online datasets; and unpublished research data. Studies were eligible for inclusion if they reported laboratory-confirmed incidence data of human infection of influenza virus, respiratory syncytial virus, parainfluenza virus, or metapneumovirus, or a combination of these, for at least 12 consecutive months (or 52 weeks equivalent); stable testing practice throughout all years reported; virus results among residents in well-defined geographical locations; and aggregated virus results at least on a monthly basis. Data were extracted through a three-stage process, from which we calculated monthly annual average percentage (AAP) as the relative strength of virus activity. We defined duration of epidemics as the minimum number of months to account for 75% of annual positive samples, with each component month defined as an epidemic month. Furthermore, we modelled monthly AAP of influenza virus and respiratory syncytial virus using site-specific temperature and relative humidity for the prediction of local average epidemic months. We also predicted global epidemic months of influenza virus and respiratory syncytial virus on a 5° by 5° grid. The systematic review in this study is registered with PROSPERO, number CRD42018091628. We initally identified 37 335 eligible studies. Of 21 065 studies remaining after exclusion of duplicates, 1081 full-text articles were assessed for eligibility, of which 185 were identified as eligible. We included 246 sites for influenza virus, 183 sites for respiratory syncytial virus, 83 sites for parainfluenza virus, and 65 sites for metapneumovirus. Influenza virus had clear seasonal epidemics in winter months in most temperate sites but timing of epidemics was more variable and less seasonal with decreasing distance from the equator. Unlike influenza virus, respiratory syncytial virus had clear seasonal epidemics in both temperate and tropical regions, starting in late summer months in the tropics of each hemisphere, reaching most temperate sites in winter months. In most temperate sites, influenza virus epidemics occurred later than respiratory syncytial virus (by 0·3 months [95% CI -0·3 to 0·9]) while no clear temporal order was observed in the tropics. Parainfluenza virus epidemics were found mostly in spring and early summer months in each hemisphere. Metapneumovirus epidemics occurred in late winter and spring in most temperate sites but the timing of epidemics was more diverse in the tropics. Influenza virus epidemics had shorter duration (3·8 months [3·6 to 4·0]) in temperate sites and longer duration (5·2 months [4·9 to 5·5]) in the tropics. Duration of epidemics was similar across all sites for respiratory syncytial virus (4·6 months [4·3 to 4·8]), as it was for metapneumovirus (4·8 months [4·4 to 5·1]). By comparison, parainfluenza virus had longer duration of epidemics (6·3 months [6·0 to 6·7]). Our model had good predictability in the average epidemic months of influenza virus in temperate regions and respiratory syncytial virus in both temperate and tropical regions. Through leave-one-out cross validation, the overall prediction error in the onset of epidemics was within 1 month (influenza virus -0·2 months [-0·6 to 0·1]; respiratory syncytial virus 0·1 months [-0·2 to 0·4]). This study is the first to provide global representations of month-by-month activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus. Our model is helpful in predicting the local onset month of influenza virus and respiratory syncytial virus epidemics. The seasonality information has important implications for health services planning, the timing of respiratory syncytial virus passive prophylaxis, and the strategy of influenza virus and future respiratory syncytial virus vaccination. European Union Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).


* Comparison of Two Moldable Calcium Phosphate-Based Bone Graft Materials in a Noninstrumented Canine Interspinous Implantation Model.
There is a continuing search for novel synthetic materials as an alternative to autologous bone grafting. Different technologies are explored to promote bone formation, which include the addition of BioGlass™ particles in calcium phosphate (CaP)-based materials and the use of surface modification in the form of submicron surface topographies. In this work, we aimed at comparing the bone formation in a noninstrumented canine interspinous model of moldable formulations of a submicron-surface structured tricalcium phosphate/alkylene oxide copolymer (CaP/AOC) or a tricalcium phosphate/BioGlass/collagen (CaP/BG/C) bone graft material. Intramuscular implantation was carried out as well to evaluate soft tissue responses. Eight mature male mongrel dogs underwent single-level, noninstrumented interspinous implantation, where the bone graft materials were implanted at either side of the spinous processes (L3-L4), with separation by the interspinous ligament ensuring comparison of both materials in each animal (n = 8 per material). The materials were also implanted in paraspinal muscle pouches. Animals were euthanized 12 weeks after surgery and the lumbar spines excised and intramuscular implants retrieved. Undecalcified sections were prepared for histological evaluation and histomorphometry was performed to quantify bone formation and material resorption. After 12 weeks, all submicron structured CaP/AOC implants showed abundant bone formation in the (L3-L4) interspinous space (20.8% ± 6.8%), whereas bone was not found in the CaP/BG/C implants (0% ± 0%). Intramuscularly, the CaP/AOC material triggered significant bone formation (12.0% ± 7.8%), whereas CaP/BG/C did not form any bone. In both the spinal and muscular sites, resorption of the CaP/AOC material was evident by a decrease in Feret diameter of the CaP granules as well as in their histological surface compared with the starting material, whereas CaP/BG/C material had a milder resorption. This study shows that a submicron-surface structured CaP/AOC bone graft material has superior bone-forming properties in both an interspinous implantation model and intramuscularly, as compared with a CaP/BG/C bone graft material.


Control of idiopathic ventricular fibrillation by implantable cardioverter-defibrillator in a child who survived sudden death.
Idiopathic ventricular fibrillation (VF) is extremely rare in children who have not previously undergone cardiac surgery. Patients resuscitated from idiopathic VF remain at risk for recurrence. The use of an implantable cardioverter-defibrillator (ICD) effectively prevents such recurrences. We report the case of a 12-year-old girl who had a history of recurrent syncope and had survived an episode of VF. Serial studies after prolonged but successful resuscitation, including echocardiography, an electrocardiogram (ECG), and coronary angiography failed to reveal abnormal cardiac structures responsible for VF. No abnormal conduction pathways or abnormal early or late after depolarization were found on electrophysiologic study. The ST segments of the 12-lead ECG remained normal after procainamide challenge. The patient underwent ICD implantation 2 weeks after admission and syncope did not recur during a follow-up of 14 months. This report emphasizes that idiopathic VF may be responsible for syncope in children. ICD therapy prevents the recurrence of idiopathic VF and the associated risk of sudden death.


Effect of sodium, amine and stannous fluoride at the same concentration and different pH on in vitro erosion.
This study aimed to compare the effects 0.5% and 1% sodium, amine and stannous fluoride at different pH on enamel erosion in vitro. Bovine enamel samples were submitted to a cyclic de- and remineralisation for 3 days. Each day, the samples were exposed for 120 min to pooled human saliva and subsequently treated with one of the fluoride solutions for 3 min: amine fluoride (AmF, 0.5% and 1% F(-)), sodium fluoride (NaF, 0.5% and 1% F(-)), each at pH 3.9 and 7.0, and stannous fluoride (SnF(2), 0.5% and 1% F(-)), at pH: 3.9. Additionally, two groups were treated with fluoride-free placebo solutions (pH: 3.9 and 7.0) and one group served as control (no fluoridation). Ten specimens each group were inserted in a so-called artificial mouth and eroded six times daily with hydrochloric acid (pH 2.6) for 90 s each intermitted by exposure to artificial saliva (1h). After 3 days, enamel loss was analyzed profilometrically and evaluated statistically by ANOVA. Only the acidic 0.5% and 1% SnF(2) and 1% AmF solutions were able to reduce erosive enamel loss significantly, while all other solutions and placebos did not differ significantly from the control. Between the acidic SnF(2) and the 1% AmF solutions no significant differences could be detected. At the same concentrations, acidic SnF(2) and AmF may be more effective than NaF to protect enamel against erosion.


Peripherally Restricted Cannabinoids for the Treatment of Pain.
The use of cannabinoids for the treatment of chronic diseases has increased in the United States, with 23 states having legalized the use of marijuana. Although currently available cannabinoid compounds have shown effectiveness in relieving symptoms associated with numerous diseases, the use of cannabis or cannabinoids is still controversial mostly due to their psychotropic effects (e.g., euphoria, laughter) or central nervous system (CNS)-related undesired effects (e.g., tolerance, dependence). A potential strategy to use cannabinoids for medical conditions without inducing psychotropic or CNS-related undesired effects is to avoid their actions in the CNS. This approach could be beneficial for conditions with prominent peripheral pathophysiologic mechanisms (e.g., painful diabetic neuropathy, chemotherapy-induced neuropathy). In this article, we discuss the scientific evidence to target the peripheral cannabinoid system as an alternative to cannabis use for medical purposes, and we review the available literature to determine the pros and cons of potential strategies that can be used to this end.


Cost-benefit analysis of acoustic recorders as a solution to sampling challenges experienced monitoring cryptic species.
The inferences that can be made from any study are limited by the quality of the sampling design. By bad luck, when monitoring species that are difficult to detect (cryptic), sampling designs become dictated by what is feasible rather than what is desired. We calibrated and conducted a cost-benefit analysis of four acoustic recorder options that were being considered as potential solutions to several sampling restrictions experienced while monitoring the Australasian bittern, a cryptic wetland bird. Such sampling restrictions are commonly experienced while monitoring many different endangered species, particularly those that are cryptic. The recorder options included mono and stereo devices, with two sound file processing options (visual and audible analysis). Recording devices provided call-count data similar to those collected by field observers but at a fraction of the cost, which meant that "idealistic" sampling regimes, previously thought to be too expensive, became feasible for bitterns. Our study is one of the few to assess the monetary value of recording devices in the context of data quality, allowing trade-offs (and potential solutions) commonly experienced while monitoring cryptic endangered species to be shown and compared more clearly. The ability to overcome challenges of monitoring cryptic species in this way increases research possibilities for data deficient species and is applicable to any species with similar monitoring challenges.


Marginal evidence for cosmic acceleration from Type Ia supernovae.
The 'standard' model of cosmology is founded on the basis that the expansion rate of the universe is accelerating at present - as was inferred originally from the Hubble diagram of Type Ia supernovae. There exists now a much bigger database of supernovae so we can perform rigorous statistical tests to check whether these 'standardisable candles' indeed indicate cosmic acceleration. Taking account of the empirical procedure by which corrections are made to their absolute magnitudes to allow for the varying shape of the light curve and extinction by dust, we find, rather surprisingly, that the data are still quite consistent with a constant rate of expansion.


EEG Correlates of Relative Motion Encoding.
A large portion of the visual cortex is organized retinotopically, but perception is usually non-retinotopic. For example, a reflector on the spoke of a bicycle wheel appears to move on a circular or prolate cycloidal orbit as the bicycle moves forward, while in fact it traces out a curtate cycloidal trajectory. The moving bicycle serves as a non-retinotopic reference system to which the motion of the reflector is anchored. To study the neural correlates of non-retinotopic motion processing, we used the Ternus-Pikler display, where retinotopic processing in a stationary reference system is contrasted against non-retinotopic processing in a moving one. Using high-density EEG, we found similar brain responses for both retinotopic and non-retinotopic rotational apparent motion from the earliest evoked peak (around 120 ms) and throughout the rest of the visual processing, but only minor correlates of the motion of the reference system itself (mainly around 100-120 ms). We suggest that the visual system efficiently discounts the motion of the reference system from early on, allowing a largely reference system independent encoding of the motion of object parts.


Screening of novel RGD peptides to modify nanoparticles for targeted cancer therapy.
New targeted RGD peptides obtained by solid phase peptide synthesis (SPPS) were successfully screened by Molecular Operating Environment (MOE) and used for the building of the 6-O-carboxymethyl chitosan based carrier with an active target on the surface. CRGDYC-6-O-carboxymethyl chitosan based nanoparticles (NPs) loaded with doxorubicin hydrochloride (DOX) were successfully prepared by an ionic gelation method with the carrier synthesized before. Synthesis conditions and formulation parameters were optimized by determining the characteristics of nanoparticles including the particle size and drug encapsulation efficiency. 6-O-Carboxymethyl chitosan concentration, calcium chloride concentration and calcium chloride/6-O-carboxymethyl chitosan ratio all had effects on the particle size and drug encapsulation efficiency. Nanoparticles with an average diameter of 193.4 nm, an average drug loading efficiency of up to 69.5% and an average drug loading of up to 0.395% were prepared successfully with the optimal formulation. Flow cytometry and confocal microscopy analyses showed that the cellular uptake of DOX in human breast cancer cell lines (MCF-7) was higher in the CRGDYC-modified nanoparticles compared with the unmodified nanoparticles. In vivo imaging showed that the distribution of CRGDYC-modified nanoparticles in the tumor site was higher compared with the unmodified nanoparticles. These results suggest that CRGDYC-6-O-carboxymethyl chitosan may be a promising cancer targeting carrier which can enhance the intracellular uptake and cytotoxicity of the drug-loaded nanoparticles.


Thermalization of oscillator chains with onsite anharmonicity and comparison with kinetic theory.
We perform microscopic molecular dynamics simulations of particle chains with an onsite anharmonicity to study relaxation of spatially homogeneous states to equilibrium, and directly compare the simulations with the corresponding Boltzmann-Peierls kinetic theory. The Wigner function serves as a common interface between the microscopic and kinetic level. We demonstrate quantitative agreement after an initial transient time interval. In particular, besides energy conservation, we observe the additional quasiconservation of the phonon density, defined via an ensemble average of the related microscopic field variables and exactly conserved by the kinetic equations. On superkinetic time scales, density quasiconservation is lost while energy remains conserved, and we find evidence for eventual relaxation of the density to its canonical ensemble value. However, the precise mechanism remains unknown and is not captured by the Boltzmann-Peierls equations.


Associations among cataract prevalence, sunlight hours, and altitude in the Himalayas.
The relationship between cataract prevalence, altitude, and sunlight hours was investigated in a large national probability sample survey of 105 sites in the Himalayan kingdom of Nepal, December 1980 through April 1981. Cataract of senile or unknown etiology was diagnosed by ophthalmologists in 873 of 30,565 full-time life-long residents of survey sites. Simultaneously, the altitude of sites was measured using a standard mountain altimeter. Seasonally adjusted average daily duration of sunlight exposure for each site was calculated by a method which took into account latitude and obstructions along the skyline. Age- and sex-standardized cataract prevalence was 2.7 times higher in sites at an altitude of 185 meters or less than in sites over 1000 meters. Cataract prevalence was negatively correlated with altitude (r = -0.533, p less than 0.0001). However, a positive correlation between cataract prevalence and sunlight was observed (r = 0.563, p less than 0.0001). Sites with an average of 12 hours of sunlight exposure had 3.8 times as much cataract as sites with an average of only seven hours of exposure. Sunlight was blocked from reaching certain high altitude sites by tall neighboring mountains.


Analysis of lactation shapes in extended lactations.
In order to describe the temporal evolution of milk yield (MY) and composition in extended lactations, 21 658 lactations of Italian Holstein cows were analyzed. Six empirical mathematical models currently used to fit 305 standard lactations (Wood, Wilmink, Legendre, Ali and Schaeffer, quadratic and cubic splines) and one function developed specifically for extended lactations (a modification of the Dijkstra model) were tested to identify a suitable function for describing patterns until 1000 days in milk (DIM). Comparison was performed on individual patterns and on average curves grouped according to parity (primiparous and multiparous) and lactation length (standard ≤305 days, and extended from 600 to 1000 days). For average patterns, polynomial models showed better fitting performances when compared with the three or four parameters models. However, LEG and spline regression, showed poor prediction ability at the extremes of the lactation trajectory. The Ali and Schaeffer polynomial and Dijkstra function were effective in modelling average curves for MY and protein percentage, whereas a reduced fitting ability was observed for fat percentage and somatic cell score. When individual patterns were fitted, polynomial models outperformed nonlinear functions. No detectable differences were observed between standard and extended patterns in the initial phase of lactation, with similar values of peak production and time at peak. A considerable difference in persistency was observed between 200 and 305 DIM. Such a difference resulted in an estimated difference between standard and extended cycle of about 7 and 9 kg/day for daily yield at 305 DIM and of 463 and 677 kg of cumulated milk production at 305 DIM for the first- and second-parity groups, respectively. For first and later lactation animals, peak yield estimates were nearly 31 and 38 kg, respectively, and occurred at around 65 and 40 days. The asymptotic level of production was around 9 kg for multiparous cows, whereas the estimate was negative for first parity.


The prognostic significance of Cdc6 and Cdt1 in breast cancer.
DNA replication is a critical step in cell proliferation. Overexpression of MCM2-7 genes correlated with poor prognosis in breast cancer patients. However, the roles of Cdc6 and Cdt1, which work with MCMs to regulate DNA replication, in breast cancers are largely unknown. In the present study, we have shown that the expression levels of Cdc6 and Cdt1 were both significantly correlated with an increasing number of MCM2-7 genes overexpression. Both Cdc6 and Cdt1, when expressed in a high level, alone or in combination, were significantly associated with poorer survival in the breast cancer patient cohort (n = 1441). In line with this finding, the expression of Cdc6 and Cdt1 was upregulated in breast cancer cells compared to normal breast epithelial cells. Expression of Cdc6 and Cdt1 was significantly higher in ER negative breast cancer, and was suppressed when ER signalling was inhibited either by tamoxifen in vitro or letrozole in human subjects. Importantly, breast cancer patients who responded to letrozole expressed significantly lower Cdc6 than those patients who did not respond. Our results suggest that Cdc6 is a potential prognostic marker and therapeutic target in breast cancer patients.


Anomalies in the disappearance of the extraordinary electromagnetic transmission in subwavelength hole arrays.
We studied the evolution of the Extraordinary Electromagnetic Transmission (EET) through subwavelength hole arrays versus hole size. Here, we show that for large holes EET vanishes and is replaced by another unusual transmission. A specific hole size is found where all the characteristics of the EET vanish and where most usual models fail to describe the transmission except full 3D simulations. The transition between these two domains is characterized by the discontinuity of parameters describing the transmission, in particular the resonance frequency. This transition exhibits a first order phase transition like behavior.


Controlled Formation and Binding Selectivity of Discrete Oligo(methyl methacrylate) Stereocomplexes.
The triple-helix stereocomplex of poly(methyl methacrylate) (PMMA) is a unique example of a multistranded synthetic helix that has significant utility and promise in materials science and nanotechnology. To gain a fundamental understanding of the underlying assembly process, discrete stereoregular oligomer libraries were prepared by combining stereospecific polymerization techniques with automated flash chromatography purification. Stereocomplex assembly of these discrete building blocks enabled the identification of (1) the minimum degree of polymerization required for the stereocomplex formation and (2) the dependence of the helix crystallization mode on the length of assembling precursors. More significantly, our experiments resolved binding selectivity between helical strands with similar molecular weights. This presents new opportunities for the development of next-generation polymeric materials based on a triple-helix motif.


Pulse wave velocity in familial combined hyperlipidemia.
In the present cross-sectional study we investigated whether familial combined hyperlipidemia (FCH) is associated with an increased arterial wall stiffness, and whether measures of arterial wall stiffness in FCH family members could contribute to cardiovascular risk stratification. Ninety-eight subjects with FCH and 230 unaffected relatives filled out a questionnaire about their smoking habits, medical history, and medication use. Fasting venous blood was drawn after discontinuation of any lipid-lowering medication. Pulse wave velocity (PWV) and augmentation index (AIx) were determined by applanation tonometry as surrogate markers of arterial stiffness. Patients with FCH had a significantly increased PWV compared to their unaffected relatives (9.07 +/- 2.75 v 8.28 +/- 2.62 m/sec, P = .005), whereas AIx was not increased (21.6 +/- 12.7 v 15.6 +/- 14.1, P = .96). Age- and gender-adjusted PWV was an equally good predictor of the presence of cardiovascular disease (CVD) in FCH family members as the most predictive combination of age- and gender-adjusted clinical and biochemical risk factors, including total cholesterol, HDL-cholesterol, and systolic blood pressure (area under the receiver operating curve (ROC) [AUC] 0.83 [0.76-0.90] v AUC 0.84 [0.78-0.91], P = .83). Addition of PWV to the multivariable prognostic model, including these age- and gender-adjusted traditional risk factors, did not increase the predictive ability for CVD (AUC 0.84 [0.79-0.89]). Patients with FCH are characterized by an increased arterial stiffness. The PWV predicts the presence of CVD equally well as any combination of clinical and traditional biochemical risk factors, but PWV has no additional value in addition to traditional risk factor screening in FCH families.


Safety and feasibility of laparoscopic surgery for elderly rectal cancer patients in Japan: a nationwide study.
This study aimed to analyse the perioperative results from a national dataset of rectal cancer resections in elderly patients. The clinical records of patients undergoing rectal cancer surgery between 2012 and 2014 were retrieved from the Japanese National Clinical Database and analysed retrospectively. Patients were categorized according to age and those 80 years or older were defined as elderly. Subgroups were also defined according to the surgical approach (laparoscopy versus open surgery). The short-term outcomes, including mortality, anastomotic leak, surgical site infections and medical complications were compared between subgroups. Of 56 175 patients undergoing rectal cancer surgery, some 6717 patients were elderly and laparoscopy was performed in 46.8 per cent of the sample. When comparing laparoscopy and open surgery in elderly patients, the operative mortality rate (1.5 versus 2.8 per cent; P < 0.001), the incidence of anastomotic leakage (5.2 versus 6.5 per cent; P = 0.026), surgical site infections (6.0 versus 8.0 per cent; P = 0.001), pneumonia (1.4 versus 2.5 per cent; P = 0.001), renal failure (0.7 versus 1.3 per cent; P = 0.016) and cardiac events (0.3 versus 0.8 per cent; P = 0.008) were lower for laparoscopy than for open surgery. The overall complication rate in elderly patients (19.5 per cent) was comparable to that in the younger group (P = 0.07). However, incidence of systemic complications was significantly higher in elderly than in younger patients (all P < 0.001). Laparoscopy was safe and feasible in elderly patients compared with open surgery. However, the rates of systemic complications were significantly higher than in younger patients.


Changing patterns of malaria epidemiology between 2002 and 2010 in Western Kenya: the fall and rise of malaria.
The impact of insecticide treated nets (ITNs) on reducing malaria incidence is shown mainly through data collection from health facilities. Routine evaluation of long-term epidemiological and entomological dynamics is currently unavailable. In Kenya, new policies supporting the provision of free ITNs were implemented nationwide in June 2006. To evaluate the impacts of ITNs on malaria transmission, we conducted monthly surveys in three sentinel sites with different transmission intensities in western Kenya from 2002 to 2010. Longitudinal samplings of malaria parasite prevalence in asymptomatic school children and vector abundance in randomly selected houses were undertaken monthly from February 2002. ITN ownership and usage surveys were conducted annually from 2004 to 2010. Asymptomatic malaria parasite prevalence and vector abundances gradually decreased in all three sites from 2002 to 2006, and parasite prevalence reached its lowest level from late 2006 to early 2007. The abundance of the major malaria vectors, Anopheles funestus and An. gambiae, increased about 5-10 folds in all study sites after 2007. However, the resurgence of vectors was highly variable between sites and species. By 2010, asymptomatic parasite prevalence in Kombewa had resurged to levels recorded in 2004/2005, but the resurgence was smaller in magnitude in the other sites. Household ITN ownership was at 50-70% in 2009, but the functional and effective bed net coverage in the population was estimated at 40.3%, 49.4% and 28.2% in 2010 in Iguhu, Kombewa, and Marani, respectively. The resurgence in parasite prevalence and malaria vectors has been observed in two out of three sentinel sites in western Kenya despite a high ownership of ITNs. The likely factors contributing to malaria resurgence include reduced efficacy of ITNs, insecticide resistance in mosquitoes and lack of proper use of ITNs. These factors should be targeted to avoid further resurgence of malaria transmission.


In vitro comparison of intracranial stent visibility using various concentrations of gadolinium contrast agent under 1.5 T and 3 T MR angiography.
MR angiography (MRA) is an increasingly used evaluation method following intracranial stenting. However, the various artifacts created by the stent limit this technique. The purpose of this study was to investigate the effects of various concentrations of gadolinium contrast agent on the visibility and signal characteristics of two stents using the a contrast enhanced MRA technique. Two intracranial stents (Enterprise and Helistent) were placed in polyvinyl chloride tubes as vascular phantoms. They were filled with six different doses of gadolinium contrast agent (1.0, 2.0, 4.0, 6.0, 8.0, and 10.0 mmol/L dimeglumine gadopentetate, respectively) and imaged using 3 T and 1.5 T MR systems. Relative in-stent signal (RIS) was calculated and artificial luminal narrowing (ALN) was obtained using pixel by pixel analysis. The Enterprise stent, performed in both 1.5 T and 3 T MR systems, showed mean RIS values much less than those for the Helistent for all different doses of gadolinium solution. Increased gadolinium concentration resulted in a gradual reduction in RIS values in the Enterprise group. Also, ALN in the Enterprise group showed no or little change with various gadolinium doses. The Enterprise stent demonstrated good luminal visibility regardless of gadolinium concentration. The relative in-stent signals were more predictable in the Enterprise stent with various doses of gadolinium. Therefore, the Enterprise stent has been shown to provide better in-stent visibility compared with the Helistent using various gadolinium doses.


Calcitonin directly attenuates collagen type II degradation by inhibition of matrix metalloproteinase expression and activity in articular chondrocytes.
Calcitonin was recently reported to counter progression of cartilage degradation in an experimental model of osteoarthritis, and the effects were primarily suggested to be mediated by inhibition of subchondral bone resorption. We investigated direct effects of calcitonin on chondrocytes by assessing expression of the receptor and pharmacological effects on collagen type II degradation under ex vivo and in vivo conditions. Localization of the calcitonin receptor on articular chondrocytes was investigated by immunohistochemistry, and the expression by reverse transcriptase polymerase chain reaction (RT-PCR). In bovine articular cartilage explants, cartilage degradation was investigated by release of C-terminal telopeptides of collagen type II (CTX-II), induced by tumor necrosis factor-alpha (TNF-alpha) [20 ng/ml] and oncostatin M (OSM) [10 ng/ml], with salmon calcitonin [0.0001-1 microM]. In vivo, cartilage degradation was investigated in ovariectomized (OVX) rats administered with oral calcitonin [2 mg/kg calcitonin] for 9 weeks. The calcitonin receptor was identified in articular chondrocytes by immunohistochemistry and RT-PCR. Calcitonin concentration-dependently increased cAMP levels in isolated chondrocytes. Explants cultured with TNF-alpha and OSM showed a 100-fold increase in CTX-II release compared to vehicle-treated controls (P<0.001). The degradation of type II collagen in these explants was concentration-dependently inhibited by calcitonin, 65% protection at 10 nM calcitonin (P<0.01). TNF-alpha and OSM induced a pronounced increase in matrix metalloproteinase (MMP) activity, which was strongly inhibited by calcitonin. In vivo, administration of salmon calcitonin to OVX rats resulted in significant (P<0.001) decrease in CTX-II levels. These results are the first evidence of calcitonin receptor expression on articular chondrocytes and that the chondroprotective effects of calcitonin might involve the inhibition of MMP expression.


Progesterone induction of calcitonin expression in the murine mammary gland.
Progesterone, via its nuclear receptor, is mandatory not only for the induction and specification of mammary gland ductal side-branching and lobuloalveologenesis but also for carcinogen-induced mammary tumorigenesis. Notwithstanding these recent advances, a more comprehensive molecular explanation of progesterone-induced mammary morphogenesis is contingent upon the identification and characterization of mammary molecular targets that are responsive to the progesterone signal. Toward this goal, we report that calcitonin, a 32 amino acid peptide hormone involved in calcium homeostasis, is exclusively expressed in, and secreted from, luminal epithelial cells within the mammary gland of the pregnant mouse, and, importantly, its expression is progesterone-dependent. Conversely, the calcitonin receptor is present during all stages of post-natal mammary development examined, is localized to the myoepithelial cell lineage, and is not regulated by progesterone. Because calcitonin induction spatiotemporally correlates with increases in progesterone-induced mammary gland proliferation and structural remodeling, we posit that calcitonin - through its receptor - may be involved in one or both of these progesterone-dependent processes.


Patient-reported outcomes of implant placement performed concomitantly with transcrestal sinus floor elevation or entirely in native bone.
Based on the hypothesis that maxillary sinus floor elevation with a transcrestal approach (tSFE) does not increase the morbidity of implant surgery, the study evaluated the patient-reported outcomes as well as the type and incidence of complications when implants are placed either concomitantly with tSFE (performed according to Trombelli et al. 2008, 2010a,b) or entirely in native bone. Data from the record charts of patients undergone implant placement for single-tooth rehabilitation in the posterior maxilla were retrospectively obtained from four clinical centers. Cases for tSFE group were included if they showed an extent of sinus lift ≥4 mm concomitantly to implant placement. Cases for N group were included when implant placement was performed entirely in native bone. Patient-reported outcomes had been assessed using 100-mm visual analog scales (postoperative pain, VASpain ) and visual rating scales (level of discomfort, VRSdiscomfort ; willingness to undergo the same surgery, VRSwillingness ). The dose of analgesics had been self-recorded. A convenience sample of 14 patients and 17 patients (contributing with one implant site each) treated with tSFE and N, respectively, was obtained for this study. Membrane perforation occurred in 1 tSFE case, without compromising the completion of the procedure. VASpain remained low (<12) in both groups. A tendency of VASpain to decrease with time was observed in both groups. The area under the curve for VASpain (AUCpain ), indicating the level of pain experience through the first week following surgery, was 18.0 (IR: 8.5-85.0) and 11.5 (IR: 4.5-18.5) in tSFE and N groups, respectively, with no significant inter-group differences (P = 0.084). The dose of analgesics was similarly low between groups. No significant inter-group difference in VRSdiscomfort and VRSwillingness was observed. Implant placement performed either concomitantly with tSFE (according to Trombelli et al. 2008, 2010a,b) or entirely in native bone is associated with limited incidence of complications, low postoperative pain and medication and are both well tolerated.


Ternary semiconductor ZnxAg1-xS nanocomposites for efficient photocatalytic degradation of organophosphorus pesticides.
The construction of ternary semiconductor nanostructures has attracted much attention in photocatalysis by virtue of their tunable elemental composition and band structure. Here, ternary semiconductor ZnxAg1-xS (0 ≤ x ≤ 1) composites were successfully prepared by a simple and low-cost hydrothermal method without using any surfactant. Combined analyses using XRD, N2 sorption, SEM, TEM and UV-vis DRS revealed that the ternary composite semiconductor materials exhibited well-developed crystalline frameworks, large surface areas of 15-70 m2 g-1, sizes of 10-30 nm, and outstanding UV light absorption properties. Data from XRD and TEM indicate that photocatalysis might contribute to the formation of the strong interfacial interaction between ZnS and Ag2S nanoparticles. The photocatalytic activities were investigated via the degradation of organophosphorus pesticides, including malathion (MLT), monocrotophos (MCP) and chlorpyrifos (CPS), using the ZnxAg1-xS composites under UV light irradiation. The toxicity of MLT, MCP, and CPS was reduced by photocatalysis and photolysis; however, photocatalysis had a greater impact. Superior photocatalytic performance was exhibited by the Zn0.5Ag0.5S catalyst owing to its large surface area and the presence of Ag0 with improved charge transfer in comparison with that of bare ZnS and Ag2S. Assays of stability and reusability indicated that the Zn0.5Ag0.5S composite retained more than 85% of its activity after five cycles of use. On the basis of the results, a possible photocatalytic mechanism of the prepared samples was proposed. This study indicates a potential application of the ternary semiconductor materials in the efficient UV light-driven photocatalytic degradation of other pollutants that may cause environmental pollution.


Application of Selected Muscle Strength and Body Mass Cut Points for the Diagnosis of Sarcopenia in Men and Women With or at Risk for HIV Infection.
Persons with HIV may experience greater mobility limitations than uninfected populations. Accurate tools are needed to identify persons at greatest risk of decline. We evaluated the performance of novel muscle weakness metrics (grip, grip/body mass index [BMI], grip/weight, grip/total body fat, grip/arm lean mass) and association with slowness and falls in older persons with or at risk for HIV infection as part of the work of the Sarcopenia Definitions and Outcomes Consortium (SDOC). We assessed the prevalence of sarcopenia among 398 men (200 HIV+, 198 HIV-) from the Multicenter AIDS Cohort Study and 247 women (162 HIV+, 85 HIV-) from the Women's Interagency HIV Study using previously validated muscle weakness metrics discriminative of slowness. Sensitivity and specificity were used to compare new muscle weakness and slowness criteria to previously proposed sarcopenia definitions. The prevalence of muscle weakness ranged from 16% to 66% among men and 0% to 47% among women. Grip/BMI was associated with slowness among men with HIV only. Grip/BMI had low sensitivity (25%-30%) with moderate to high specificity (68%-89%) for discriminating of slowness; all proposed metrics had poor performance in the discrimination of slowness (area under the curve [AUC] < 0.62) or fall status (AUC < 0.56). The combination of muscle weakness and slowness was not significantly associated with falls (p ≥ .36), with a low sensitivity in identifying those sustaining one or more falls (sensitivity ≤ 16%). Clinical utility of new sarcopenia metrics for identification of slowness or falls in men and women with or at risk for HIV is limited, given their low sensitivity.


Drastic difference between hole and electron injection through the gradient shell of CdxSeyZn1-xS1-y quantum dots.
Ultrafast fluorescence spectroscopy was used to investigate the hole injection in CdxSeyZn1-xS1-y gradient core-shell quantum dot (CSQD) sensitized p-type NiO photocathodes. A series of CSQDs with a wide range of shell thicknesses was studied. Complementary photoelectrochemical cell measurements were carried out to confirm that the hole injection from the active core through the gradient shell to NiO takes place. The hole injection from the valence band of the QDs to NiO depends much less on the shell thickness when compared to the corresponding electron injection to n-type semiconductor (ZnO). We simulate the charge carrier tunneling through the potential barrier due to the gradient shell by numerically solving the Schrödinger equation. The details of the band alignment determining the potential barrier are obtained from X-ray spectroscopy measurements. The observed drastic differences between the hole and electron injection are consistent with a model where the hole effective mass decreases, while the gradient shell thickness increases.


Generation of pure lymphatic endothelial cells from human pluripotent stem cells and their therapeutic effects on wound repair.
Human pluripotent stem cells (hPSCs) have emerged as an important source for cell therapy. However, to date, no studies demonstrated generation of purified hPSC-derived lymphatic endothelial cells (LECs) and tested their therapeutic potential in disease models. Here we sought to differentiate hPSCs into the LEC lineage, purify them with LEC markers, and evaluate their therapeutic effects. We found that an OP9-assisted culture system reinforced by addition of VEGF-A, VEGF-C, and EGF most efficiently generated LECs, which were then isolated via FACS-sorting with LYVE-1 and PODOPLANIN. These hPSC-derived LYVE-1(+)PODOPLANIN(+)cells showed a pure committed LEC phenotype, formed new lymphatic vessels, and expressed lymphangiogenic factors at high levels. These hPSC-derived LECs enhanced wound healing through lymphangiogenesis and lymphvasculogenesis. Here we report, for the first time, that LECs can be selectively isolated from differentiating hPSCs, and that these cells are potent for lymphatic vessel formation in vivo and wound healing. This system and the purified hPSC-derived LECs can serve as a new platform for studying LEC development as well as for cell therapy.